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CloseTolazamide: Drug informationTolazamide: Drug information(For additional information see "Tolazamide: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Pharmacologic CategoryAntidiabetic Agent, SulfonylureaDosing: AdultDiabetes mellitus, type 2Diabetes mellitus, type 2: Oral:Initial: 100 to 250 mg/day with breakfast or the first main meal of the dayFasting blood sugar <200 mg/dL: 100 mg/dayFasting blood sugar >200 mg/dL: 250 mg/dayPatient is malnourished, underweight, or not eating properly: 100 mg/dayAdjustment/titration: Increase in increments of 100 to 250 mg/day at weekly intervals to response; doses >500 mg/day may be given in 2 divided doses; maximum daily dose: 1 g (doses >1 g/day are not likely to improve control)Conversion from insulin to tolazamide:<20 units day = 100 mg/day21 to <40 units/day = 250 mg/day≥40 units/day = 250 mg/day and 50% of insulin doseDosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling. However, conservative initial and maintenance doses are recommended (active metabolites are renally eliminated).Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling. However, conservative initial and maintenance doses and careful monitoring of blood glucose are recommended.Dosing: Older AdultInitial: 100 mg once daily; use with caution.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productTablet, Oral: Generic: 250 mg [DSC], 500 mg [DSC]Generic Equivalent Available: USYesAdministration: AdultOral: Administer with food once a day with breakfast or the first main meal; administer doses >500 mg/day in 2 equally divided dosesUse: Labeled IndicationsAdjunct to diet for the management of mild-to-moderately severe, stable, type 2 diabetes mellitusGuideline recommendations: First-generation sulfonylureas (eg, tolazamide) are not recommended treatment options for type 2 diabetes; later-generation sulfonylureas with lower hypoglycemic risks (eg, glipizide) are preferred (ADA 2020).Medication Safety IssuesSound-alike/look-alike issues: TOLAZamide may be confused with TOLBUTamide, tolcaponeTolinase may be confused with OrinaseHigh alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.Central nervous system: Disulfiram-like reaction, dizziness, fatigue, headache, malaise, vertigoDermatologic: Maculopapular rash, morbilliform rash, pruritus, skin photosensitivity, skin rash, urticariaEndocrine & metabolic: Hepatic porphyria, hypoglycemia, hyponatremia, porphyria cutanea tarda, SIADH (syndrome of inappropriate antidiuretic hormone secretion)Gastrointestinal: Anorexia, constipation, diarrhea, epigastric fullness, heartburn, nausea, vomitingGenitourinary: Diuretic effectHematologic & oncologic: Agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, pancytopenia, thrombocytopeniaHepatic: Cholestatic jaundiceNeuromuscular & skeletal: WeaknessContraindicationsHypersensitivity to tolazamide, sulfonylureas, or any component of the formulation; type 1 diabetes mellitus; diabetic ketoacidosisWarnings/PrecautionsConcerns related to adverse effects:• Cardiovascular mortality: Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS), have not supported an association. In patients with established atherosclerotic cardiovascular disease (ASCVD), other agents are preferred (ADA 2020).• Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, malnourished patients and in patients with impaired renal or hepatic function; use with caution.• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.Disease-related concerns:• Bariatric surgery:– Altered absorption: Use IR formulations after surgery to minimize the potential effects of bypassing stomach and proximal small bowel with gastric bypass or more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Apovian 2015). ER formulations may have altered release and absorption patterns after gastric bypass or sleeve gastrectomy (but not gastric band). Compared to control, Tmax in a gastric bypass cohort administered tolbutamide was significantly shorter (1.4 ± 1.8 vs 5.1 ± 1.7 hours; P < 0.001), while Cmax and AUC0-∞ were not altered (Tandra 2013).– Hypoglycemia: Use an antidiabetic agent without the potential for hypoglycemia if possible; hypoglycemia may occur after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020). Insulin secretion and sensitivity may be partially or completely restored after these procedures (gastric bypass is most effective, followed by sleeve and finally band) (Korner 2009; Peterli 2012). First-phase insulin secretion and hepatic insulin sensitivity have been shown to be significantly improved in the immediate days after gastric bypass and sleeve gastrectomy. The restorative effects of these procedures on peripheral insulin sensitivity may occur later in the 3- to 12-month period postsurgery (Mingrone 2016).– Weight gain: Evaluate risk vs benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Patients with G6PD deficiency may be at an increased risk of sulfonylurea-induced hemolytic anemia; however, cases have also been described in patients without G6PD deficiency during postmarketing surveillance. Use with caution and consider a nonsulfonylurea alternative in patients with G6PD deficiency.• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).Other warnings/precautions:• Secondary failure: Loss of efficacy may be observed following prolonged use as a result of the progression of type 2 diabetes mellitus which results in continued beta cell destruction. In patients who were previously responding to sulfonylurea therapy, consider additional factors which may be contributing to decreased efficacy (eg, inappropriate dose, nonadherence to diet and exercise regimen). If no contributing factors can be identified, consider discontinuing use of the sulfonylurea due to secondary failure of treatment.Metabolism/Transport EffectsSubstrate of CYP2C9 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased.Risk C: Monitor therapyAlcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur.Risk C: Monitor therapyAlpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapyAlpha-Glucosidase Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with an alpha-glucosidase inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modificationAlpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyAminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).Risk X: Avoid combinationAminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).Risk C: Monitor therapyAmiodarone: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapyAndrogens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyAntidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapyBeta-Blockers: May enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Risk C: Monitor therapyBeta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyBeta-Blockers (Nonselective): May enhance the hypoglycemic effect of Sulfonylureas. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Sulfonylureas. Risk C: Monitor therapyBortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyCarbocisteine: Sulfonylureas may enhance the adverse/toxic effect of Carbocisteine. Specifically, sulfonylureas may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products.Risk C: Monitor therapyChloramphenicol (Systemic): May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapyClarithromycin: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapyCYP2C9 Inducers (Moderate): May decrease the serum concentration of Sulfonylureas. Risk C: Monitor therapyCYP2C9 Inhibitors (Moderate): May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapyDexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Risk C: Monitor therapyDipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modificationDirect Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyEtilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyFibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapyGlucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Risk D: Consider therapy modificationGuanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyHerbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapyHyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyHypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapyHypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents.Risk C: Monitor therapyLumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapyMaitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyMecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine.Risk X: Avoid combinationMethoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic).Risk C: Monitor therapyMetreleptin: May enhance the hypoglycemic effect of Sulfonylureas. Management: Sulfonylurea dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin.Monitor closely for signs or symptoms of hypoglycemia. Risk D: Consider therapy modificationMiconazole (Oral): May enhance the hypoglycemic effect of Sulfonylureas. Miconazole (Oral) may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapyMitiglinide: May enhance the adverse/toxic effect of Sulfonylureas. Risk X: Avoid combinationMonoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyPegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyPorfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.Risk C: Monitor therapyProbenecid: May decrease the protein binding of Sulfonylureas. Probenecid may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapyProthionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyQuinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapyRifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapyRitodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapySalicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapySelective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapySodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modificationSulfonamide Antibiotics: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapyTetracyclines: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapyThiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyThiazolidinediones: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Risk D: Consider therapy modificationVerteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.Risk C: Monitor therapyVitamin K Antagonists (eg, warfarin): Sulfonylureas may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas.Risk C: Monitor therapyVoriconazole: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapyFood InteractionsPossible disulfiram-like reaction with concurrent ethanol use. Management: Monitor patients.Reproductive ConsiderationsSulfonylureas are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)Pregnancy ConsiderationsSevere hypoglycemia lasting 4 to 10 days has been noted in infants born to mothers taking a sulfonylurea at the time of delivery. Additional adverse events have been reported and may be influenced by maternal glycemic control (Piacquadio 1991). The manufacturer recommends if tolazamide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date.Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2021; Blumer 2013).Agents other than tolazamide are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).Breastfeeding ConsiderationsIt is not known if tolazamide is present in breast milk.According to the manufacturer, due to the potential for hypoglycemia in the breastfeeding infant, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.Monitoring ParametersSigns and symptoms of hypoglycemia (fatigue, sweating, numbness of extremities); blood glucose.HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).Reference RangeRecommendations for glycemic control in patients with diabetes:Nonpregnant adults with diabetes (ADA 2021):HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).Older adults (≥65 years of age) (ADA 2021):Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (LeRoith 2019).HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).Classification of hypoglycemia (ADA 2021):Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.Mechanism of ActionStimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sitesPharmaco*kineticsOnset of hypoglycemic effect: 20 minutesPeak hypoglycemic effect: 4-6 hoursDuration: 10-24 hours Absorption: RapidProtein binding: 94% Metabolism: Extensively hepatic to 5 metabolites (activity 0% to 70%) Half-life elimination: 7 hours Time to peak, serum: 3-4 hoursExcretion: Urine (85%); feces (7%)Pricing: USTablets (TOLAZamide Oral)250 mg (per each): $2.31500 mg (per each): $3.49Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalDesumide (TW);Diabewas (IT);Esulin (TW);Huacose (TW);Tolanase (GB);Tolinase (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, NL, OM, SA, SY, YE)For country code abbreviations (show table)Alexopoulos AS, Blair R, Peters AL. Management of preexisting diabetes in pregnancy: a review. JAMA. 2019;321(18):1811-1819. doi:10.1001/jama.2019.4981 [PubMed 31087027]American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 201: pregestational diabetes mellitus. Obstet Gynecol. 2018;132(6):e228-e248. doi: 10.1097/AOG.0000000000002960. [PubMed 30461693]American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131(2):e49-e64. [PubMed 29370047]American Diabetes Association (ADA). Standards of medical care in diabetes–2021. Diabetes Care. 2021;44(suppl 1):S1-S232. https://care.diabetesjournals.org/content/44/Supplement_1. Accessed January 13, 2021.Apovian CM, Aronne LJ, Bessesen DH, et al; Endocrine Society. Pharmacological management of obesity: an Endocrine Society clinical practice guideline [published correction appears in J Clin Endocrinol Metab. 2015;100(5):2135-2136]. J Clin Endocrinol Metab. 2015;100(2):342-362. doi: 10.1210/jc.2014-3415 [PubMed 25590212]“A Study of the Effects of Hypoglycemia Agents on Vascular Complications in Patients With Adult-Onset Diabetes. VI. Supplementary Report on Nonfatal Events in Patients Treated With Tolbutamide. The University Group Diabetes Program,” Diabetes, 1976, 25(12):1129-53. [PubMed 992232]Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227-4249. [PubMed 24194617]Brackett CC, Singh H, Block JH. Likelihood and mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group. Pharmacotherapy. 2004;24(7):856-870. [PubMed 15303450]“Effect of Intensive Blood-Glucose Control With Metformin on Complications in Overweight Patients With Type 2 Diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group,” Lancet, 1998, 352(9131):854-65. [PubMed 9742977]Egan AM, Dow ML, Vella A. A review of the pathophysiology and management of diabetes in pregnancy. Mayo Clin Proc. 2020;95(12):2734-2746. doi:10.1016/j.mayocp.2020.02.019 [PubMed 32736942]“Intensive Blood-Glucose Control With Sulphonylureas or Insulin Compared With Conventional Treatment and Risk of Complications in Patients With Type 2 Diabetes (UKPDS 33) UK Prospective Diabetes Study (UKPDS) Group,” Lancet, 1998, 352(9131):837-53. [PubMed 9742976]Johnson KK, Green DL, Rife JP, Limon L. Sulfonamide cross-reactivity: fact or fiction? [published correction appears in Ann Pharmacother. 2005;39(7-8):1373]. Ann Pharmacother. 2005;39(2):290-301. [PubMed 15644481]Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2020;98(supp 4):S1-S115. doi:10.1016/j.kint.2020.06.019 [PubMed 32998798]Korner J, Inabnet W, Febres G, et al. Prospective study of gut hormone and metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass. Int J Obes (Lond). 2009;33(7):786-795. doi: 10.1038/ijo.2009.79. [PubMed 19417773]LeRoith D, Biessels GJ, Braithwaite SS, et al. Treatment of diabetes in older adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1520-1574. doi: 10.1210/jc.2019-00198. [PubMed 30903688]Mechanick JI, Apovian C, Brethauer S, et al. Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures - 2019 update: cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, the Obesity Society, American Society for Metabolic & Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Surg Obes Relat Dis. 2020;16(2):175-247. doi:10.1016/j.soard.2019.10.025 [PubMed 31917200]Metzger BE, Buchanan TA, Coustan DR, et al, "Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus," Diabetes Care, 2007, 30(Suppl 2):S251-60. [PubMed 17596481]Mingrone G, Cummings DE. Changes of insulin sensitivity and secretion after bariatric/metabolic surgery. Surg Obes Relat Dis. 2016;12(6):1199-1205. doi: 10.1016/j.soard.2016.05.013. [PubMed 27568471]Peterli R, Steinert RE, Woelnerhanssen B, et al. Metabolic and hormonal changes after laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy: a randomized, prospective trial. Obes Surg. 2012;22(5):740-748. doi: 10.1007/s11695-012-0622-3. [PubMed 22354457]Piacquadio K, Hollingsworth DR, and Murphy H, "Effects of In-Utero Exposure to Oral Hypoglycaemic Drugs," Lancet, 1991, 338(8771):866-9. [PubMed 1681225]Slatore CG, Tilles SA. Sulfonamide hypersensitivity. Immunol Allergy Clin North Am. 2004;24(3):477-490. [PubMed 15242722]Tandra S, Chalasani N, Jones DR, Mattar S, Hall SD, Vuppalanchi R. Pharmaco*kinetic and pharmacodynamic alterations in the Roux-en-Y gastric bypass recipients. Ann Surg. 2013;258(2):262-269. doi: 10.1097/SLA.0b013e31827a0e82 [PubMed 23222033]Tolazamide [prescribing information]. Morgantown, WV: Mylan Pharmaceuticals Inc; December 2009.Tornero P, De Barrio M, Baeza ML, Herrero T. Cross-reactivity among p-amino group compounds in sulfonamide fixed drug eruption: diagnostic value of patch testing. Contact Dermatitis. 2004;51(2):57-62. [PubMed 15373844]Topic 10002 Version 190.0

CloseTinzaparin (United States: Not available): Drug informationTinzaparin (United States: Not available): Drug information(For additional information see "Tinzaparin (United States: Not available): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: CanadaInnohepPharmacologic CategoryAnticoagulant;Anticoagulant, Low Molecular Weight HeparinDosing: AdultAnticoagulant in extracorporeal circuit during hemodialysisAnticoagulant in extracorporeal circuit during hemodialysis (recommendations apply to stable patients with chronic renal failure): IV:Dialysis session ≤4 hours (no hemorrhage risk): Initial bolus (via arterial side of circuit or IV): 4,500 anti-Xa units at beginning of dialysis; typically achieves plasma concentrations of 0.5 to 1 anti-Xa units/mL; may give larger bolus for dialysis sessions >4 hours. For subsequent dialysis sessions, may adjust dose as necessary in increments of 500 anti-Xa units based on previous outcome.Dialysis session >4 hours (hemorrhage risk): Initial bolus (IV only): 2,250 anti-Xa units at beginning of dialysis (do not add to dialysis circuit). A smaller second IV dose may be administered during dialysis sessions >4 hours. For subsequent dialysis sessions, adjust dose as necessary to achieve plasma concentrations of 0.2 to 0.4 anti-Xa units/mL.Mechanical prosthetic heart valve to bridge anticoagulationMechanical prosthetic heart valve (aortic or mitral position) to bridge anticoagulation (off-label use):Note: Bridging during intervals of subtherapeutic anticoagulation should be considered for patients with mechanical mitral or tricuspid valve replacement; however, for patients with mechanical aortic valve replacement, bridging is not required unless an additional thromboembolic risk factor is present or patient has an older generation mechanical aortic valve (ACC/AHA [Otto 2021]).SUBQ: 175 anti-Xa units/kg once daily (ACCP [Douketis 2012]).Venous thromboembolism prophylaxisVenous thromboembolism prophylaxis:Bariatric surgery, moderate to high venous thromboembolism risk (off-label use): Based on limited evidence: SUBQ: Initial: 75 anti-Xa units/kg once daily starting on postoperative day 1 (minimum dose: 4,500 anti-Xa units once daily and maximum dose: 14,000 anti-Xa units once daily); round dose to the closest possible syringe size; duration of therapy is typically 10 days postoperatively (Douketis 2018; Tseng 2018). Note: Optimal duration of prophylaxis is unknown, but is usually continued until hospital discharge and may be extended for up to 6 weeks postoperatively depending upon venous thromboembolism (VTE) risk. There is no consensus on indications for extended prophylaxis following bariatric surgery (Lim 2021).Total hip arthroplasty:Preoperative initiation regimen: SUBQ: 50 anti-Xa units/kg given 2 hours preoperatively, followed by 50 anti-Xa units/kg once daily (manufacturer's labeling); guidelines recommend initiation of a low molecular weight heparin (eg, tinzaparin) ≥12 hours preoperatively (ACCP [Falck-Ytter 2012]); clinical practice may differ on timing of initiation, refer to institutional protocols.Postoperative initiation regimen: SUBQ: 75 anti-Xa units/kg once daily, with initial dose given ≥12 hours postoperatively (ACCP [Falck-Ytter 2012]; manufacturer's labeling); clinical practice may differ on timing of initiation, refer to institutional protocols.Duration of therapy: Optimal duration of prophylaxis is unknown, but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days (ACCP [Falck-Ytter 2012]).Total knee arthroplasty: SUBQ: 75 anti-Xa units/kg once daily, with initial dose given ≥12 hours preoperatively or ≥12 hours postoperatively (ACCP [Falck-Ytter 2012]; manufacturer's labeling). Body weight dosing using prefilled syringes may also be considered, refer to manufacturer labeling for detailed dosing recommendations.Duration of therapy: Optimal duration of prophylaxis is unknown, but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days (ACCP [Falck-Ytter 2012].Medical patients with acute illness at moderate and high risk for venous thromboembolism (off-label use): SUBQ: 4,500 anti-Xa units once daily; continue for length of hospital stay or until patient is fully ambulatory and risk of VTE has diminished (ACCP [Kahn 2012]; Thrombosis Canada 2020). Extended prophylaxis beyond acute hospital stay is not routinely recommended (ACCP [Kahn 2012]; Sharma 2012). However, in high-risk coronavirus disease 2019 (COVID-19) patients who are discharged from the hospital, some experts would consider extended prophylaxis with a direct oral anticoagulant (DOAC) (eg, rivaroxaban) (Cuker 2021).General surgery: SUBQ: 3,500 anti-Xa units once daily, with initial dose given 2 hours prior to surgery and then continued postoperatively for 7 to 10 days.Venous thromboembolism treatmentVenous thromboembolism treatment:Note: For timing of initiating oral anticoagulant, see Transitioning between anticoagulants.Deep vein thrombosis and/or pulmonary embolism treatment: SUBQ: 175 anti-Xa units/kg once daily.Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and depends on many factors, such as whether provoking events were present, patient risk factors for recurrence and bleeding, and individual preference.Provoked venous thromboembolism: 3 months (provided the provoking risk factor is no longer present) (ACCP [Stevens 2021]).Unprovoked venous thromboembolism or provoked venous thromboembolism with a persistent risk factor: ≥3 months depending on risk of VTE recurrence and bleeding (ACCP [Stevens 2021]; ISTH [Baglin 2012]).Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.Venous thromboembolism treatment in patients with active cancer:Months 1 to 6: SUBQ: Initial: 175 anti-Xa units/kg once daily for a total duration of 3 to 6 months (ASCO [Key 2020]; Bauer 2019).Maintenance beyond 6 months: ACCP and ASCO guidelines for VTE prophylaxis/treatment recommend considering continuing anticoagulation beyond 6 months in select patients due to the persistent high risk of recurrence in those with active cancer; consider risk vs benefit of bleeding and recurrence (ACCP [Stevens 2021]; ASCO [Key 2020]).Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol(s) for additional detail:Transitioning from another anticoagulant to tinzaparin:Transitioning from therapeutic IV unfractionated heparin infusion to therapeutic-dose tinzaparin: Discontinue unfractionated heparin (UFH) and begin tinzaparin within 1 hour. Note: If aPTT is not in therapeutic range at the time UFH is discontinued, consult local protocol (Nutescu 2007).Transitioning from tinzaparin to another anticoagulant:Transitioning from therapeutic-dose tinzaparin to therapeutic IV unfractionated heparin infusion: Start IV UFH (rate based on indication) 1 to 2 hours before the next dose of tinzaparin would have been due. Note: Omit IV UFH loading dose (Nutescu 2007).Transitioning from prophylactic tinzaparin to therapeutic IV unfractionated heparin: UFH should be started without delay. A UFH bolus/loading dose may be used if indicated.Transitioning from therapeutic-dose tinzaparin to warfarin: Start warfarin and continue tinzaparin until INR is within therapeutic range (Wittkowsky 2018). Note: Overlap tinzaparin with warfarin until INR is ≥2 for at least 2 measurements taken ~24 hours apart (duration of overlap is ~5 days) (ACCP [Ageno 2012]).Transitioning from therapeutic-dose tinzaparin to a direct oral anticoagulant: Start direct oral anticoagulant within 2 hours prior to the next scheduled dose of tinzaparin.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultCrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, primarily undergoes renal elimination and clearance is decreased in renal impairment; use with caution.CrCl <30 mL/minute: Evidence suggests no accumulation in patients with CrCl ≥20 mL/minute, but there are limited data available in patients with a CrCl <20 mL/minute. While the manufacturer recommends that a dose reduction be considered in patients with CrCl <30 mL/minute, there are no specific dosage adjustments provided in the manufacturer's labeling; use with caution.Hemodialysis: Not dialyzable (NCS/SCCM [Frontera 2016])Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling. Does not undergo hepatic metabolism; however, has been associated with transient increases in transaminase levels; use with caution.Dosing: PediatricNote: 1 mg of tinzaparin equals 70 to 120 units of anti-Xa activityDeep vein thrombosis and/or pulmonary embolism treatmentDeep vein thrombosis and/or pulmonary embolism treatment (off-label dose) (Monagle 2012): SubQ: Infants, Children, and Adolescents: Note: May initiate a vitamin K antagonist on day 1 of tinzaparin therapy; discontinue tinzaparin on day 6 or later if INR is not >2.Birth to 2 months: 275 anti-Xa units/kg once daily2 to 12 months: 250 anti-Xa units/kg once daily1 to 5 years: 240 anti-Xa units/kg once daily5 to 10 years: 200 anti-Xa units/kg once daily10 to 16 years: 175 anti-Xa units/kg once dailyDosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no pediatric specific recommendations; based on experience in adult patients, use with caution; tinzaparin primarily undergoes renal elimination and clearance is decreased in renal impairment.Dosing: Hepatic Impairment: PediatricThere are no pediatric specific recommendations; based on experience in adult patients, use with caution; does not undergo hepatic metabolism; however, has been associated with transient increases in transaminase levels.Dosing: Older AdultRefer to adult dosing; clearance of tinzaparin may be reduced in elderly patients. Increased sensitivity to tinzaparin in elderly patients may be possible due to a decline in renal function. Avoid use in patients >70 years of age with renal impairment (Leizorovicz 2011).Dosing: Obesity: AdultNote: Specific dosing recommendations may not be available for all indications.Venous thromboembolism prophylaxis:BMI 30 to 39 kg/m2: Use standard prophylaxis dosing.BMI ≥40 kg/m2: Increase standard prophylaxis dose by 30% (Nutescu 2009); however, the ideal dose is unknown.Venous thromboembolism treatment: Use actual body weight to calculate dose; a fixed upper dose limit is not recommended; however, increased monitoring and dosage adjustment based on anti-Xa levels may be considered (Nutescu 2009).Generic Equivalent Available: USYesDosage Forms ConsiderationsInnohep is manufactured from products derived from porcine intestinal mucosa.Dosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Injectable, Subcutaneous: Innohep: 10000 units/mL (2 mL); 20000 units/mL (2 mL) [contains benzyl alcohol, sodium metabisulfite]Solution Prefilled Syringe, Subcutaneous: Innohep: 2500 units/0.25 mL (0.25 mL); 3500 units/0.35 mL (0.35 mL); 4500 units/0.45 mL (0.45 mL)Innohep: 8000 units/0.4 mL (0.4 mL); 10,000 units/0.5 mL (0.5 mL); 12,000 units/0.6 mL (0.6 mL); 14,000 units/0.7 mL (0.7 mL); 16,000 units/0.8 mL (0.8 mL); 18,000 units/0.9 mL (0.9 mL) [contains sodium metabisulfite]Administration: AdultSubQ: Patient should be lying down or sitting. Administer by deep SubQ injection into the lower abdomen (avoiding navel area), outer thigh, lower back, or upper arm. Do not administer IM. Injection site should be varied daily. To minimize bruising, do not rub the injection site.During hemodialysis, may be administered into the arterial side of the dialyzer circuit or IV in patients with no hemorrhage risk. In patients at risk of hemorrhage, administer IV only (do not add to the dialyzer circuit).Administration: PediatricSubQ: For SubQ administration; do not administer IM. Administer by deep SubQ injection; in adults, it is recommended to alternate between the lower abdomen (avoiding navel area), outer thigh, lower back, or upper arm. Injection site should be varied daily. To minimize bruising, do not rub the injection site.Use: Labeled IndicationsNote: Not available in the United States.Anticoagulation in extracorporeal circuit during hemodialysis: Prevention of clotting in indwelling intravenous lines and extracorporeal circuit during hemodialysis (in patients without high bleeding risk).Deep vein thrombosis/pulmonary embolus (treatment): Treatment of deep vein thrombosis and/or pulmonary embolism.Postoperative thromboprophylaxis:Prevention of venous thromboembolism (VTE) following orthopedic surgery or following general surgery in patients at high risk of VTE.Use: Off-Label: AdultMechanical prosthetic heart valve (aortic or mitral position) to bridge anticoagulation; Venous thromboembolism prophylaxis, bariatric surgery (moderate to high venous thromboembolism risk); Venous thromboembolism prophylaxis, medical patients with acute illness at moderate and high risk for venous thromboembolismMedication Safety IssuesHigh alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.International issues:Tinzaparin may be confused with Tinza (international brand name for nizatidine).Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.1% to 10%:Cardiovascular: Chest pain (2%)Dermatologic: Skin rash (1%)Gastrointestinal: Constipation (1%), nausea (2%), vomiting (1%)Genitourinary: Hematuria (1%), urinary tract infection (4%)Hematologic & oncologic: Anemia, hematoma, hemorrhage (2%; major hemorrhage ≤3%, including intracranial hemorrhage, retroperitoneal hemorrhage)Local: Injection site reaction (including hematoma at injection site [prophylaxis dosing: <5%, treatment dosing: 10%], irritation at injection site, pain at injection site)Nervous system: Headache (2%), pain (2%)Neuromuscular & skeletal: Back pain (2%)Respiratory: Dyspnea (1%), epistaxis (2%)Miscellaneous: Fever (2%)<1%:Gastrointestinal: Abdominal pain, diarrheaHematologic & oncologic: Heparin-induced thrombocytopenia (type I, type II), thrombocythemiaPostmarketing:Dermatologic: Allergic dermatitis, alopecia (Sarris 2003), bullous dermatitis (including hemorrhagic [Roy 2020]), ecchymoses, erythematous rash, maculopapular rash, pruritus, skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticariaEndocrine & metabolic: Increased gamma-glutamyl transferaseGenitourinary: Priapism (Purnell 2018)Hematologic & oncologic: Bruise, purpuric diseaseHepatic: Increased serum alanine aminotransferase, increased serum aspartate aminotransferaseHypersensitivity: Hypersensitivity reactionNeuromuscular & skeletal: Osteopenia, osteoporosisContraindicationsHypersensitivity to tinzaparin, heparin, or other low molecular weight heparins (LMWH), or any component of the formulation; active bleeding from a local lesion such as an acute ulcer (eg, gastric, duodenal) or ulcerating carcinoma; history of confirmed or suspected immunologically mediated heparin-induced thrombocytopenia (HIT) or positive in vitro platelet-aggregation test in the presence of tinzaparin; acute or subacute septic endocarditis; active major hemorrhage or conditions/diseases involving increased risk of hemorrhage (eg, severe hepatic insufficiency, imminent abortion); hemophilia or major blood clotting disorders; acute cerebral insult or hemorrhagic cerebrovascular accidents without systemic emboli; uncontrolled severe hypertension; diabetic or hemorrhagic retinopathy; injury or surgery involving the brain, spinal cord, eyes or ears; spinal/epidural anesthesia in patients requiring treatment dosages of tinzaparin; use of multi-dose vials containing benzyl alcohol in children <3 years of age, premature infants, and neonates.Warnings/PrecautionsConcerns related to adverse effects:• Bleeding: Monitor patient closely for signs or symptoms of bleeding, which may occur at any site. Certain patients are at increased risk of bleeding. Risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; severe uncontrolled hypertension; history of hemorrhagic stroke; or use shortly after brain, spinal, or ophthalmology surgery; those concomitantly treated with drugs that increase the risk of bleeding (eg, antiplatelet agents, anticoagulants); recent GI bleeding; thrombocytopenia or platelet defects; severe liver disease; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures. Withhold or discontinue for minor bleeding. Protamine infusion may be necessary for serious bleeding (consult Protamine monograph for dosing recommendations).• Hyperkalemia: Monitor for hyperkalemia. Heparin can cause hyperkalemia by suppressing aldosterone production; similar reactions could occur with LMWHs. Most commonly occurs in patients with risk factors for the development of hyperkalemia (eg, diabetes, renal dysfunction, preexisting metabolic acidosis, concomitant use of potassium-sparing diuretics or potassium supplements, long-term use of tinzaparin, and hematoma in body tissues).• Thrombocytopenia: Cases of thrombocytopenia including thrombocytopenia with thrombosis have occurred. Use with caution in patients with history of thrombocytopenia (drug-induced or congenital) or platelet defects; monitor platelet count closely. Use is contraindicated in patients with history of confirmed or suspected heparin-induced thrombocytopenia (HIT) or positive in vitro test for antiplatelet antibodies in the presence of tinzaparin. Discontinue therapy and consider alternative treatment if platelets are <100,000/mm3 and/or thrombosis develops.• Thrombocytosis: Asymptomatic thrombocytosis has been observed with use, particularly in patients undergoing orthopedic surgery or with concurrent inflammatory process; discontinue use with increased platelet counts and evaluate the risks/necessity of further therapy.Disease-related concerns:• GI ulceration: Use with caution in patients with history of GI ulcer.• Hepatic impairment: Use with caution in hepatic impairment; associated with transient, dose-dependent increases in AST/ALT/GGT which typically resolve within 2 to 4 weeks of therapy discontinuation.• Prosthetic heart valves: Prosthetic valve thrombosis has been reported in patients receiving thromboprophylaxis therapy with LMWHs. Pregnant women may be at increased risk.• Renal impairment: Use with caution in severe renal impairment; clearance is decreased in patients with CrCl ≤50 mL/minute; consider dosage reduction in patients with CrCl <30 mL/minute.Special populations:• Older adult: Use with caution due to increased bleeding risks. Avoid use in patients >70 years of age with renal impairment. In a trial terminated early, an increase in all-cause mortality has been observed in patients ≥70 years (mean age: >82 years) with CrCl ≤60 mL/minute treated with tinzaparin compared to unfractionated heparin for acute DVT and/or PE (Leizorovicz 2011).• Extreme body weights: Use with caution in patients <45 kg or >120 kg; limited experience in these patients. Individualized clinical and laboratory monitoring are recommended.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol and should not be used in pregnant women. In neonates, large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”); the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.• Porcine intestinal mucosa: This product is derived from porcine intestinal mucosa and should not be used in patients allergic to pork products.• Sodium metabisulfite: Some dosage forms contain sodium metabisulfite which may cause allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people; this is observed more frequently in asthmatics.Other warnings/precautions:• Administration: For subcutaneous use only (except in hemodialysis patients); do not administer IM and avoid IM administration of other medications due to the risk of hematoma formation.• Conversion to other products: Not to be used interchangeably (unit for unit) with heparin or any other low molecular weight heparins.• Neuraxial anesthesia: Spinal or epidural hematomas, including subsequent paralysis, may occur with recent or anticipated neuraxial anesthesia (epidural or spinal) or spinal puncture in patients anticoagulated with LMWH or heparinoids. Consider risk versus benefit prior to spinal procedures; risk is increased by the use of concomitant agents which may alter hemostasis, the use of indwelling epidural catheters for analgesia, a history of spinal deformity or spinal surgery, as well as traumatic or repeated epidural or spinal punctures. Optimal timing between neuraxial procedures and tinzaparin administration is not known. Delay placement or removal of catheter for at least 12 hours after administration of the last prophylactic dose and at least 24 hours after the last treatment dose of tinzaparin; consider doubling these times in patients with creatinine clearance <30 mL/minute. Risk of neuraxial hematoma may still exist since antifactor Xa levels are still detectable at these time points. Consider holding the next tinzaparin dose for 24 hours if the spinal puncture caused trauma. Patient should be observed closely for bleeding and signs and symptoms of neurological impairment if therapy is administered during or immediately following diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia. If neurological compromise is noted, urgent treatment is necessary. If spinal hematoma is suspected, diagnose and treat immediately; spinal cord decompression may be considered although it may not prevent or reverse neurological sequelae.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyAgents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyAlemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyAliskiren: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Aliskiren.Risk C: Monitor therapyAngiotensin II Receptor Blockers: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Angiotensin II Receptor Blockers.Risk C: Monitor therapyAngiotensin-Converting Enzyme Inhibitors: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors.Risk C: Monitor therapyAntithrombin: May enhance the anticoagulant effect of Heparins (Low Molecular Weight). Risk C: Monitor therapyApixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combinationBromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapyCaplacizumab: May enhance the anticoagulant effect of Anticoagulants. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modificationCollagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased.Risk C: Monitor therapyDabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combinationDasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyDeferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased.Risk C: Monitor therapyDeoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased.Risk C: Monitor therapyDesirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin.Management: Discontinue treatment with other anticoagulants prior to desirudin initiation.If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation. Risk D: Consider therapy modificationEdoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Risk X: Avoid combinationEplerenone: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Eplerenone.Risk C: Monitor therapyFactor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human).Risk C: Monitor therapyHemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combinationHerbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapyIbritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding.Risk C: Monitor therapyIbrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapyIcosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyInotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyKanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyLimaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapyLipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyMesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyMiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combinationNintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased.Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyObinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased.Risk C: Monitor therapyOmacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased.Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combinationOmega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyPalifermin: Heparins (Low Molecular Weight) may increase the serum concentration of Palifermin.Risk C: Monitor therapyPentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyPentoxifylline: May enhance the anticoagulant effect of Heparins (Low Molecular Weight). Risk C: Monitor therapyPotassium Salts: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium Salts.Risk C: Monitor therapyPotassium-Sparing Diuretics: Heparins (Low Molecular Weight) may enhance the hyperkalemic effect of Potassium-Sparing Diuretics.Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Risk C: Monitor therapyProstacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapyRivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods.Risk X: Avoid combinationSalicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapySugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapySulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyThrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: Monitor for signs and symptoms of bleeding if these agents are combined. For the treatment of acute ischemic stroke, avoidance with anticoagulants is often recommended, see full Lexicomp or drug interaction monograph for details. Risk C: Monitor therapyTibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyTipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyUrokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combinationVitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapyVitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyVorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combinationZanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapyReproductive ConsiderationsPatients undergoing assisted reproduction therapy (ART) may be at increased risk for thrombosis. Venous thromboembolism prophylaxis is not routinely recommended for patients undergoing ART; however, prophylactic doses of low-molecular-weight heparin (LMWH) are recommended for patients who develop severe ovarian hyperstimulation syndrome (ACCP [Bates 2012]; ASH [Bates 2018]; SOGC [Shmorgun 2017]). In addition, prophylactic doses of LMWH are recommended in patients undergoing ART who have a positive antiphospholipid antibody test but are not diagnosed with antiphospholipid syndrome (APS), as well as patients diagnosed with obstetric APS. Therapeutic doses of LMWH are recommended in patients undergoing ART diagnosed with thrombotic APS (ACR [Sammaritano 2020]).Pregnancy ConsiderationsTinzaparin does not cross the placenta.An increased risk of fetal bleeding or teratogenic effects has not been reported (ACCP [Bates 2012]).Due to pregnancy-induced physiologic changes, some pharmaco*kinetic properties of low-molecular-weight heparin (LMWH) may be altered; dosing adjustment may be required. Prophylactic doses of LMWH may also need modified in pregnant patients at extremes of body weight (ACOG 2018).Use is contraindicated in conditions involving increased risks of hemorrhage, including patients with imminent abortion.The risk of venous thromboembolism (VTE) is increased in pregnant patients, especially during the third trimester and first week postpartum. LMWH is recommended over unfractionated heparin for the treatment of acute VTE in pregnant patients. LMWH is also recommended over unfractionated heparin for VTE prophylaxis in pregnant patients with certain risk factors (eg, hom*ozygous factor V Leiden, antiphospholipid antibody syndrome with ≥3 previous pregnancy losses) (ACCP [Bates 2012]; ACOG 2018; ASH [Bates 2018]; ESC [Regitz-Zagrosek 2018]). Consult current recommendations for appropriate use in pregnancy.LMWH may be used prior to cesarean delivery in patients with additional risk factors for developing VTE. Risk factors may include a personal history of deep vein thrombosis or pulmonary embolism, inherited thrombophilia, or patients with class III obesity (Pacheco 2020).LMWH may also be used in pregnant patients with mechanical heart valves. When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), burden of therapy, and maternal preference should be considered. Patients with mechanical heart valves have an increased risk of adverse fetal and maternal outcomes (including valve thrombosis), and these risks are greater without appropriate anticoagulation. Increased monitoring of anti-factor Xa levels is required; frequent dose titration may be needed to maintain adequate therapeutic anti-factor Xa concentrations during pregnancy (consult current recommendations for details) (ACC/AHA [Otto 2021]; ESC [Regitz-Zagrosek 2018]).LMWH is the recommended class of anticoagulants for pregnant patients hospitalized for manifestations of COVID-19, taking into consideration risk factors for bleeding, including threatened delivery. Prophylactic doses are recommended during hospitalization if there are no contraindications to use. Recommendations for or against the use of therapeutic doses are not available due to insufficient data in pregnant patients with COVID-19 without VTE. Patients prescribed antithrombotic therapy prior to a COVID-19 diagnosis should continue their therapy (NIH 2022).Multiple-dose vials contain benzyl alcohol (avoid use in pregnant patients due to association with gasping syndrome in premature infants); use of preservative-free formulation is recommended.Breastfeeding ConsiderationsIt is not known if tinzaparin is present in breast milk.Small amounts of another low-molecular-weight heparin (LMWH) have been detected in breast milk; however, because they have a low oral bioavailability, LMWHs are unlikely to cause adverse events in a breastfeeding infant. According to the manufacturer, caution should be used if administered to a breastfeeding patient. LMWH is considered compatible with breastfeeding (ACCP [Bates 2012]; ACOG 2018; ASH [Bates 2018]).Monitoring ParametersCBC with platelet count (at baseline then periodically throughout therapy); renal function (use co*ckcroft-Gault formula); hepatic function; potassium (baseline and regularly thereafter in patients at risk for hyperkalemia); stool for occult blood. Routine monitoring of anti-Xa levels is generally not recommended; however, anti-Xa levels may be beneficial in certain patients (eg, children, obese patients, patients with severe renal insufficiency receiving therapeutic doses, and possibly pregnant women receiving therapeutic doses) (ACCP [Guyatt 2012]). Peak anti-Xa levels are measured 4 to 6 hours after administration. Monitoring of PT and/or aPTT is not recommended.Reference RangeAnti-Xa level (measured 4 hours after administration): Fixed-dose (3,500 units): 0.15 anti-Xa units/mL; weight-based (75 to 175 units/kg): 0.34 to 0.70 anti-Xa units/mL; in treatment of venous thromboembolism, a target of 0.85 anti-Xa units/mL has been recommended (Garcia 2012)Children: Target anti-Xa level: 0.5 to 1 anti-Xa units/mL 4 to 6 hours after administration or 0.5 to 0.8 anti-Xa units/mL 2 to 6 hours after administration (Monagle 2012)Mechanism of ActionTinzaparin is a low molecular weight heparin (average molecular weight ranges between 5,500 and 7,500 daltons, distributed as <2,000 daltons [<10%], 2,000 to 8,000 daltons [60% to 72%], and >8,000 daltons [22% to 36%]) that binds antithrombin III, enhancing the inhibition of several clotting factors, particularly factor Xa. Tinzaparin anti-Xa activity (70 to 120 units/mg) is greater than anti-IIa activity (~55 units/mg) and it has a higher ratio of antifactor Xa to antifactor IIa activity compared to unfractionated heparin. Low molecular weight heparins have a small effect on the activated partial thromboplastin time.Pharmaco*kineticsNote: Values reflective of anti-Xa activity.Duration: Detectable anti-Xa activity persists for 24 hoursAbsorption: Slow; absorption half-life ~3 hours after subcutaneous administrationDistribution: 4 LMetabolism: Does not undergo hepatic metabolismBioavailability: SubQ: ~90%Half-life elimination: 82 minutes; prolonged in renal impairmentTime to peak: 4 to 6 hoursExcretion: UrineBrand Names: InternationalInnohep (AE, BE, BH, DE, DK, ES, FI, FR, GB, GR, HK, IE, JO, KW, LB, LK, LU, MY, NL, NZ, PH, PK, PT, QA, RO, SA, SE, SG, TH, TR, TW);Innohep-PFS (CR, DO, GT, HN, NI, PA, SV);Logiparin (IN)For country code abbreviations (show table)Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):S44-S88. doi:10.1378/chest.11-2292 [PubMed 22315269]Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]American College of Obstetricians and Gynecologists' (ACOG) Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 196: Thromboembolism in pregnancy. Obstet Gynecol. 2018;132(1):e1-e17. doi:10.1097/AOG.0000000000002706 [PubMed 29939938]Baglin T, Bauer K, Douketis J, Buller H, Srivastava A, Johnson G; SSC of the ISTH. Duration of anticoagulant therapy after a first episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost. 2012;10(4):698-702. doi:10.1111/j.1538-7836.2012.04662.x [PubMed 22332937]Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):e691-e736. doi:10.1378/chest.11-2300 [PubMed 22315276]Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2018;2(22):3317-3359. doi:10.1182/bloodadvances.2018024802 [PubMed 30482767]Bauer KA. Anticoagulation therapy for VTE (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 4, 2019.Centers for Disease Control and Prevention (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm [PubMed 6810084]Cuker A, Peyvandi F. Coronavirus disease 2019 (COVID-19): hypercoagulability. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 22, 2021.Douketis JD, Mithoowani S. Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 18, 2018.Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e326S-e350S. [PubMed 22315266]Erkens PM, Gandara E, Wells P, et al. Safety of outpatient treatment in acute pulmonary embolism. J Thromb Haemost. 2010;8(11):2412-2417. doi:10.1111/j.1538-7836.2010.04041 [PubMed 20735722]Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e278S-e325S. doi:10.1378/chest.11-2404 [PubMed 22315265]Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al; Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. [PubMed 26714677]Garcia DA, Baglin TP, Weitz JI, et al. Parenteral Anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):24-43. [PubMed 22315264]Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in Nonorthopedic Surgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):e227-e277. [PubMed 22315263]Guyatt GH, Akl EA, Crowther M, et al. Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(suppl):7-47. [PubMed 22315257]Hainer JW, Barrett JS, Assaid CA, et al. Dosing in Heavy-weight/Obese Patients With the LMWH, Tinzaparin: A Pharmacodynamic Study. Thromb Haemost. 2002;87(5):817-823. [PubMed 12038783]"Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics (AAP) Committee on Drugs. Pediatrics. 1997;99(2):268-278. [PubMed 9024461]Innohep (tinzaparin) [product monograph]. Thornville, Ontario, Canada: LEO Pharma Inc; May 2017.Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e195S-e226S. doi:10.1378/chest.11-2296 [PubMed 22315261]Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e419S-e496S. doi:10.1378/chest.11-2301 [PubMed 22315268]Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026 [PubMed 26867832]Kearon C, Ginsberg JS, Julian JA, et al; Fixed-Dose Heparin (FIDO) Investigators. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. 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Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures - 2019 update: cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic & Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Surg Obes Relat Dis. 2020;16(2):175-247. doi:10.1016/j.soard.2019.10.025 [PubMed 31917200]Monagle P, Chan A, Goldenberg NA, et al. Antithrombotic Therapy in Neonates and Children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition). Chest. 2012;141(2)(suppl):e737-e801. [PubMed 22315277]Nagge J, Jackevicius C, Dzavik V, et al. Acute Profound Thrombocytopenia Associated With Eptifibatide Therapy. Pharmacotherapy. 2003;23(3):374-379. [PubMed 12627937]National Institutes of Health. COVID-19 treatment guidelines panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. https://www.covid19treatmentguidelines.nih.gov/. Updated May 31, 2022. Accessed August 4, 2022.Nutescu EA, Dager W. Heparin, low molecular weight heparin, and fondaparinux. In: Gulseth M, ed. Managing Anticoagulation Patients in the Hospital. American Society of Health-System Pharmacists; 2007:181.Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother. 2009;43(6):1064-1083. [PubMed 19458109]Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143(5):e72-e227. doi:10.1161/CIR.0000000000000923 [PubMed 33332150]Pacheco LD, Saade G, Metz TD; Society for Maternal-Fetal Medicine (SMFM). Society for Maternal-Fetal Medicine consult series #51: thromboembolism prophylaxis for cesarean delivery. Am J Obstet Gynecol. 2020;223(2):B11-B17. doi:10.1016/j.ajog.2020.04.032 [PubMed 32360109]Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al; ESC Scientific Document Group. 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018;39(34):3165-3241. doi:10.1093/eurheartj/ehy340 [PubMed 30165544]Richter C, Sitzmann J, Lang P, et al. Excretion of low molecular weight heparin in human milk. Br J Clin Pharmacol. 2001;52(6):708-710. [PubMed 11736885]Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020;72(4):529-556. doi:10.1002/art.41191 [PubMed 32090480]Sharma A, Chatterjee S, Lichstein E, Mukherjee D. Extended thromboprophylaxis for medically ill patients with decreased mobility: does it improve outcomes? J Thromb Haemost. 2012;10(10):2053-2060. doi:10.1111/j.1538-7836.2012.04874.x [PubMed 22863355]Shmorgun D, Claman P. No-268-the diagnosis and management of ovarian hyperstimulation syndrome. J Obstet Gynaecol Can. 2017;39(11):e479-e486. doi:10.1016/j.jogc.2017.09.003 [PubMed 29080733]Simonneau G, Sors H, Charbonnier B, et al. A Comparison of Low-Molecular-Weight Heparin With Unfractionated Heparin for Acute Pulmonary Embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire. N Engl J Med. 1997;337(10):663-669. [PubMed 9278462]Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest. 2021;160(6):e545-e608. doi:10.1016/j.chest.2021.07.055 [PubMed 34352278]Thombosis Canada. Thromboprophylaxis: hospitalized medical patients. https://thrombosiscanada.ca/wp-content/uploads/2020/03/Thromboprophylaxis-Medical-Patients-24March2020-1.pdf. Published March 24, 2020. Accessed October 19, 2020.Tseng EK, Kolesar E, Handa P, et al. Weight-adjusted tinzaparin for the prevention of venous thromboembolism after bariatric surgery. J Thromb Haemost. 2018;16(10):2008-2015. doi:10.1111/jth.14263 [PubMed 30099852]Warkentin TE, Kelton JG. Temporal Aspects of Heparin-Induced Thrombocytopenia. N Engl J Med. 2001;344(17):1286-1292. [PubMed 11320387]Wittkowsky AK. Warfarin. In: Anticoagulation Therapy: A Clinical Practice Guide, 2ed. Dager W, ed. American Society of Health-System Pharmacists; 2018.You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):S531-S575. doi:10.1378/chest.11-2304 [PubMed 22315271]Topic 10009 Version 203.0

CloseTrifluoperazine: Drug informationTrifluoperazine: Drug information(For additional information see "Trifluoperazine: Patient drug information" and see "Trifluoperazine: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningIncreased mortality in elderly patients with dementia-related psychosis:Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients between 1.6 and 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was approximately 4.5%, compared to a rate of approximately 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Trifluoperazine is not approved for the treatment of patients with dementia-related psychosis.Pharmacologic CategoryFirst Generation (Typical) Antipsychotic;Phenothiazine DerivativeDosing: AdultSchizophreniaSchizophrenia: Oral: Initial: 2 to 5 mg twice daily; titrate dose gradually based on response and tolerability; usual dosage: 15 or 20 mg/day in divided doses although some patients may require up to 40 mg/day.Discontinuation of therapy: In the treatment of chronic psychiatric disease switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (APA [Keepers 2020]; Lambert 2007; Moncrieff 2020; Post 2020).Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Stroup 2022).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling; use is contraindicated in patients with hepatic disease.Dosing: Pediatric(For additional information see "Trifluoperazine: Pediatric drug information")SchizophreniaSchizophrenia: Note: Use has been replaced by newer agents (AACAP [McClellan 2007]; NICE 2013). Dosage should be individualized; use lowest effective dose and shortest effective duration; periodically reassess the need for continued treatment:Children 6 to 12 years: Hospitalized or well-supervised patients: Initial: Oral: 1 mg administered 1 to 2 times daily; gradually titrate to effects as tolerated; daily maintenance range: 1 to 15 mg/day in 1 to 2 divided doses; usual maximum daily dose: 15 mg/day; older children with severe symptoms may require higher dosesAdolescent: Initial: 2 to 5 mg twice daily; gradually titrate dose as tolerated; usual maintenance dose range: 15 to 20 mg/day in 2 divided doses; maximum daily dose: 40 mg/day; in small for age patients, consider initial doses at the lower end of the rangeDiscontinuation of therapy: Children and Adolescents: American Academy of Child and Adolescent Psychiatry (AACAP), American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), National Institute for Health and Care Excellence (NICE), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (AACAP [McClellan 2007]; APA [Lehman 2004]; Cerovecki 2013; CPA 2005; NICE 2013; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months and the APA guidelines recommend reducing the dose by 10% each month (APA [Lehman 2004]; CPA 2005). Continuing antiparkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). When switching antipsychotics, three strategies have been suggested: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited and results are conflicting (Cerovecki 2013; Remington 2005).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer’s labeling. Dialysis: Not dialyzable (0% to 5%).Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling; use is contraindicated in patients with hepatic disease.Dosing: Older AdultRefer to adult dosing. Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia or psychosis. Titrate dosage slowly and monitor carefully (Howard 2000).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Generic: 1 mg, 2 mg, 5 mg, 10 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Generic: 1 mg, 2 mg, 5 mg, 10 mg, 20 mgAdministration: PediatricOral: May be taken with food to decrease GI upset; do not take within 2 hours of any antacidsUse: Labeled IndicationsSchizophrenia: Management of schizophrenia.Medication Safety IssuesSound-alike/look-alike issues:Trifluoperazine may be confused with trihexyphenidylStelazine may be confused with selegilineOlder Adult: High-Risk Medication:Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2019]).Pediatric patients: High-risk medication:KIDs List: Dopamine antagonists, when used in pediatric patients <18 years of age, are identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list; use should be avoided in infants and used with caution in children and adolescents due to risk of acute dystonia (dyskinesia) (strong recommendation; moderate quality of evidence) (PPA [Meyers 2020]).Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Frequency not defined.Cardiovascular: Hypotension, orthostatic hypotensionCentral nervous system: Decreased seizure threshold, dizziness, disruption of body temperature regulation, extrapyramidal reaction (akathisia, dystonia, Parkinsonian-like syndrome, tardive dyskinesia), headache, neuroleptic malignant syndrome (NMS)Dermatologic: Skin discoloration (blue-gray), skin photosensitivity (includes increased sensitivity to sun), skin rashEndocrine & metabolic: Change in libido, change in menstrual flow, galactorrhea, gynecomastia, hyperglycemia, hypoglycemia, weight gainGastrointestinal: Constipation, nausea, stomach pain, vomiting, xerostomiaGenitourinary: Difficulty in micturition, ejacul*tory disorder, lactation, mastalgia, priapism, urinary retentionHematologic & oncologic: Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, immune thrombocytopenia, leukopenia, pancytopeniaHepatic: Cholestatic jaundice, hepatotoxicityNeuromuscular & skeletal: TremorOphthalmic: Corneal changes, lens disease, retinitis pigmentosaRespiratory: Nasal congestionContraindicationsHypersensitivity to trifluoperazine, phenothiazines, or any component of the formulation; comatose or greatly depressed states due to CNS depressants; bone marrow suppression; blood dyscrasias; hepatic diseaseWarnings/PrecautionsConcerns related to adverse effects:• Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics (Haddad 2002; Stollberger 2005).• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. Relative to other antipsychotics, trifluoperazine has a high potency of cholinergic blockade (Tardy 2014).• Antiemetic effects: May mask toxicity of other drugs or conditions (eg, intestinal obstruction, Reye syndrome, brain tumor) due to antiemetic effects.• Blood dyscrasias: Leukopenia, neutropenia, thrombocytopenia, anemia, agranulocytosis (sometimes fatal), and pancytopenia have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).• Esophageal dysmotility/Aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (ie, Alzheimer disease), particularly in patients >75 years (Herzig 2017; Maddalena 2004).• Extrapyramidal symptoms (EPS): May cause EPS, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia. Risk of dystonia (and possibly other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Keepers 2020]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability (Landi 2005; Seppala 2018).• Hepatic effects: Liver damage and jaundice of the cholestatic type of hepatitis have been reported with use.• Hyperprolactinemia: Use associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.• Neuroleptic malignant syndrome (NMS): May be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability. Following recovery from NMS, reintroduction of drug therapy should be carefully considered; if an antipsychotic agent is resumed, monitor closely for NMS.• Ocular effects: May cause pigmentary retinopathy, and lenticular and corneal deposits, particularly with prolonged therapy (Oshika 1995).• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia) (APA [Keepers 2020]).• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects (Kwok 2005; Martinez 2002).Disease-related concerns:• Cardiovascular disease: Use with caution in patients with cardiovascular disease.• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. The APA recommends giving preference to second generation antipsychotics over first generation antipsychotics in elderly patients with dementia-related psychosis due to a potentially greater risk of harm relative to second generation antipsychotics (APA [Reus 2016]). Trifluoperazine is not approved for the treatment of dementia-related psychosis.• Hepatic impairment: Contraindicated in patients with hepatic disease.• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures; first-generation antipsychotics may lower the seizure threshold (APA [Keepers 2020]).Other warnings/precautions:• Appropriate use: Anxiety: Trifluoperazine is not the first drug of choice for most patients with nonpsychotic anxiety. Do not exceed recommended dose and duration; use of trifluoperazine at higher doses or for longer intervals may cause persistent tardive dyskinesia (may be irreversible).• Discontinuation of therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).Metabolism/Transport EffectsSubstrate of UGT1A4Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapyAcetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapyAclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combinationAgents With Seizure Threshold Lowering Potential: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased. Risk C: Monitor therapyAlcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).Risk C: Monitor therapyAlizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyAmifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine.Risk C: Monitor therapyAminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).Risk X: Avoid combinationAminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).Risk C: Monitor therapyAmisulpride (Oral): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome or increased QTc interval may be increased. Risk C: Monitor therapyAmphetamines: Antipsychotic Agents may enhance the adverse/toxic effect of Amphetamines. Antipsychotic Agents may diminish the stimulatory effect of Amphetamines.Risk C: Monitor therapyAntacids: May decrease the absorption of Antipsychotic Agents (Phenothiazines). Risk C: Monitor therapyAnticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapyAnti-Parkinson Agents (Dopamine Agonist): May diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible. If antipsychotic use is necessary, consider using atypical antipsychotics such as clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modificationAntipsychotic Agents: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased.Risk C: Monitor therapyAzelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBeta-Blockers: Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers.Risk C: Monitor therapyBlonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin.Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modificationBotulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapyBrexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone.Risk C: Monitor therapyBrimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combinationBromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBuprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine.Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modificationBuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapyCabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combinationCannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products.Risk C: Monitor therapyCannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.Risk C: Monitor therapyChloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapyChlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modificationChlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapyCimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium.Risk X: Avoid combinationCloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine.Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modificationCNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapyDaridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationDeutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapyDexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine.Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modificationDexmethylphenidate-Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined.Risk C: Monitor therapyDifelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDoxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants isnot recommended. Risk C: Monitor therapyDroperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modificationEluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline.Risk X: Avoid combinationEsketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyFlunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine.Risk X: Avoid combinationFlunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modificationGastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic).Risk C: Monitor therapyGlucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased.Risk C: Monitor therapyGlycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation).Risk X: Avoid combinationGlycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combinationGuanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine.Risk C: Monitor therapyHydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modificationIohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased.Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modificationIomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased.Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modificationIopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased.Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modificationIpratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combinationItopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride.Risk C: Monitor therapyKava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyKratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationLemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modificationLevosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride.Risk X: Avoid combinationLithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapyLofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMagnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine.Management: Consider alternatives to one of these agents when possible.While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modificationMethotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modificationMethoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic).Risk C: Monitor therapyMetoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combinationMetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE.Risk C: Monitor therapyMetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapyMianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapyMinocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron.Risk C: Monitor therapyNitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption.Risk C: Monitor therapyOlopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOpioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists.Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOrphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine.Risk X: Avoid combinationOxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combinationOxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products.Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modificationOxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE.Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationParaldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde.Risk X: Avoid combinationPerampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyPiribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents.Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid combinationPorfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.Risk C: Monitor therapyPotassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride.Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Risk X: Avoid combinationPotassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate.Risk X: Avoid combinationPramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combinationProcarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyQuinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide.Risk C: Monitor therapyRamosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron.Risk C: Monitor therapyRevefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin.Risk X: Avoid combinationRopeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased.Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modificationRufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapySaquinavir: Antipsychotic Agents (Phenothiazines) may enhance the arrhythmogenic effect of Saquinavir.Risk X: Avoid combinationSecretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin.Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider therapy modificationSerotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapySodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities.Risk C: Monitor therapySulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride.Risk X: Avoid combinationSuvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant.Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary.Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationTetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapyThalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide.Risk X: Avoid combinationThiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics.Risk C: Monitor therapyThiopental: Antipsychotic Agents (Phenothiazines) may enhance the adverse/toxic effect of Thiopental.Risk C: Monitor therapyTiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium.Risk X: Avoid combinationTopiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate.Risk C: Monitor therapyTrimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyTriptorelin: Hyperprolactinemic Agents may diminish the therapeutic effect of Triptorelin.Risk X: Avoid combinationUmeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combinationValerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyVerteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.Risk C: Monitor therapyZolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem.Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg formen who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modificationPregnancy ConsiderationsAdverse events have not been observed in animal reproduction studies, except when using doses that were also maternally toxic. Prolonged jaundice, extrapyramidal signs, or hyporeflexia have been reported in newborn infants following maternal use of phenothiazines. Antipsychotic use during the third trimester of pregnancy has a risk for extrapyramidal and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization. Breastfeeding ConsiderationsTrifluoperazine is excreted in breast milk and was measurable in the serum of three nursing infants (adverse events were not reported). Milk concentrations may be higher than those found in the maternal serum (Yoshida 1999). Infants should be monitored for signs of adverse events. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.Monitoring ParametersMental status; vital signs (as clinically indicated); weight, height, BMI, waist circumference (baseline; at every visit for the first 6 months; quarterly with stable antipsychotic dose); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with pre-existing low WBC or history of drug-induced leukopenia/neutropenia); electrolytes and liver function (annually and as clinically indicated); fasting plasma glucose level/HbA1c (baseline, then yearly; in patients with diabetes risk factors or if gaining weight, repeat 4 months after starting antipsychotic, then yearly); lipid panel (baseline; repeat every 2 years if LDL level is normal; repeat every 6 months if LDL level is >130 mg/dL); changes in menstruation, libido, development of galactorrhea, erectile and ejacul*tory function (at each visit for the first 12 weeks after the antipsychotic is initiated or until the dose is stable, then yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 6 months; high-risk patients every 3 months); visual changes (inquire yearly); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004); fall risk (baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk) (Landi 2005; Seppala 2018).Mechanism of ActionTrifluoperazine is a piperazine phenothiazine antipsychotic which blocks dopamine, subtype 2 (D2), receptors in mesolimbocortical and nigrostriatal areas of the brain (APA [Lehman, 2004]). Pharmaco*kineticsOnset of action: Schizophrenia: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).Duration of action: Variable.Metabolism: Metabolized in the gut after administration and hepatically to active metabolites N-desmethyltrifluoperazine, 7-hydroxyrifluoperazine, and other metabolites (Midha 1984).Half-life elimination: 3 to 12 hours (Midha 1984).Time to peak, serum: 1.5 to 6 hours (Midha 1984).Pricing: USTablets (Trifluoperazine HCl Oral)1 mg (per each): $0.87 - $1.342 mg (per each): $1.29 - $2.005 mg (per each): $1.62 - $2.5510 mg (per each): $2.45 - $3.08Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalApo-Trifluoperazine (PL);Befrin (KR);Deanger (TW);Domilium (TW);Espazine (IN);Flupazine (CR, DO, GT, HN, MX, NI, PA, SV);Flurazin (TW);Gencalm (IN);Hestazin (TW);Jatroneural (DE);Jatroneural Retard (AT);Leptazine (VE);Modalina (IT);Modiur (CO);Neocalm (IN);Sizonil (BD);Stela (BD);Stelazine (AE, AR, AU, BB, BF, BH, BJ, BM, BR, BS, BZ, CI, CO, CR, CY, DO, ET, GB, GH, GM, GN, GR, GT, GY, HK, HN, ID, IE, IL, IQ, IR, JM, JO, KE, KW, LB, LR, LY, MA, ML, MR, MT, MU, MW, MX, NE, NG, NI, NL, NZ, OM, PA, PH, PK, PL, SA, SC, SD, SL, SN, SR, SV, SY, TN, TR, TT, TZ, UG, YE, ZA, ZM, ZW);Stelazine MR (TR);Stellasil (EG, QA);Stelosi (ID);Sycazine (LK);Telazine (BD);Terfluzine (FR, HU, PL);Tridil (BD);Triflazine (TH);Triflumed (TH);Triftazin (RU, UA);Triozine (TH)For country code abbreviations (show table)2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi: 10.1111/jgs.15767. [PubMed 30693946]Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry. 2003;60(12):1228-1235. doi:10.1001/archpsyc.60.12.1228 [PubMed 14662555]American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry. 2004;65(2):267-272. [PubMed 15003083]Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403-439. doi:10.1177/0269881114525674 [PubMed 24713617]Cerovecki A, Musil R, Klimke A, et al. Withdrawal symptoms and rebound syndromes associated with switching and discontinuing atypical antipsychotics: theoretical background and practical recommendations. CNS Drugs. 2013;27(7):545-572. doi:10.1007/s40263-013-0079-5 [PubMed 23821039]Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs. 2002;62(11):1649-1671. [PubMed 12109926]Hasan A, Falkai P, Wobrock T, et al; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;13(5):318-378. doi: 10.3109/15622975.2012.696143. [PubMed 22834451]Herzig SJ, LaSalvia MT, Naidus E, et al. Antipsychotics and the risk of aspiration pneumonia in individuals hospitalized for nonpsychiatric conditions: a cohort study. J Am Geriatr Soc. 2017;65(12):2580-2586. doi: 10.1111/jgs.15066. [PubMed 29095482]Howard R, Rabins PV, Seeman MV, Jeste DV. Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group. Am J Psychiatry. 2000;157(2):172-178. doi:10.1176/appi.ajp.157.2.172 [PubMed 10671383]Katzman MA, Bleau P, Blier P, et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;(suppl 1):S1. doi:10.1186/1471-244X-14-S1-S1 [PubMed 25081580]Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868-872. doi:10.1176/appi.ajp.2020.177901 [PubMed 32867516]Kwok JS, Chan TY. Recurrent heat-related illnesses during antipsychotic treatment. Ann Pharmacother. 2005;39(11):1940-1942. [PubMed 16174785]Lambert TJ. Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes. J Clin Psychiatry. 2007;68(suppl 6):10-13. [PubMed 17650054]Landi F, Onder G, Cesari M, Barillaro C, Russo A, Bernabei R; Silver Network Home Care Study Group. Psychotropic medications and risk for falls among community-dwelling frail older people: an observational study. J Gerontol A Biol Sci Med Sci. 2005;60(5):622-6226. doi:10.1093/gerona/60.5.622 [PubMed 15972615]Lehman AF, Lieberman JA, Dixon LB, et al; American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(suppl 2):1-56. 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CloseIsavuconazole (isavuconazonium sulfate): Drug informationIsavuconazole (isavuconazonium sulfate): Drug information(For additional information see "Isavuconazole (isavuconazonium sulfate): Patient drug information" and see "Isavuconazole (isavuconazonium sulfate): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USCresembaBrand Names: CanadaCresembaPharmacologic CategoryAntifungal Agent, Azole Derivative;Antifungal Agent, Oral;Antifungal Agent, ParenteralDosing: AdultNote: Dosage expressed as milligrams of isavuconazonium sulfate; switching between the IV and oral formulations of isavuconazonium sulfate is acceptable; for maintenance dosing, it is not necessary to restart dosing with the initial dose regimen when switching between formulations.Aspergillosis, invasiveAspergillosis, invasive: IV, Oral: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily (Maertens 2016). Start maintenance dose 12 to 24 hours after the last loading dose.Duration of therapy: Minimum of 6 to 12 weeks, although duration is highly dependent on degree/duration of immunosuppression, disease site, and evidence of disease improvement (IDSA [Patterson 2016]).CandidiasisCandidiasis:Esophageal, fluconazole-refractory disease (alternative agent) (off-label use): Oral: 744 mg (isavuconazole 400 mg) as a single dose, then 186 mg (isavuconazole 100 mg) once daily for 14 to 28 days or 744 mg (isavuconazole 400 mg) once weekly for 4 weeks (HHS [OI adult 2021]; Kauffman 2021; Viljoen 2015).Mucormycosis, invasiveMucormycosis, invasive: IV, Oral: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily (Marty 2016). Start maintenance dose 12 to 24 hours after the last loading dose.Prophylaxis against invasive fungal infectionsProphylaxis against invasive fungal infections (alternative agent) (off-label use):Hematology malignancy or hematopoietic cell transplant:IV, Oral: Initial: 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses; Maintenance: 372 mg (isavuconazole 200 mg) once daily (Bogler 2021; Bose 2021; Fontana 2020).Duration of therapy: Varies based on degree and duration of immunosuppression (Bogler 2021; Bose 2021; Fontana 2020; IDSA [Taplitz 2018]).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultNo dosage adjustment necessary.Dosing: Hepatic Impairment: AdultMild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.Severe impairment (Child-Pugh class C):There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.Dosing: Pediatric(For additional information see "Isavuconazole (isavuconazonium sulfate): Pediatric drug information")Note: Dosage expressed as milligrams of isavuconazonium sulfate; 372 mg isavuconazonium sulfate = 200 mg isavuconazole. Switching between the IV and oral formulations of isavuconazonium sulfate is acceptable; the same dose and frequency can be used; additional loading doses are NOT necessary.General dosing, invasive fungal infection: Children and Adolescents <18 years: Very limited data available: IV, Oral: Initial (loading doses): 10 mg isavuconazonium sulfate/kg/dose every 8 hours for 6 doses; maximum dose: 372 mg isavuconazonium sulfate/dose. Maintenance (begin 12 to 24 hours after last loading dose): 10 mg isavuconazonium sulfate/kg/dose every 24 hours; maximum dose: 372 mg isavuconazonium sulfate/dose. Dosing based on a pharmaco*kinetic and safety study and a small number of case reports. The pharmaco*kinetic study utilized isavuconazonium sulfate 74.5 mg capsules, which are not currently commercially available (Arrieta 2021; Ashkenazi-Hoffnung 2020; Ferdjallah 2021; Ross 2020).Aspergillosis, invasiveAspergillosis, invasive: Adolescents ≥18 years: IV, Oral: Initial (loading doses): 372 mg isavuconazonium sulfate every 8 hours for 6 doses; maintenance (begin 12 to 24 hours after last loading dose): 372 mg isavuconazonium sulfate every 24 hours (manufacturer's labeling). Minimum duration is 6 to 12 weeks; duration should be individualized depending on degree and duration of immunosuppression, disease site, and evidence of improvement (IDSA [Patterson 2016]).Candidiasis, esophagealCandidiasis, esophageal (alternative agent): Multiple regimens reported: HIV-infected: Adolescents: Oral: 744 mg isavuconazonium sulfate as a single dose, followed by 186 mg isavuconazonium sulfate every 24 hours or 372 mg isavuconazonium sulfate as a single dose, followed by 93 mg isavuconazonium sulfate every 24 hours or 744 mg isavuconazonium sulfate once weekly; treat for 14 to 21 days (HHS [adult OI] 2022).Mucormycosis, invasiveMucormycosis, invasive (salvage treatment): Adolescents ≥13 years weighing ≥40 kg: Limited data available in ages <18 years: IV, Oral: Initial (loading doses): 372 mg isavuconazonium sulfate every 8 hours for 6 doses; maintenance (begin 12 to 24 hours after last loading dose): 372 mg isavuconazonium sulfate every 24 hours (ECMM/MSG-ERC [Cornely 2019]; manufacturer's labeling). Treatment duration is highly individualized depending on degree and duration of immunosuppression, disease site, clinical resolution, and improvement on imaging studies; typically weeks to months or longer (ECMM/MSG-ERC [Cornely 2019]).Dosing: Kidney Impairment: PediatricAltered kidney function: Adolescents ≥18 years: No dosage adjustment necessary in any degree of kidney impairment; less than 1% is eliminated by the kidney.Hemodialysis: Not readily dialyzable; no dosage adjustment necessary.Dosing: Hepatic Impairment: PediatricAdolescents ≥18 years:Mild or moderate impairment: No dosage adjustment necessary.Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral, as sulfate: Cresemba: 186 mg (isavuconazole 100 mg) [contains disodium edta]Solution Reconstituted, Intravenous, as sulfate [preservative free]: Cresemba: 372 mg (isavuconazole 200 mg) (1 ea)Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral, as sulfate: Cresemba: 186 mg (isavuconazole 100 mg) [contains disodium edta]Solution Reconstituted, Intravenous, as sulfate: Cresemba: 372 mg (isavuconazole 200 mg) (1 ea)Administration: AdultIV: Infuse over a minimum of 1 hour; must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron). Flush line with NS or D5W before and after infusion. Do not administer as an IV bolus injection. Do not mix or infuse with other medications.Nasogastric tube: Administer within 1 hour of reconstitution. Once dose administered, flush nasogastric tube with three 5 mL rinses of water.Oral: Administer with or without food. The manufacturer recommends to swallow capsules whole; do not chew, crush, dissolve, or open. Administration of isavuconazonium sulfate by opening capsules and mixing contents with saline or tube feed formulations for administration via enteral feeding tubes has resulted in comparable isavuconazole concentrations to IV administration and intact capsule formulations. If capsules are opened, consider assessing serum concentrations to ensure absorption (Adamsick 2019; McCreary 2020).Administration: PediatricIV: Infuse over a minimum of 1 hour; must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron). Flush line with NS or D5W before and after infusion. Do not administer as an IV bolus injection. Do not mix or infuse with other medications.Oral: Administer with or without food. The manufacturer recommends swallowing capsules whole and states not to chew, crush, dissolve, or open capsules. However, oral administration of isavuconazonium sulfate by opening capsules and mixing contents with an acidic beverage or soft food [eg, yogurt] has resulted in comparable isavuconazole concentrations to IV administration and administration of intact capsule formulations. If capsules are opened, consider assessing serum concentrations to ensure absorption (Cornu 2018; DeLeonardis 2020).Feeding tube administration:Using parenteral formulation: Administer via nasogastric (NG) tube within 1 hour of reconstitution. Once dose administered, flush NG tube with three 5 mL rinses of water.Using capsules: Administer isavuconazonium sulfate via enteral feeding tubes (eg, gastrostomy tube, gastrojejunostomy [GJ] tube) by opening capsules and mixing contents with water, saline, or tube feed formulations (eg, 372 mg isavuconazonium sulfate in 10 mL saline); isavuconazole concentrations were found to be comparable to those achieved with IV administration; consider assessing serum concentrations to ensure absorption (Adamsick 2019; Garner 2021; McCreary 2020).Use: Labeled IndicationsAspergillosis: Treatment of invasive aspergillosis in patients ≥18 years of age.Mucormycosis: Treatment of invasive mucormycosis in patients ≥18 years of age.Use: Off-Label: AdultCandidiasis, esophageal, fluconazole-refractory disease; Prophylaxis against invasive fungal infectionsAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Cardiovascular: Peripheral edema (15%)Endocrine & metabolic: Hypokalemia (19%)Gastrointestinal: Abdominal pain (17%), constipation (14%), diarrhea (24%), nausea (28%), vomiting (25%)Hepatic: Increased liver enzymes (17%)Nervous system: Fatigue (11%), headache (17%), insomnia (11%)Respiratory: Dyspnea (17%)1% to 10%:Cardiovascular: Atrial fibrillation (<5%), atrial flutter (<5%), bradycardia (<5%), chest pain (9%), ECG changes (reduced QT interval) (<5%), hypotension (8%), palpitations (<5%), supraventricular extrasystole (<5%), supraventricular tachycardia (<5%), syncope (<5%), thrombophlebitis (<5%), ventricular premature contractions (<5%)Dermatologic: Alopecia (<5%), dermatitis (<5%), erythema of skin (<5%), exfoliative dermatitis (<5%), pruritus (8%), skin rash (9%), urticaria (<5%)Endocrine & metabolic: Hypoalbuminemia (<5%), hypoglycemia (<5%), hypomagnesemia (5%), hyponatremia (<5%)Gastrointestinal: Abdominal distention (<5%), cholecystitis (<5%), cholelithiasis (<5%), decreased appetite (9%), dysgeusia (<5%), dyspepsia (6%), gastritis (<5%), gingivitis (<5%), stomatitis (<5%)Genitourinary: Hematuria (<5%), proteinuria (<5%)Hematologic & oncologic: Agranulocytosis (<5%), leukopenia (<5%), pancytopenia (<5%), petechia (<5%)Hepatic: Hepatic failure (<5%), hepatitis (<5%), hepatomegaly (<5%), increased serum alanine aminotransferase (>3 × ULN ≤4%; >10 × ULN ≤1%), increased serum aspartate aminotransferase (>3 × ULN ≤4%; >10 × ULN ≤1%)Hypersensitivity: Hypersensitivity reaction (<5%)Local: Injection-site reaction (6%)Nervous system: Anxiety (8%), chills (<5%), confusion (<5%), delirium (9%), depression (<5%), drowsiness (<5%), encephalopathy (<5%), falling (<5%), hallucination (<5%), hypoesthesia (<5%), malaise (<5%), migraine (<5%), paresthesia (<5%), peripheral neuropathy (<5%), seizure (<5%), stupor (<5%), tremor (<5%), vertigo (<5%)Neuromuscular & Skeletal: Back pain (10%), myositis (<5%), neck pain (<5%), ostealgia (<5%)Ophthalmic: Optic neuropathy (<5%)Otic: Tinnitus (<5%)Renal: Renal failure syndrome (10%)Respiratory: Acute respiratory failure (7%), bronchospasm (<5%), tachypnea (<5%)Frequency not defined:Hepatic: Cholestasis, increased serum alkaline phosphatase, increased serum bilirubinRenal: Acute kidney injuryRespiratory: CoughMiscellaneous: Infusion-related reactionPostmarketing: Hypersensitivity: AnaphylaxisContraindicationsHypersensitivity to isavuconazonium sulfate (eg, isavuconazole) or any component of the formulation; concurrent use of strong CYP3A4 inhibitors (eg, ketoconazole, high-dose ritonavir [400 mg every 12 hours]); concurrent use of strong CYP3A4 inducers (eg, rifampin, carbamazepine, St. John’s wort, long-acting barbiturates); familial short QT syndrome.Canadian labeling: Additional contraindications (not in US labeling): Concurrent use of moderate CYP3A4/5 inducers (eg, efavirenz, etravirine).Warnings/PrecautionsConcerns related to adverse effects:• Hepatic effects: Severe reactions (hepatic failure [including fatalities], hepatitis, and cholestasis) have been reported in patients with serious underlying medical conditions (eg, hematologic malignancy). Other reactions (elevations in AST, ALT, alkaline phosphatase and total bilirubin) have also been reported; these elevations are generally reversible and do not require discontinuation of therapy. Monitor liver function tests at baseline and periodically during therapy. If abnormal liver function tests develop, monitor closely for development of severe hepatic reactions. Discontinue therapy if clinical signs and symptoms of liver disease develop.• Hypersensitivity: Anaphylactic reactions, with fatal outcome, have been reported with isavuconazonium sulfate. Discontinue isavuconazonium sulfate if a patient experiences an anaphylactic reaction. Serious hypersensitivity (eg, anaphylaxis) and severe skin reactions (eg, Stevens-Johnson syndrome) have been reported with other azole antifungal agents. Discontinue if a severe skin reaction occurs. There is no information regarding cross-sensitivity between isavuconazonium sulfate and other azoles. Use with caution in patients with hypersensitivity reactions to other azoles.Disease-related concerns:• Hepatic impairment: Use with caution and monitor for adverse effects in patients with severe hepatic impairment (Child-Pugh class C).Dosage form specific issues:• Drug particulates: Following dilution for IV infusion, may form precipitate from the insoluble isavuconazole. Use an infusion set with an in-line filter (pore size 0.2 to 1.2 micron) for IV administration.• Infusion-related reactions: Infusion reactions (eg, hypotension, dizziness, chills, dyspnea, paresthesia and hypoesthesia) have been reported during IV administration. Discontinue the infusion if these reactions occur.Metabolism/Transport EffectsSubstrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (moderate), OCT1, OCT2, P-glycoprotein/ABCB1; Induces CYP2B6 (weak)Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Abemaciclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib.Management: Monitor for increased abemaciclib toxicities if combined with moderate CYP3A4 inhibitors. Consider reducing the abemaciclib dose in 50 mg decrements if necessary. Risk C: Monitor therapyAcalabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib.Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use. Risk D: Consider therapy modificationAfatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib.Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider therapy modificationAlfentanil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alfentanil.Management: If use of alfentanil and moderate CYP3A4 inhibitors is necessary, consider dosage reduction of alfentanil until stable drug effects are achieved. Frequently monitor patients for respiratory depression and sedation when these agents are combined. Risk D: Consider therapy modificationAlfuzosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alfuzosin.Risk C: Monitor therapyAliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren.Risk C: Monitor therapyAlitretinoin (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Alitretinoin (Systemic).Risk C: Monitor therapyALPRAZolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ALPRAZolam.Management: Consider alternatives to this combination when possible. If combined, consider an alprazolam dose reduction and monitor for increased alprazolam effects and toxicities (eg, sedation, lethargy). Risk D: Consider therapy modificationAmiodarone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Amiodarone.Risk C: Monitor therapyAmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine.Risk C: Monitor therapyAmphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B.Risk C: Monitor therapyApixaban: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Apixaban.Risk C: Monitor therapyAprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant.Risk X: Avoid combinationARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole.Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy, indication, or dosage form. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapyARIPiprazole Lauroxil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole Lauroxil.Risk C: Monitor therapyAstemizole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Astemizole.Management: Avoid concomitant use of astemizole and moderate CYP3A4 inhibitors whenever possible. If combined, monitor closely for increased astemizole toxicities, especially for QTc interval prolongation. Risk D: Consider therapy modificationAsunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir.Risk X: Avoid combinationAtogepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Atogepant.Risk C: Monitor therapyAtorvastatin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Atorvastatin.Risk C: Monitor therapyAvacopan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avacopan.Risk C: Monitor therapyAvanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil.Management: The maximum avanafil dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects (eg, hypotension, syncope, priapism). Risk D: Consider therapy modificationAvapritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avapritinib.Management: Avoid use of moderate CYP3A4 inhibitors with avapritinib. If this combination cannot be avoided, reduce the avapritinib dose to 100 mg daily for the treatment of GIST or to 50 mg daily for the treatment of advanced systemic mastocytosis. Risk D: Consider therapy modificationAxitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Axitinib.Risk C: Monitor therapyBarnidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Barnidipine.Risk C: Monitor therapyBedaquiline: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Bedaquiline. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bedaquiline.Risk C: Monitor therapyBenidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benidipine.Risk C: Monitor therapyBenzhydrocodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased.Risk C: Monitor therapyBerotralstat: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Berotralstat.Management: Decrease the berotralstat dose to 110 mg daily when combined with P-glycoprotein (P-gp) inhibitors. Risk D: Consider therapy modificationBilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine.Risk X: Avoid combinationBlonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin.Risk C: Monitor therapyBortezomib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bortezomib.Risk C: Monitor therapyBosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib.Risk X: Avoid combinationBrexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole.Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Risk C: Monitor therapyBrigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brigatinib.Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inhibitors when possible. If such a combination cannot be avoided, reduce the dose of brigatinib by approximately 40% (ie, from 180 mg to 120 mg, from 120 mg to 90 mg, or from 90 mg to 60 mg). Risk D: Consider therapy modificationBromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine.Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Risk D: Consider therapy modificationBudesonide (Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Oral Inhalation).Risk C: Monitor therapyBudesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic).Management: Avoid the concomitant use of CYP3A4 inhibitors and oral budesonide. If patients receive both budesonide and CYP3A4 inhibitors, they should be closely monitored for signs and symptoms of corticosteroid excess. Risk D: Consider therapy modificationBudesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical).Risk X: Avoid combinationBuprenorphine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Buprenorphine.Risk C: Monitor therapyBuPROPion: CYP2B6 Inducers (Weak) may decrease the serum concentration of BuPROPion.Risk C: Monitor therapyBusPIRone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of BusPIRone.Risk C: Monitor therapyCabozantinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cabozantinib.Risk C: Monitor therapyCannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased.Risk C: Monitor therapyCariprazine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Cariprazine. Specifically, concentrations of didesmethylcariprazine (DDCAR), the primary active metabolite of cariprazine, may increase. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cariprazine.Risk C: Monitor therapyCeliprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol.Risk C: Monitor therapyCilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol.Management: Decrease the dose of cilostazol to 50 mg twice daily when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationCisapride: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cisapride.Management: Consider alternatives to this combination. Prescribing information for some moderate CYP3A4 inhibitors state coadministration with cisapride is contraindicated, while some others recommend monitoring and dose titration. Risk D: Consider therapy modificationClindamycin (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Clindamycin (Systemic).Risk C: Monitor therapyClofarabine: OCT2 Inhibitors may increase the serum concentration of Clofarabine.Risk C: Monitor therapyClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCloZAPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of CloZAPine.Risk C: Monitor therapyCobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib.Management: Avoid this combination when possible. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose from 60 mg to 20 mg daily. Avoid concomitant use in patients already receiving reduced cobimetinib doses. Risk D: Consider therapy modificationCodeine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Codeine.Risk C: Monitor therapyColchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine.Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. See interaction monograph for details. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modificationColchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased.Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a P-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details. Risk D: Consider therapy modificationConivaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Conivaptan.Risk C: Monitor therapyCopanlisib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Copanlisib.Risk C: Monitor therapyCrizotinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Crizotinib.Risk C: Monitor therapyCycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic).Risk C: Monitor therapyCycloSPORINE (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of CycloSPORINE (Systemic).Risk C: Monitor therapyCYP3A4 Inducers (Moderate): May decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Moderate) may decrease isavuconazole serum concentrations. Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Risk X: Avoid combinationCYP3A4 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Moderate) may increase isavuconazole serum concentrations. Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Risk X: Avoid combinationDabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate.Risk C: Monitor therapyDabrafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dabrafenib.Risk C: Monitor therapyDalfampridine: OCT2 Inhibitors may increase the serum concentration of Dalfampridine.Management: Consider alternatives to this combination. Carefully weigh the risk of seizures against the benefit of combining OCT2 inhibitors with dalfampridine. Risk D: Consider therapy modificationDapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine.Management: The dose of dapoxetine should be limited to 30 mg per day when used together with a moderate inhibitor of CYP3A4. Risk D: Consider therapy modificationDaridorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Daridorexant.Management: Limit the daridorexant dose to 25 mg, no more than once per night, when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationDarifenacin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Darifenacin.Risk C: Monitor therapyDasatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dasatinib.Risk C: Monitor therapyDeflazacort: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort.Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Risk D: Consider therapy modificationDelamanid: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Delamanid.Risk C: Monitor therapyDexAMETHasone (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DexAMETHasone (Systemic).Risk C: Monitor therapyDiazePAM: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DiazePAM.Risk C: Monitor therapyDichlorphenamide: Antifungal Agents (Azole Derivatives, Systemic) may enhance the hypokalemic effect of Dichlorphenamide.Risk C: Monitor therapyDigoxin: Isavuconazonium Sulfate may increase the serum concentration of Digoxin.Risk C: Monitor therapyDilTIAZem: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DilTIAZem.Risk C: Monitor therapyDisopyramide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Disopyramide.Risk C: Monitor therapyDOCEtaxel: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOCEtaxel.Risk C: Monitor therapyDofetilide: MATE1/2-K Inhibitors may increase the serum concentration of Dofetilide.Risk X: Avoid combinationDomperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone.Risk X: Avoid combinationDOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional).Risk X: Avoid combinationDOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Liposomal).Risk C: Monitor therapyDronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol.Risk C: Monitor therapyDronedarone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronedarone.Risk C: Monitor therapyEbastine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ebastine.Risk C: Monitor therapyEdoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban.Risk C: Monitor therapyElbasvir and Grazoprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elbasvir and Grazoprevir.Risk C: Monitor therapyEletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan.Risk X: Avoid combinationElexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor.Management: When combined with moderate CYP3A4 inhibitors, twoelexacaftor/tezacaftor/ivacaftor (100 mg/50 mg/75 mg) tablets should be given in the morning, every other day. Ivacaftor (150 mg) should be given in the morning, every other day on alternate days. Risk D: Consider therapy modificationEliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat.Management: Reduce eliglustat dose to 84 mg daily in CYP2D6 EMs when used with moderate CYP3A4 inhibitors. Avoid use of moderate CYP3A4 inhibitors in CYP2D6 IMs or PMs. Use in CYP2D6 EMs or IMs also taking strong or moderate CYP2D6 inhibitors is contraindicated. Risk D: Consider therapy modificationEncorafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Encorafenib.Management: Avoid use of encorafenib and moderate CYP3A4 inhibitors when possible. If combined, decrease the encorafenib dose from 450 mg to 225 mg; 300 mg to 150 mg; and 225 mg or 150 mg to 75 mg. Resume prior dose once inhibitor discontinued for 3 to 5 half-lives. Risk D: Consider therapy modificationEntrectinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Entrectinib.Management: Avoid moderate CYP3A4 inhibitors during treatment with entrectinib. Reduce dose to 200 mg/day if combination cannot be avoided in adults and those 12 yrs of age or older with a BSA of at least 1.5 square meters. Avoid if BSA is less than 1.5 square meters Risk D: Consider therapy modificationEplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone.Management: If coadministered with moderate CYP3A4 inhibitors, the max dose of eplerenone is 25 mg daily if used for heart failure; if used for hypertension initiate eplerenone 25 mg daily, titrate to max 25 mg twice daily. Risk D: Consider therapy modificationErgot Derivatives (Vasoconstrictive CYP3A4 Substrates): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates).Risk C: Monitor therapyErlotinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Erlotinib.Risk C: Monitor therapyErythromycin (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Erythromycin (Systemic).Risk C: Monitor therapyEszopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eszopiclone.Risk C: Monitor therapyEtoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide.Risk C: Monitor therapyEtoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate.Risk C: Monitor therapyEtravirine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Etravirine.Risk C: Monitor therapyEverolimus: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Everolimus.Management: Afinitor: For TSC-associated SEGA or TSC-associated seizures reduce everolimus dose 50%. For other Afinitor indications, reduce everolimus dose to 2.5 mg/day, increase to 5 mg/day if tolerated. Zortress: Monitor for increased everolimus concentrations. Risk D: Consider therapy modificationFedratinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fedratinib.Risk C: Monitor therapyFelodipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Felodipine.Risk C: Monitor therapyFentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL.Management: Consider fentanyl dose reductions when combined with a moderate CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modificationFexinidazole: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Fexinidazole.Management: Avoid use of fexinidazole and moderate CYP3A4 inhibitors when possible. If combined, monitor for reduced fexinidazole efficacy. Risk D: Consider therapy modificationFinerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Finerenone.Risk C: Monitor therapyFlibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin.Management: Use of flibanserin with moderate CYP3A4 inhibitors is contraindicated. If starting flibanserin, start 2 weeks after the last dose of the CYP3A4 inhibitor. If starting a CYP3A4 inhibitor, start 2 days after the last dose of flibanserin. Risk X: Avoid combinationFlucloxacillin: May decrease the serum concentration of Isavuconazonium Sulfate. Risk C: Monitor therapyFluticasone (Nasal): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fluticasone (Nasal).Risk C: Monitor therapyFluticasone (Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fluticasone (Oral Inhalation).Risk C: Monitor therapyFosamprenavir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosamprenavir.Risk C: Monitor therapyFosaprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosaprepitant.Risk X: Avoid combinationFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFutibatinib: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Futibatinib.Risk C: Monitor therapyGilteritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Gilteritinib.Risk C: Monitor therapyGlasdegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Glasdegib.Risk C: Monitor therapyGlecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir.Risk C: Monitor therapyGuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE.Management: Reduce the extended-release guanfacine dose 50% when combined with a moderate CYP3A4 inhibitor. Monitor for increased guanfacine toxicities when these agents are combined. Risk D: Consider therapy modificationHalofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine.Risk C: Monitor therapyHYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone.Risk C: Monitor therapyIbrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib.Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Risk D: Consider therapy modificationIfosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide.Risk C: Monitor therapyIloperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Iloperidone.Risk C: Monitor therapyInfigratinib: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Infigratinib.Risk X: Avoid combinationIrinotecan Products: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, the serum concentration of SN-38 may be increased. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Irinotecan Products.Risk C: Monitor therapyIsradipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Isradipine.Risk C: Monitor therapyItraconazole: May increase the serum concentration of Isavuconazonium Sulfate. Risk X: Avoid combinationIvabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine.Risk X: Avoid combinationIvacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor.Management: Ivacaftor dose reductions may be required; consult full drug interaction monograph content for age- and weight-specific dosage recommendations. Risk D: Consider therapy modificationIvosidenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivosidenib.Management: Avoid use of moderate CYP3A4 inhibitors with ivosidenib whenever possible. If combined, monitor for increased ivosidenib toxicities, including QTc prolongation. Risk D: Consider therapy modificationIxabepilone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ixabepilone.Risk C: Monitor therapyLapatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lapatinib.Risk C: Monitor therapyLapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib.Risk C: Monitor therapyLarotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib.Risk C: Monitor therapyLarotrectinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Larotrectinib.Risk C: Monitor therapyLefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin.Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Risk D: Consider therapy modificationLemborexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lemborexant.Risk X: Avoid combinationLercanidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lercanidipine.Risk C: Monitor therapyLevamlodipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levamlodipine.Risk C: Monitor therapyLevomethadone: Isavuconazonium Sulfate may decrease the serum concentration of Levomethadone.Risk C: Monitor therapyLevomilnacipran: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Levomilnacipran.Risk C: Monitor therapyLidocaine (Systemic): CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Lidocaine (Systemic). Specifically, concentrations of monoethylglycinexylidide (MEGX) may be increased. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lidocaine (Systemic).Risk C: Monitor therapyLomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide.Risk X: Avoid combinationLonafarnib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lonafarnib.Risk X: Avoid combinationLopinavir: May increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, lopinavir/ritonavir may increase isavuconazole serum concentrations. Isavuconazonium Sulfate may decrease the serum concentration of Lopinavir. Management: Consider alternatives to this combination. If coadministered, use caution and monitor for increased isavuconazonium effects and toxicities as well as reduced concentrations and effects of lopinavir/ritonavir. Risk D: Consider therapy modificationLovastatin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lovastatin.Risk C: Monitor therapyLumateperone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lumateperone.Management: Limit the lumateperone dose to 21 mg once daily when used with a moderate CYP3A4 inhibitor. Risk D: Consider therapy modificationLurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone.Management: US labeling recommends reducing lurasidone dose by 50% with a moderate CYP3A4 inhibitor and initiating 20 mg/day, max 80 mg/day. Some non-US labels recommend initiating lurasidone 20 mg/day, max 40 mg/day. Avoid concurrent use of grapefruit products. Risk D: Consider therapy modificationLurbinectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurbinectedin.Management: Avoid concomitant use of lurbinectedin and moderate CYP3A4 inhibitors when possible. If combined, consider a lurbinectedin dose reduction as clinically indicated. Risk D: Consider therapy modificationMacitentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Macitentan.Risk C: Monitor therapyManidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine.Risk C: Monitor therapyMaraviroc: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Maraviroc.Risk C: Monitor therapyMavacamten: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mavacamten.Management: Start mavacamten at 5 mg/day if stable on a moderate CYP3A4 inhibitor. For those stable on mavacamten who are initiating a moderate CYP3A4 inhibitor, reduce mavacamten dose by one dose level. Risk D: Consider therapy modificationMeperidine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Meperidine.Risk C: Monitor therapyMetFORMIN: MATE1/2-K Inhibitors may increase the serum concentration of MetFORMIN.Risk C: Monitor therapyMethadone: Isavuconazonium Sulfate may decrease the serum concentration of Methadone.Risk C: Monitor therapyMethylPREDNISolone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of MethylPREDNISolone.Risk C: Monitor therapyMethysergide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Methysergide.Risk X: Avoid combinationMidazolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Midazolam.Management: Avoid concomitant use of nasal midazolam and moderate CYP3A4 inhibitors. Consider alternatives to use with oral midazolam whenever possible and consider using lower midazolam doses. Monitor patients for sedation and respiratory depression if combined. Risk D: Consider therapy modificationMidostaurin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Midostaurin.Risk C: Monitor therapyMirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil.Risk C: Monitor therapyMitapivat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mitapivat.Management: When coadministered with moderate CYP3A4 inhibitors, doses of mitapivat should not exceed 20 mg twice daily. Additionally, patients should be monitored for changes in hemoglobin response and increased mitapivat adverse effects. Risk D: Consider therapy modificationMizolastine: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Mizolastine.Risk X: Avoid combinationMobocertinib: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Mobocertinib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mobocertinib.Management: Avoid use of moderate CYP3A4 inhibitors with mobocertinib when possible. If combined, the mobocertinib dose should be reduced by approximately 50% (ie, from 160 mg to 80 mg, 120 mg to 40 mg, or 80 mg to 40 mg). Monitor QTc interval closely. Risk D: Consider therapy modificationMorphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic).Risk C: Monitor therapyMycophenolate: Isavuconazonium Sulfate may increase the serum concentration of Mycophenolate.Risk C: Monitor therapyNadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol.Risk C: Monitor therapyNaldemedine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine.Risk C: Monitor therapyNaldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.Risk C: Monitor therapyNalfurafine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine.Risk C: Monitor therapyNaloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol.Management: The use of naloxegol and moderate CYP3A4 inhibitors should be avoided. If concurrent use is unavoidable, reduce naloxegol dose to 12.5 mg once daily and monitor for signs of opiate withdrawal (eg, hyperhidrosis, chills, diarrhea, anxiety, irritability). Risk D: Consider therapy modificationNeratinib: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Neratinib.Risk X: Avoid combinationNIFEdipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NIFEdipine.Risk C: Monitor therapyNilotinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nilotinib.Risk C: Monitor therapyNiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine.Risk C: Monitor therapyNintedanib: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Nintedanib.Risk C: Monitor therapyNirmatrelvir and Ritonavir: Isavuconazonium Sulfate may increase the serum concentration of Nirmatrelvir and Ritonavir. Nirmatrelvir and Ritonavir may increase the serum concentration of Isavuconazonium Sulfate.Risk C: Monitor therapyNisoldipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nisoldipine.Risk X: Avoid combinationNitrendipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nitrendipine.Risk C: Monitor therapyOlaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib.Management: Avoid use of moderate CYP3A4 inhibitors with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib tablets should be reduced to 150 mg twice daily and the dose of olaparib capsules should be reduced to 200 mg twice daily. Risk D: Consider therapy modificationOliceridine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Oliceridine.Risk C: Monitor therapyOlmutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olmutinib.Risk C: Monitor therapyOrelabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Orelabrutinib.Risk X: Avoid combinationOxyCODONE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased.Risk C: Monitor therapyPAcl*taxel (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PAcl*taxel (Conventional).Risk C: Monitor therapyPAcl*taxel (Protein Bound): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PAcl*taxel (Protein Bound).Risk C: Monitor therapyPacritinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pacritinib.Risk X: Avoid combinationPalbociclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Palbociclib.Risk C: Monitor therapyPalovarotene: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Palovarotene.Risk C: Monitor therapyPanobinostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Panobinostat.Risk C: Monitor therapyPAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib.Risk X: Avoid combinationPemigatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pemigatinib.Management: If combined use cannot be avoided, reduce the pemigatinib dose from 13.5 mg daily to 9 mg daily, or from 9 mg daily to 4.5 mg daily. Resume prior pemigatinib dose after stopping the moderate inhibitor once 3 half-lives of the inhibitor has passed. Risk D: Consider therapy modificationPexidartinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pexidartinib.Management: Avoid use of pexidartinib with moderate CYP3A4 inhibitors if possible. If combined, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg per day to 200 mg once daily. Risk D: Consider therapy modificationPimavanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimavanserin.Risk C: Monitor therapyPimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus.Risk C: Monitor therapyPimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide.Risk X: Avoid combinationPiperaquine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Piperaquine.Risk C: Monitor therapyPONATinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of PONATinib.Risk C: Monitor therapyPralsetinib: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Pralsetinib.Risk C: Monitor therapyPrazepam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Prazepam.Risk C: Monitor therapyPraziquantel: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Praziquantel.Risk C: Monitor therapyQUEtiapine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of QUEtiapine.Risk C: Monitor therapyQuiNIDine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of QuiNIDine.Risk C: Monitor therapyQuinidine (Non-Therapeutic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Quinidine (Non-Therapeutic).Risk C: Monitor therapyQuiNINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of QuiNINE.Risk C: Monitor therapyRanolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine.Management: Limit the ranolazine dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors. Monitor for increased ranolazine effects and toxicities during concomitant use. Risk D: Consider therapy modificationRed Yeast Rice: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Red Yeast Rice.Risk C: Monitor therapyRegorafenib: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Regorafenib.Risk C: Monitor therapyRelugolix: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix.Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider therapy modificationRelugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Relugolix, Estradiol, and Norethindrone.Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider therapy modificationRibociclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ribociclib.Risk C: Monitor therapyRifabutin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rifabutin.Risk C: Monitor therapyRifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin.Risk C: Monitor therapyRimegepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rimegepant.Management: If taking rimegepant for the acute treatment of migraine, avoid a second dose of rimegepant within 48 hours when used concomitantly with moderate CYP3A4 inhibitors. No dose adjustment needed if using rimegepant for prevention of episodic migraine. Risk D: Consider therapy modificationRimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant.Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider therapy modificationRiociguat: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Riociguat.Risk C: Monitor therapyRisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RisperiDONE.Risk C: Monitor therapyRivaroxaban: Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Rivaroxaban.Management: No action is needed in patients with normal renal function. Do not use this combination in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. Risk D: Consider therapy modificationRoflumilast-Containing Products: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Roflumilast-Containing Products.Risk C: Monitor therapyRomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin.Risk C: Monitor therapyRupatadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine.Risk C: Monitor therapyRuxolitinib (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ruxolitinib (Systemic).Risk C: Monitor therapySaccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii.Risk X: Avoid combinationSalmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol.Risk C: Monitor therapySAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin.Risk C: Monitor therapySelpercatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Selpercatinib.Management: Avoid combination if possible. If use is necessary, reduce selpercatinib dose as follows: from 120 mg twice/day to 80 mg twice/day, or from 160 mg twice/day to 120 mg twice/day. Risk D: Consider therapy modificationSelumetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Selumetinib.Management: Avoid concomitant use when possible. If combined, selumetinib dose reductions are recommended and vary based on body surface area and selumetinib dose. For details, see the full drug interaction monograph or selumetinib prescribing information. Risk D: Consider therapy modificationSertindole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sertindole.Risk X: Avoid combinationSildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil.Risk C: Monitor therapySilodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin.Risk C: Monitor therapySilodosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Silodosin.Risk C: Monitor therapySimeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir.Risk X: Avoid combinationSimvastatin: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simvastatin.Risk C: Monitor therapySirolimus (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sirolimus (Conventional).Management: Monitor for increased serum concentrations of sirolimus if combined with a moderate CYP3A4 inhibitor. Lower initial sirolimus doses or sirolimus dose reductions will likely be required. Risk D: Consider therapy modificationSirolimus (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Conventional).Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider therapy modificationSirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus (Protein Bound).Risk X: Avoid combinationSolifenacin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Solifenacin.Risk C: Monitor therapySonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib.Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible.When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Risk D: Consider therapy modificationSt John's Wort: May decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, St Johns Wort may decrease isavuconazole serum concentrations. Risk X: Avoid combinationSUNItinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SUNItinib.Risk C: Monitor therapySuvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant.Management: The recommended dose of suvorexant is 5 mg daily in patients receiving a moderate CYP3A4 inhibitor. The dose can be increased to 10 mg daily (maximum dose) if necessary for efficacy. Risk D: Consider therapy modificationTacrolimus (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tacrolimus (Systemic).Risk C: Monitor therapyTacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tacrolimus (Systemic).Risk C: Monitor therapyTacrolimus (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tacrolimus (Topical).Risk C: Monitor therapyTadalafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tadalafil.Risk C: Monitor therapyTalazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib.Risk C: Monitor therapyTamsulosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin.Risk C: Monitor therapyTazemetostat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tazemetostat.Management: Avoid when possible. If combined, reduce tazemetostat dose from 800 mg twice daily to 400 mg twice daily, from 600 mg twice daily to 400 mg in AM and 200 mg in PM, or from 400 mg twice daily to 200 mg twice daily. Risk D: Consider therapy modificationTegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod.Risk C: Monitor therapyTemsirolimus: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, concentrations of sirolimus may be increased.Risk C: Monitor therapyTeniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide.Risk C: Monitor therapyTenofovir Disoproxil Fumarate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tenofovir Disoproxil Fumarate.Risk C: Monitor therapyTerfenadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Terfenadine.Risk C: Monitor therapyTetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol.Risk C: Monitor therapyTetrahydrocannabinol and Cannabidiol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol.Risk C: Monitor therapyTezacaftor and Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor and Ivacaftor.Management: If combined with moderate CYP3A4 inhibitors, give tezacaftor/ivacaftor in the morning, every other day; give ivacaftor in the morning, every other day on alternate days. Tezacaftor/ivacaftor dose depends on age and weight; see full Lexi-Interact monograph Risk D: Consider therapy modificationThiotepa: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Thiotepa.Risk C: Monitor therapyTicagrelor: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor.Risk C: Monitor therapyTofacitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tofacitinib.Risk C: Monitor therapyTolterodine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolterodine.Risk C: Monitor therapyTolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan.Management: Avoid this combination with Samsca brand of tolvaptan. Reduce dose for Jynarque brand: 90 mg AM and 30 mg PM, reduce to 45 mg AM and 15 mg PM; 60 mg AM and 30 mg PM, reduce to 30 mg AM and 15 mg PM; 45 mg AM and 15 mg PM, reduce to 15 mg AM and PM. Risk D: Consider therapy modificationTopotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan.Risk X: Avoid combinationToremifene: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Toremifene.Risk C: Monitor therapyTrabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin.Risk C: Monitor therapyTraMADol: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of TraMADol.Risk C: Monitor therapyTraZODone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of TraZODone.Risk C: Monitor therapyTriazolam: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Triazolam.Management: Consider triazolam dose reduction in patients receiving concomitant moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationUbrogepant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ubrogepant.Management: Use an initial ubrogepant dose of 50 mg and avoid a second dose for 24 hours when used with moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationUbrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant.Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Risk D: Consider therapy modificationUdenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil.Risk C: Monitor therapyUlipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal.Risk C: Monitor therapyValbenazine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Valbenazine.Risk C: Monitor therapyVardenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vardenafil.Management: Limit Levitra (vardenafil) dose to a single 5 mg dose within a 24-hour period if combined with moderate CYP3A4 inhibitors. Avoid concomitant use of Staxyn (vardenafil) and moderate CYP3A4 inhibitors. Combined use is contraindicated outside of the US. Risk D: Consider therapy modificationVemurafenib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vemurafenib.Risk C: Monitor therapyVenetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax.Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with moderate CYP3A4 inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationVerapamil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Verapamil.Risk C: Monitor therapyVilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone.Risk C: Monitor therapyVinBLAStine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of VinBLAStine.Risk C: Monitor therapyVinCRIStine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of VinCRIStine.Risk C: Monitor therapyVinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal).Risk X: Avoid combinationVindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine.Risk C: Monitor therapyVinflunine: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Vinflunine. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vinflunine.Risk C: Monitor therapyVoclosporin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Voclosporin.Management: Decrease the voclosporin dose to 15.8 mg in the morning and 7.9 mg in the evening when combined with moderate CYP3A4 inhibitors. Risk D: Consider therapy modificationVorapaxar: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vorapaxar.Risk C: Monitor therapyZanubrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zanubrutinib.Management: Decrease the zanubrutinib dose to 80 mg twice daily during coadministration with a moderate CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details. Risk D: Consider therapy modificationZopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone.Risk C: Monitor therapyReproductive ConsiderationsEvaluate pregnancy status prior to use; patients who could become pregnant should use effective contraception during therapy and for 28 days after the last isavuconazonium sulfate dose.Pregnancy ConsiderationsBased on data from animal reproduction studies, in utero exposure to isavuconazonium sulfate may cause fetal harm.Breastfeeding ConsiderationsIt is not known if isavuconazonium sulfate is present breast milk.The manufacturer recommends breastfeeding be discontinued during maternal isavuconazonium sulfate therapy.Monitoring ParametersHypersensitivity reactions with initial doses, LFTs (eg AST, ALT, alkaline phosphatase, total bilirubin) at baseline and periodically during therapy. Infusion-related reactions (eg hypotension, dyspnea, chills, dizziness, paresthesias, hypoesthesia) during IV infusion.Routine therapeutic drug monitoring is not recommended; consider assessing serum drug concentrations if there is concern for toxicity, therapeutic failure, or possibility of impaired drug absorption (Adamsick 2019; Andes 2018; McCreary 2020; MSG-ERC [Johnson 2020]; Schmitt-Hoffman 2009).Reference RangeOptimal drug concentrations have not been established; however, most adult patients achieve levels >1 mg/L with standard dosing regimens; an upper limit associated with toxicity has not been determined (Andes 2018; Desai 2017).Mechanism of ActionIsavuconazonium sulfate is a prodrug that is rapidly hydrolyzed in the blood to active isavuconazole. Isavuconazole inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase. This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weakens the membrane structure and function.Pharmaco*kineticsDistribution: Vss: Isavuconazole: IV: ~450 L.Protein binding: Isavuconazole: >99% (primarily to albumin).Metabolism: Isavuconazonium sulfate (prodrug) is rapidly hydrolyzed in the blood by esterases to active isavuconazole and an inactive cleavage product. Isavuconazole is metabolized by CYP3A4, CYP 3A5, and UGT.Bioavailability: Oral: Isavuconazole: 98%.Half-life elimination: IV: Isavuconazole: 130 hours.Time to peak: Isavuconazole:IV: Children and Adolescents: Median range: 1.07 to 1.08 hours (range: 1.02 to 1.35 hours) (Arrieta 2021).Oral:Children ≥6 years and Adolescents: Median range: 3.98 to 4 hours (range: 1.98 to 8.03 hours) (Arrieta 2021).Adults: 2 to 3 hours.Excretion: Urine (<1% as unchanged isavuconazole); feces (33% as unchanged isavuconazole) (Townsend 2018).Pharmaco*kinetics: Additional ConsiderationsHepatic function impairment: Patients with mild and moderate hepatic impairment had 40% and 48% lower isavuconazole Cl values, respectively, compared with healthy subjects, resulting in 64% and 84% increased drug exposure, respectively. In addition, patients with moderate hepatic impairment had 30% lower Cmax, compared with healthy subjects.Pricing: USCapsules (Cresemba Oral)186 mg (per each): $121.16Solution (reconstituted) (Cresemba Intravenous)372 mg (per each): $412.82Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalCresemba (AT, BB, BE, CH, CZ, DE, DK, EE, FI, FR, GB, HR, IE, LT, LV, NL, NO, PL, PT, RO, SE, SK, TW)For country code abbreviations (show table)Adamsick ML, Elshaboury RH, Gift T, Mansour MK, Kotton CN, Gandhi RG. Therapeutic drug concentrations of isavuconazole following the administration of isavuconazonium sulfate capsules via gastro-jejunum tube: a case report. Transpl Infect Dis. 2019;21(2):e13048. doi:10.1111/tid.13048 [PubMed 30636363]Andes D, Kovanda L, Desai A, Kitt T, Zhao M, Walsh TJ. Isavuconazole concentration in real-world practice: consistency with results from clinical trials. Antimicrob Agents Chemother. 2018;62(7):e00585-18. doi:10.1128/AAC.00585-18 [PubMed 29735569]Arrieta AC, Neely M, Day JC, et al. Safety, tolerability, and population pharmaco*kinetics of intravenous and oral isavuconazonium sulfate in pediatric patients. Antimicrob Agents Chemother. 2021;65(8):e0029021. doi:10.1128/AAC.00290-21 [PubMed 34031051]Ashkenazi-Hoffnung L, Bilavsky E, Levy I, et al. Isavuconazole as successful salvage therapy for mucormycosis in pediatric patients. Pediatr Infect Dis J. 2020;39(8):718-724. doi:10.1097/INF.0000000000002671 [PubMed 32251256]Barg AA, Malkiel S, Bartuv M, Greenberg G, Toren A, Keller N. Successful treatment of invasive mucormycosis with isavuconazole in pediatric patients. Pediatr Blood Cancer. 2018;65(10):e27281. doi:10.1002/pbc.27281 [PubMed 29932282]Bogler Y, Stern A, Su Y, et al. Efficacy and safety of isavuconazole compared with voriconazole as primary antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients. Med Mycol. 2021;59(10):970-979. doi:10.1093/mmy/myab025 [PubMed 34036319]Bose P, McCue D, Wurster S, et al. Isavuconazole as primary antifungal prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome: an open-label, prospective, phase 2 study. Clin Infect Dis. 2021;72(10):1755-1763. doi:10.1093/cid/ciaa358 [PubMed 32236406]Candidiasis (Mucocutaneous). In: US Department of Health and Human Services (HHS) Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/Adult_OI.pdf. Updated May 26, 2020. Accessed June 16, 2021.Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology (ECMM) in cooperation with the Mycoses Study Group Education and Research Consortium (MSG-ERC). Lancet Infect Dis. 2019;19(12):e405-e421. doi:10.1016/S1473-3099(19)30312-3 [PubMed 31699664]Cornely OA, Böhme A, Schmitt-Hoffmann A, Ullmann AJ. Safety and pharmaco*kinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia patients with neutropenia: results of a phase 2, dose escalation study. Antimicrob Agents Chemother. 2015 Apr;59(4):2078-2085. [PubMed 25624327]Cornu M, Bruno B, Loridant S, et al. Successful outcome of disseminated mucormycosis in a 3-year-old child suffering from acute leukaemia: the role of isavuconazole? A case report. BMC Pharmacol Toxicol. 2018;19(1):81. doi:10.1186/s40360-018-0273-7 [PubMed 30522521]Cresemba (isavuconazonium) [prescribing information]. Northbrook, IL: Astellas Pharma US Inc; February 2022.Cresemba (isavuconazonium) [product monograph]. Blainville, Quebec, Canada: Avir Pharma Inc; April 2022.Desai AV, Kovanda LL, Hope WW, et al. Exposure-response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi. Antimicrob Agents Chemother. 2017;61(12):e01034-17. doi:10.1128/AAC.01034-17 [PubMed 28923872]Decembrino N, Perruccio K, Zecca M, et al. A case series and literature review of isavuconazole use in pediatric patients with hemato-oncologic diseases and hematopoietic stem cell transplantation. Antimicrob Agents Chemother. 2020;64(3):e01783-19. doi:10.1128/AAC.01783-19 [PubMed 31871077]De Leonardis F, Novielli C, Giannico B, Mariggiò MA, Castagnola E, Santoro N. Isavuconazole treatment of cerebral and pulmonary aspergillosis in a pediatric patient with acute lymphoblastic leukemia: case report and review of literature. J Pediatr Hematol Oncol. 2020;42(6):e469-e471. doi:10.1097/MPH.0000000000001508 [PubMed 31094909]Falci DR, Pasqualotto AC. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013;6:163-174. [PubMed 24187505]Ferdjallah A, Nelson KM, Meyer K, Jennissen CA, Ebens CL. Isavuconazonium sulfate use in multi-modal management of invasive mucormycosis in four pediatric allogeneic hematopoietic cell transplant patients. J Pediatr Pharmacol Ther. 2021;26(8):863-867. doi:10.5863/1551-6776-26.8.863 [PubMed 34790078]Fontana L, Perlin DS, Zhao Y, et al. Isavuconazole prophylaxis in patients with hematologic malignancies and hematopoietic cell transplant recipients. Clin Infect Dis. 2020;70(5):723-730. doi:10.1093/cid/ciz282 [PubMed 30958538]Garner LM, Echols CD, Wilson WS. Enteral tube administration of isavuconazole in a pediatric patient. Pediatr Blood Cancer. 2021;68(9):e29108. doi:10.1002/pbc.29108 [PubMed 33991386]Johnson MD, Lewis RE, Dodds Ashley ES, et al. Core recommendations for antifungal stewardship: a statement of the Mycoses Study Group Education and Research Consortium. J Infect Dis. 2020;222(suppl 3):S175-S198. doi:10.1093/infdis/jiaa394 [PubMed 32756879]Kauffman CA. Esophageal candidiasis in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com. Accessed September 23, 2021.Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760-769. doi:10.1016/S0140-6736(15)01159-9 [PubMed 26684607]Marty FM, Ostrosky-Zeichner L, Cornely OA, et al; VITAL and FungiScope Mucormycosis Investigators. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16(7):828-837. doi:10.1016/S1473-3099(16)00071-2McCreary EK, Nguyen MH, Davis MR, et al. Achievement of clinical isavuconazole blood concentrations in transplant recipients with isavuconazonium sulphate capsules administered via enteral feeding tube. J Antimicrob Chemother. Published online July 25, 2020. doi:10.1093/jac/dkaa274 [PubMed 32710097]Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America (IDSA). Clin Infect Dis. 2016;63(4):e1-e60. doi:10.1093/cid/ciw326. http://cid.oxfordjournals.org/content/early/2016/06/22/cid.ciw326.full.pdf+html. Accessed August 8, 2016. [PubMed 27365388]Peixoto D, Gagne LS, Hammond SP, et al. Isavuconazole treatment of a patient with disseminated mucormycosis. J Clin Microbiol. 2014; 52(3):1016-1019. [PubMed 24403304]Ross JA, Karras NA, Tegtmeier B, et al. Safety of isavuconazonium sulfate in pediatrics patients with hematologic malignancies and hematopoietic cell transplantation with invasive fungal infections: a real world experience. J Pediatr Hematol Oncol. 2020;42(4):261-265. doi:10.1097/MPH.0000000000001787 [PubMed 32218096]Salas MQ, Mussetti A, Muñóz C, et al. Isavuconazole prophylaxis against invasive fungal infections in allogeneic stem cell transplantation: a single-center experience. Hematol Transfus Cell Ther. 2021:S2531-1379(21)00024-9. doi:10.1016/j.htct.2021.01.002 [PubMed 33583766]Schmitt-Hoffmann A, Roos B, Spickermann J, et al. Effect of mild and moderate liver disease on the pharmaco*kinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557. Antimicrob Agents Chemother. 2009;53(11):4885-4890. doi:10.1128/AAC.00319-09 [PubMed 19667286]Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update. J Clin Oncol. 2018;36(30):3043-3054. doi:10.1200/JCO.18.00374 [PubMed 30179565]Townsend R, Kato K, Hale C, et al. Two phase 1, open-label, mass balance studies to determine the pharmaco*kinetics of 14 C-labeled isavuconazonium sulfate in healthy male volunteers. Clin Pharmacol Drug Dev. 2018;7(2):207-216. doi:10.1002/cpdd.376 [PubMed 28750160]US Department of Health and Human Services (HHS) Panel on Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed May 1, 2020.US Department of Health and Human Services (HHS) Panel on Opportunistic Infections in Adults and Adolescents With HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/whats-new. Updated April 12, 2022. Accessed June 20, 2022.Viljoen J, Azie N, Schmitt-Hoffmann AH, Ghannoum M. A phase 2, randomized, double-blind, multicenter trial to evaluate the safety and efficacy of three dosing regimens of isavuconazole compared with fluconazole in patients with uncomplicated esophageal candidiasis. Antimicrob Agents Chemother. 2015;59(3):1671-1679. doi:10.1128/AAC.04586-14 [PubMed 25561337]Topic 100324 Version 222.0

CloseVancomycin: Drug informationVancomycin: Drug information(For additional information see "Vancomycin: Patient drug information" and see "Vancomycin: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningRisk of embryo-fetal toxicity due to excipients:A formulation of vancomycin injection contains the excipients polyethylene glycol (PEG 400) and N-acetyl D-alanine (NADA), which resulted in fetal malformations in animal reproduction studies at dose exposures approximately 8 and 32 times, respectively, higher than the exposures at the human equivalent dose. If use of vancomycin is needed during the first or second trimester of pregnancy, use other available formulations of vancomycin.Brand Names: USFirvanq;Vancocin;Vancosol Pack [DSC]Brand Names: CanadaJAMP Vancomycin;JAMP-Vancomycin;Vancocin;Vancomycin HClPharmacologic CategoryGlycopeptideDosing: AdultUsual dosage range: Note: Initial IV dosing in nonobese patients should be based on actual body weight; subsequent dosing should generally be adjusted based on therapeutic monitoring. Trough monitoring has traditionally been used for therapeutic monitoring; however, for serious methicillin-resistant S. aureus (MRSA) infections (eg, bacteremia, infective endocarditis, meningitis, osteomyelitis, pneumonia, sepsis), AUC monitoring is preferred (Ref). For patients with uncomplicated skin and soft tissue infections who are not obese and have normal renal function, therapeutic monitoring is generally not needed (Ref). Risk of toxicity (eg, acute kidney injury) increases as a function of trough concentration, especially when trough is maintained above 15 to 20 mg/L; recent data suggest risk increases along the vancomycin AUC continuum, especially when daily AUC exceeds 650 to 1,300 mg•h/L (Ref).Oral: Note: Ineffective for treating systemic infections: 125 to 500 mg 4 times daily.IV: Note: Ineffective for treating C. difficile infections.Intermittent infusion: 15 to 20 mg/kg/dose (rounded to the nearest 250 mg) every 8 to 12 hours initially; for serious MRSA infections (eg, bacteremia, infective endocarditis, meningitis, osteomyelitis, pneumonia, sepsis), adjust based on therapeutic monitoring to achieve a target AUC/minimum inhibitory concentration (MIC) determined by broth microdilution (MICBMD) ratio of 400 to 600 (assuming a vancomycin MICBMD of 1 mg/L; see "Reference Range" for more information). Trough-only monitoring (target trough: 15 to 20 mg/L) is no longer recommended in patients with serious MRSA infections (Ref), but may be needed in nonserious MRSA or non-MRSA infections. Early and frequent monitoring for dosage adjustments is recommended, especially when empiric doses exceed 4 g/day (Ref).Loading dose: Seriously ill patients with documented/suspected MRSA infection: A loading dose of 20 to 35 mg/kg (based on actual body weight; maximum: 3 g/dose) may be considered to rapidly achieve target concentrations. After administration of the loading dose, the initiation of the maintenance dose should occur at the next dosing interval (eg, for a prescribed interval of every 8 hours, initiate the maintenance dose 8 hours after the start of the loading dose) (Ref).Continuous infusion: Note: May be considered for critically ill patients who are unable to achieve AUC target with intermittent infusion dosing. Loading dose: 15 to 20 mg/kg, followed by a maintenance continuous infusion dose of 30 to 40 mg/kg/day (up to 60 mg/kg/day) to achieve a target steady state concentration of 20 to 25 mg/L (Ref).Indication-specific dosing:Bloodstream infectionBloodstream infection:Empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Treat uncomplicated S. aureus infection for ≥14 days from first negative blood culture, with longer courses warranted for endocarditis or metastatic sites of infection (Ref).Empiric therapy or pathogen-specific therapy for methicillin-resistant coagulase-negative staphylococci: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring. Treat uncomplicated bacteremia for 5 to 7 days from day of first negative blood culture, with longer courses warranted for endocarditis or metastatic sites of infection (Ref). For catheter-related bloodstream infections, consider antibiotic lock therapy for catheter salvage, in addition to systemic therapy (Ref).Antibiotic lock technique (catheter-salvage strategy) (off-label use): Note: For infections caused by susceptible organisms when the catheter cannot be removed; use in addition to systemic antibiotics. Catheter salvage is not recommended for S. aureus(Ref).Intracatheter: Prepare lock solution to final concentration of vancomycin 2.5 to 5 mg/mL; may be combined with heparin. Instill into each lumen of the catheter access port using a volume sufficient to fill the catheter (2 to 5 mL) with a dwell time of up to 72 hours, depending on frequency of catheter use. Withdraw lock solution prior to catheter use; replace with fresh vancomycin lock solution after catheter use. Antibiotic lock therapy is given for the same duration as systemic antibiotics (Ref).Cerebrospinal fluid shunt infectionCerebrospinal fluid shunt infection (off-label use): As a component of empiric therapy or pathogen-specific therapy (eg, methicillin-resistant S. aureus or coagulase-negative staphylococci):IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref).Intraventricular (adjunct to systemic therapy; use a preservative-free preparation): 5 to 20 mg/day; some experts recommend adjusting dosage and administration interval based on cerebrospinal fluid (CSF) vancomycin concentrations (goal: 10 to 20 times MIC of causative organism), ventricular size, and daily output from ventricular drain (Ref); data for monitoring are limited (Ref). When intraventricular vancomycin is administered via a ventricular drain, clamp drain for 15 to 60 minutes after administration (allows solution to equilibrate in CSF) (Ref). Note: Intraventricular administration is generally reserved for use in patients who fail parenteral therapy despite removal of CSF shunt or when CSF shunt cannot be removed (Ref).Clostridioides difficile infection, prophylaxisClostridioides difficile infection, prophylaxis (off-label use):Note: For patients with a recent history of C. difficile infection (CDI) who subsequently require systemic antibiotics. Some experts reserve for patients who are older (≥65 years of age) or are significantly immunocompromised who have been hospitalized with severe CDI in the past 3 months (Ref); other experts consider use for any patients with CDI in the prior 12 months (Ref).Oral: 125 mg once daily; continue for 5 to 7 days after completion of systemic antibiotics (Ref).Clostridioides difficile infection, treatmentClostridioides difficile infection, treatment: Note: Criteria for disease severity is based on expert opinion and should not replace clinical judgment. There is no role for vancomycin doses other than 125 mg and 500 mg (Ref).Initial, nonfulminant infection (alternative agent): Oral: 125 mg 4 times daily (Ref). Usual duration is 10 days; if delayed response to treatment, a longer duration (eg, up to 14 days) may be considered (Ref). If antibiotic(s) for a primary infection are essential, some experts extend CDI treatment one week beyond other antibiotic(s) (Ref).Recurrent, nonfulminant infection (alternative agent): Note: Regimen selection depends on prior treatment (Ref).Oral: 125 mg 4 times daily (Ref). Some experts reserve for patients who did not receive vancomycin for the initial episode (Ref). Usual duration is 10 days; if delayed response to treatment, a longer duration (eg, up to 14 days) may be considered (Ref). If antibiotic(s) for a primary infection are essential, some experts extend CDI treatment one week beyond other antibiotic(s) (Ref).Pulsed-tapered regimen: Oral: 125 mg 4 times daily for 10 to 14 days, then 125 mg twice daily for 7 days, then 125 mg once daily for 7 days, then 125 mg every 2 or 3 days for 2 to 8 weeks (Ref).Combination regimen with rifaximin: Note: Rifaximin resistance may be a concern; some experts avoid in patients who have previously received rifamycins, and others do not routinely recommend this regimen (Ref).Oral: 125 mg 4 times daily for 10 days followed by rifaximin (Ref).Fulminant infection (ie, ileus, megacolon, and/or hypotension/shock): Oral or via nasogastric tube: 500 mg 4 times daily with IV metronidazole; if ileus is present, may consider vancomycin retention enema (Ref). Usual duration is 10 days; if delayed response to treatment, a longer duration (eg, up to 14 days) may be considered (Ref). If antibiotic(s) for a primary infection are essential, some experts extend CDI treatment one week beyond other antibiotic(s) (Ref).Fulminant infection with ileus: Rectal retention enema (off-label route): 500 mg in 100 mL NS; retained for as long as possible and replaced every 6 hours. Use in combination with oral vancomycin (if the ileus is partial) or in place of oral vancomycin (if the ileus is complete) plus IV metronidazole (Ref). Note: Optimal regimen not established. Use of rectal vancomycin should be reserved for patients who have not responded to standard therapy and performed by individuals with expertise in administration, as there is risk of colonic perforation. Usual duration is 10 days; if delayed response to treatment, a longer duration (eg, up to 14 days) may be considered. If antibiotic(s) for a primary infection are essential, some experts extend CDI treatment one week beyond other antibiotic(s) (Ref).Cystic fibrosis, acute pulmonary exacerbation, moderate to severeCystic fibrosis, acute pulmonary exacerbation, moderate to severe (off-label use): Empiric or pathogen-directed therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 hours initially; adjust based on therapeutic monitoring (Ref). Duration is usually 10 to 14 days depending on clinical response (Ref).Diabetic foot infection, moderate to severeDiabetic foot infection, moderate to severe (off-label use): Empiric or pathogen-directed therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). Duration (which may include appropriate oral step-down therapy) is usually 2 to 4 weeks in the absence of osteomyelitis (Ref).Endocarditis, treatmentEndocarditis, treatment:Enterococcus (native or prosthetic valve) (penicillin-resistant strains or patients unable to tolerate beta-lactams): IV: 15 mg/kg/dose every 12 hours initially; adjust to obtain a trough concentration of 10 to 20 mg/L (Ref); some experts favor a trough of 15 to 20 mg/L (Ref). Administer in combination with gentamicin for 6 weeks (Ref).S. aureus, methicillin-resistant or methicillin-susceptible (severe-beta lactam hypersensitivity) (alternative agent): IV:Native valve: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Duration of therapy is 6 weeks (Ref).Prosthetic valve: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Duration of therapy is at least 6 weeks (combine with rifampin for the entire duration of therapy and gentamicin for the first 2 weeks) (Ref).Viridans group streptococci and S. bovis (native or prosthetic valve) (penicillin or ceftriaxone intolerance): IV: 15 mg/kg/dose every 12 hours initially; adjust based on therapeutic monitoring. Duration of therapy is 4 weeks (native valve) or 6 weeks (prosthetic valve) (Ref).Endophthalmitis, treatmentEndophthalmitis, treatment (off-label use): Intravitreal: Usual dose: 1 mg per 0.1 mL NS or sterile water injected into vitreum, usually in combination with ceftazidime (Ref). A repeat dose(s) may be considered at 24 to 48 hours based on culture result, severity of the infection, and response to treatment (Ref).Intra-abdominal infection, health care–associatedIntra-abdominal infection, health care–associated (off-label use): Empiric or pathogen-directed therapy for Enterococcus spp. in high-risk patients (eg, postoperative infection or health care–associated infection in patients with prior use of antibiotics that select for Enterococcus, immunocompromising condition, valvular heart disease, or prosthetic intravascular material): IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). Use as part of an appropriate combination regimen (Ref). Total duration of therapy (which may include transition to oral antibiotics) is 4 to 5 days following adequate source control (Ref).Intracranial abscess or spinal epidural abscessIntracranial abscess (brain abscess, intracranial epidural abscess) or spinal epidural abscess (off-label use): As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring. A loading dose may be considered in seriously ill patients (Ref). Duration generally ranges from 4 to 8 weeks for brain abscess and spinal epidural abscess and 6 to 8 weeks for intracranial epidural abscess (Ref).Meningitis, bacterialMeningitis, bacterial (off-label use): As a component of empiric therapy or pathogen-specific therapy (eg, methicillin-resistant S. aureus or penicillin- and cephalosporin-resistant S. pneumoniae): IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref).OsteomyelitisOsteomyelitis:As a component of empiric therapy or pathogen-specific therapy (eg, methicillin-resistant S. aureus): IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially (Ref); adjust based on therapeutic monitoring. A loading dose may be considered in seriously ill patients (Ref). Duration is generally ≥6 weeks; shorter courses are appropriate if the affected bone is completely resected (Ref).Peritonitis, treatmentPeritonitis, treatment (peritoneal dialysis patients) (off-label use): Note: Intraperitoneal administration is preferred to IV administration. Adjust to obtain a trough concentration between 15 and 20 mg/L (Ref). Consider a 25% dose increase in patients with significant residual renal function (urine output >100 mL/day) (Ref).Intermittent (preferred): Intraperitoneal: 15 to 30 mg/kg added to one exchange of dialysate every 5 to 7 days (allow to dwell for ≥6 hours); supplemental doses and more frequent monitoring of serum levels may be needed for patients receiving automated peritoneal dialysis (Ref).Continuous (with every exchange): Intraperitoneal: Loading dose: 30 mg/kg added to first exchange of dialysate; maintenance dose: 1.5 mg/kg/bag for each subsequent exchange of dialysate (Ref).PneumoniaPneumonia, as a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Note: Duration of therapy varies based on disease severity and response to therapy; treatment is typically given for 7 days. When used for empiric therapy, give as part of an appropriate combination regimen (Ref).Prosthetic joint infectionProsthetic joint infection (off-label use): IV:Pathogen-specific therapy for methicillin-resistant or susceptible S. aureus (alternative agent in beta-lactam intolerance): 15 to 20 mg/kg/dose every 8 to 12 hours initially (Ref); adjust based on therapeutic monitoring. A loading dose may be considered in seriously ill patients (Ref). Duration ranges from 2 to 6 weeks depending on prosthesis management, use of rifampin, and other patient-specific factors (Ref).Pathogen-specific therapy for Enterococcus spp (penicillin susceptible [alternative agent] or penicillin resistant): 15 mg/kg/dose every 12 hours initially; adjust based on therapeutic monitoring. Duration: 4 to 6 weeks (Ref). Note: In select cases (eg, debridement and retention of prosthesis or one-stage arthroplasty), give oral suppressive antibiotic therapy with an appropriate regimen following completion of initial treatment (Ref).Sepsis/septic shockSepsis/septic shock: As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours; adjust based on therapeutic monitoring (Ref). A loading dose is recommended; administer within 1 hour of suspected or confirmed sepsis (Ref). Duration is dependent on underlying source and patient response; short courses are preferred, when appropriate (Ref).Septic arthritis, without prosthetic materialSeptic arthritis, without prosthetic material: As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus or coagulase-negative staphylococci: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust dose on therapeutic monitoring. A loading dose may be considered in seriously ill patients (Ref). Total treatment duration is 3 to 4 weeks (in the absence of osteomyelitis), including appropriate oral step-down therapy (Ref); some experts recommend 4 weeks of parenteral therapy for patients with concomitant bacteremia (Ref).Skin and soft tissue infectionSkin and soft tissue infection (hospitalized patient): As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 mg/kg/dose every 12 hours initially (Ref). For patients with uncomplicated skin and soft tissue infections who are not obese and have normal renal function, therapeutic monitoring is generally not needed; for complicated or severe infections, adjust based on therapeutic monitoring (Ref). Note: For empiric therapy of necrotizing infection, must be used in combination with other agents (Ref).Streptococcus, maternal prophylaxis for prevention of neonatal diseaseStreptococcus (group B), maternal prophylaxis for prevention of neonatal disease (alternative agent) (off-label use):IV: 20 mg/kg at the onset of labor or prelabor rupture of membranes, then every 8 hours until delivery; maximum single dose: 2 g (Ref). Some experts prefer vancomycin 2 g initially and then 1 g every 12 hours thereafter until delivery (Ref). Note: Vancomycin is reserved for patients with penicillin allergy at high risk for anaphylaxis that have documented clindamycin-resistant group B Streptococcus or no available susceptibility data (Ref).Surgical prophylaxisSurgical prophylaxis (in combination with other appropriate agents when coverage for methicillin-resistant S. aureus is indicated or for gram-positive coverage in patients unable to tolerate beta-lactams) (off-label use): IV: 15 mg/kg (usual maximum: 2 g/dose initially (Ref)) started within 60 to 120 minutes prior to initial surgical incision. Vancomycin doses may be repeated intraoperatively in 2 half-lives (approximately 8 to 12 hours in patients with normal renal function) if procedure is lengthy or if there is excessive blood loss (Ref). In cases where an extension of prophylaxis is warranted postoperatively, total duration should be ≤24 hours (Ref). Postoperative prophylaxis is not recommended in clean and clean-contaminated surgeries (Ref).Surgical site infectionSurgical site infection: As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 mg/kg/dose every 12 hours initially; adjust based on therapeutic monitoring (Ref).Toxic shock syndrome, staphylococcalToxic shock syndrome, staphylococcal: As a component of empiric therapy or pathogen-specific therapy for methicillin-resistant S. aureus: IV: 15 to 20 mg/kg/dose every 8 to 12 hours initially; adjust based on therapeutic monitoring (Ref). A loading dose may be considered in seriously ill patients (Ref). Duration varies based on underlying etiology; 10 to 14 days of treatment is recommended in the absence of bacteremia or other distinct focus of infection (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Oral: There are no dosage adjustments provided in the manufacturer's labeling. However, dosage adjustment unlikely due to low systemic absorption.IV:Note: Initial IV dosing in nonobese patients should be based on actual body weight; subsequent dosing should generally be adjusted based on therapeutic monitoring. Trough monitoring has traditionally been used for therapeutic monitoring; however, for serious methicillin-resistant S. aureus (MRSA) infections (eg, bacteremia, infective endocarditis, meningitis, osteomyelitis, pneumonia, sepsis), AUC monitoring is preferred (Ref). A ratio of AUC over 24 hours to minimum inhibitory concentration (AUC/MIC) of ≥400 is the primary pharmaco*kinetic/pharmacodynamic predictor of vancomycin efficacy in serious MRSA infections (Ref). Serum concentration monitoring should be conducted within the first 48 hours of therapy for patients with suspected or documented serious infections due to MRSA, with subsequent dosing adjusted to maintain AUC/MIC between 400 to 600 in order to maximize efficacy and minimize risk of vancomycin nephrotoxicity (Ref).Altered kidney function:Intermittent infusion: Note: The following table provides general recommendations (expert opinion derived from ASHP/IDSA/PIDS/SIDP [Rybak 2020]; Golightly 2013). Refer to institution-specific policies and procedures for more detailed guidance.Vancomycin Initial Dose Adjustments in Altered Kidney FunctionCrCl (mL/minute)Suggested loading dose (when applicable)aSuggested initial maintenance doseSuggested dosing intervalaLoading doses recommended in critically ill patients with suspected/documented serious MRSA infections. A loading dose of up to 35 mg/kg may be considered in critically ill patients with sepsis. Obese patients usually require 20 to 25 mg/kg loading doses. Maximum recommended loading dose is 3 g (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).bMonitor vancomycin serum concentrations more frequently, especially early on in therapy, to achieve target concentrations as these patients may have unstable or less predictable drug clearance. Care should be taken not to administer maintenance doses when serum concentrations remain >20 mg/L (Golightly 2013; expert opinion).>90 to <13025 to 30 mg/kg15 to 20 mg/kg8 to 12 hours50 to 9020 to 25 mg/kg15 to 20 mg/kg12 hours15 to <5020 to 25 mg/kg10 to 15 mg/kg24 hours<15b20 to 25 mg/kg10 to 15 mg/kg48 to 72 hoursContinuous infusion: Loading dose: Administer an appropriate loading dose (eg, 15 to 20 mg/kg) (Ref); higher loading doses may be considered in critically ill patients with sepsis (Ref); also refer to institution-specific policies and procedures.Maintenance dose: Various protocols have been developed (Ref); recommendations may vary based on the population studied. The following is an example protocol (Ref), and doses should be adjusted to achieve a target steady state concentration of 20 to 25 mg/L (Ref); also refer to institution-specific policies and procedures.CrCl >80 to 119 mL/minute: 30 mg/kg administered over 24 hours.CrCl >50 to 80 mL/minute: 25 mg/kg administered over 24 hours.CrCl 25 to 50 mL/minute:14 mg/kg administered over 24 hours.CrCl <25 mL/minute: 7 mg/kg administered over 24 hours.Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post-trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).Intermittent infusion: Loading dose (when applicable): 25 to 35 mg/kg (Ref) followed by 15 to 20 mg/kg every 8 hours depending on degree of augmented kidney function; some patients may require more frequent dosing (eg, 15 mg/kg every 6 hours) to attain target concentrations (Ref); utilize frequent serum concentration monitoring.Continuous infusion:Loading dose: Administer an appropriate loading dose (eg, 15 to 20 mg/kg) (Ref); higher loading doses (eg, 25 mg/kg) have been used in some protocols and may vary based on population studied (Ref); also refer to institution-specific policies and procedures.Maintenance dose: 40 to 60 mg/kg/day depending on degree of augmented kidney function with frequent serum concentration monitoring; adjust to achieve a target steady state concentration of 20 to 25 mg/L (Ref).Hemodialysis, intermittent (thrice weekly): Dialyzable (25% to 40% depending on dialyzer permeability) (Ref).Vancomycin Dosing Depending on Dose Timing and Dialyzer PermeabilityaDose timing and dialyzer permeabilityVancomycin dosebaASHP/IDSA/PIDS/SIDP [Rybak 2020]bInitial recommended loading/maintenance doses. The optimal pharmaco*kinetic/pharmacodynamic target in this population is unknown, but targeting predialysis concentrations of 15 to 20 mg/L are likely to achieve AUCs of 400 to 600 mg•hour/L (ASHP/IDSA/PIDS/SIDP [Rybak 2020]; Crew 2015). Predialysis serum concentrations should be obtained no less than weekly and should determine subsequent dosing (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).cThrice-weekly dose administration. Typically, patients may require ~25% larger doses for the 3-day interdialytic period (eg, Friday to Monday) to maintain sufficient vancomycin exposure on the third day.Dose given after dialysis endsLow permeability (low flux)Loading dose: 25 mg/kgMaintenance dose: 7.5 mg/kgcHigh permeability (high flux)Loading dose: 25 mg/kgMaintenance dose: 10 mg/kgcDose given during last hours of dialysis (intradialytic)Low permeability (low flux)Loading dose: 30 mg/kgMaintenance dose: 7.5 to 10 mg/kgcHigh permeability (high flux)Loading dose: 35 mg/kgMaintenance dose: 10 to 15 mg/kgcPeritoneal dialysis:Loading dose: 20 to 25 mg/kg (Ref). A vancomycin serum concentration should be obtained ~48 to 72 hours after the loading dose, and subsequent doses (usually 10 to 15 mg/kg) should be administered based on attainment of goal serum concentrations (Ref). Doses may vary based on infection site and severity, as well as the presence or absence of residual renal function. Some experts use maintenance doses of up to 20 mg/kg/dose (Ref).CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Close monitoring of response and adverse reactions due to drug accumulation is important.Loading dose: 20 to 25 mg/kg followed by 7.5 to 10 mg/kg every 12 hours with more frequent serum concentration monitoring (Ref). In patients with suspected or confirmed serious MRSA infections, dose adjustments should be made based on AUC monitoring occurring in the first 24 to 48 hours of therapy (Ref).PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Close monitoring of response and adverse reactions due to drug accumulation is important.Loading dose (administer even if PIRRT is occurring): 20 to 25 mg/kg, followed by 15 mg/kg after each PIRRT session ends (or during the final 60 to 90 minutes of the session) with more frequent serum concentration monitoring (Ref). In patients with suspected or confirmed serious MRSA infections, dose adjustments should be made based on AUC monitoring occurring in the first 24 to 48 hours of therapy (Ref).Dosing: Hepatic Impairment: AdultOral: There are no dosage adjustments provided in the manufacturer’s labeling. However, dosage adjustment unlikely due to low systemic absorption.IV:There are no dosage adjustments provided in the manufacturer’s labeling. However, degrees of hepatic dysfunction do not affect the pharmaco*kinetics of vancomycin (Ref).Dosing: Pediatric(For additional information see "Vancomycin: Pediatric drug information")Note: For IV dosing, initial dosage recommendations for patients with normal kidney function presented; doses should be adjusted based on serum concentration monitoring; doses require adjustment in renal impairment. Consider single-dose administration with serum concentration monitoring rather than scheduled dosing in patients with urine output <1 mL/kg/hour or if serum creatinine significantly increases from baseline. Dosing presented in mg/kg/dose and mg/kg/day; routes of administration may vary (eg, IV, oral, intrathecal, intracatheter, intraperitoneal, rectal); use caution.Optimal dose and frequency not established in patients receiving extracorporeal membrane oxygenation (ECMO); available data are limited (Ref). Patient-specific considerations (eg, reason for ECMO) and variability with ECMO procedure itself make extrapolation of pharmaco*kinetic data and dosing to all patients receiving ECMO difficult; closely monitor serum concentrations and determine individual dosing needs in these patients.General dosing, susceptible infection: Infants, Children, and Adolescents: IV: Initial: 45 to 60 mg/kg/day divided every 6 to 8 hours; dose and frequency should be individualized based on serum concentrations (Ref). Note: Based on adult data, an AUC24 target of 400 mg•hour/L is recommended in patients with serious methicillin-resistant S. aureus (MRSA) infections; specific dosing recommendations may be higher when targeting this range (Ref). See "MRSA infection, serious; treatment".In general, monitoring of serum concentrations and assurance of adequate hydration status is recommended; utilize local antibiogram and protocols for further guidance.Antibiotic lock therapy; catheter salvageAntibiotic lock therapy; catheter salvage: Limited data available: Optimal dose not established:Note: For infections caused by susceptible organisms when the vascular catheter cannot be removed; use in addition to systemic antibiotics. Catheter salvage not effective in all cases; removal of catheter is recommended for infections with S. aureus (Ref). Dosing regimens variable; consider age and size of patient and catheter size (including number of lumens) when determining dose due to potential for lock to be delivered intravenously.Infants, Children, and Adolescents: Intracatheter: Usual concentrations of lock solution: 2 to 5 mg/mL of vancomycin with or without heparin additive; most common concentrations reported: vancomycin 2 mg/mL, 2.5 mg/mL, or 5 mg/mL; refer to institutional protocol if available (Ref). Concentrations described in literature range from 0.025 to 10 mg/mL with or without heparin or citrate (Ref); a vancomycin concentration of 5 mg/mL has been shown to be more efficacious than 1 mg/mL when biofilm present (Ref). Instill into each lumen of the catheter access port using a volume sufficient to fill the catheter, with a dwell time of ideally ≥8 to 12 hours and up to 72 hours, depending on frequency of catheter use. Withdraw lock solution prior to catheter use; replace with fresh vancomycin lock solution after catheter use. Antibiotic lock therapy is given for the same duration as systemic antibiotics (Ref). Note: If heparin is utilized in the lock solution, the dose used should not approach therapeutic unit/kg dose.C. difficile infection; treatmentC. difficile infection; treatment:Manufacturer's labeling: Infants, Children, and Adolescents: Oral: 40 mg/kg/day divided every 6 to 8 hours for 7 to 10 days; maximum daily dose: 2,000 mg/day.Guideline recommendations:Non-severe infection, initial or first recurrence: Children and Adolescents: Oral: 10 mg/kg/dose 4 times daily for 10 days; maximum dose: 125 mg/dose (Ref).Severe/fulminant infection, initial: Children and Adolescents:Oral: 10 mg/kg/dose 4 times daily for 10 days; maximum dose: 500 mg/dose; may consider adding IV metronidazole in critically ill patients (Ref). If patient is unable to tolerate oral therapy, may use nasogastric administration (Ref).Rectal: Note: Consider use when ileus is present. Limited data available: Rectal enema: 500 mg in 100 mL NS; dose volume is determined by age (Ref); the optimal doses have not been established in pediatric patients; suggested volumes for children: 1 to 3 years: 50 mL; 4 to 9 years: 75 mL; >10 years: 100 mL (Ref); administer 4 times daily with or without IV metronidazole (Ref).Second or subsequent recurrence: Children and Adolescents: Pulsed-tapered regimen: Oral: 10 mg/kg/dose 4 times daily for 10 to 14 days; then 10 mg/kg/dose twice daily for 7 days, then 10 mg/kg/dose once daily for 7 days, then 10 mg/kg/dose every 2 or 3 days for 2 to 8 weeks; maximum dose: 125 mg/dose (Ref).Endocarditis, treatmentEndocarditis, treatment: Note: Dosage adjustment to target trough serum concentrations of 10 to 15 mg/L is recommended in pediatric endocarditis by the AHA (Ref). Dosage adjustment to target AUC24 of 400 mg•hour/L has been recommended in the treatment of proven or suspected MRSA infections based on adult data (Ref).Empiric therapy/culture negative: Children and Adolescents: IV: Initial: 60 mg/kg/day divided every 6 hours; initial maximum daily dose: 2,000 mg/day; use in combination with other antibiotics for at least 4 to 6 weeks; longer duration may be required if prosthetic material is present or in cases of recurrent endocarditis (Ref).Streptococcus (including enterococcus): Children and Adolescents: IV: Initial: 40 mg/kg/day divided every 8 to 12 hours; initial maximum daily dose: 2,000 mg/day; treat for at least 4 to 6 weeks; a longer duration and additional antibiotics may be required depending on organism and presence of prosthetic material (Ref).S. aureus:Non-methicillin resistant: Children and Adolescents: IV: Initial: 40 mg/kg/day divided every 8 to 12 hours; initial maximum daily dose: 2,000 mg/day; treat for at least 4 to 6 weeks; a longer duration and additional antibiotics may be required depending on organism and presence of prosthetic material (Ref).Methicillin-resistant: Children and Adolescents: IV: Initial: 40 mg/kg/day divided every 8 to 12 hours for at least 6 weeks; usual initial maximum daily dose: 2,000 mg/day (Ref); however, higher initial doses have been recommended for patients with serious MRSA infection with normal renal function, though dosing based on studies and models that were not specific to endocarditis (Ref). See "MRSA infection, serious; treatment".EnterocolitisEnterocolitis (S. aureus): Infants, Children, and Adolescents: Oral: 40 mg/kg/day divided every 6 to 8 hours for 7 to 10 days; maximum daily dose: 2,000 mg/day.Meningitis, including health care-associated meningitisMeningitis, including health care-associated meningitis: Infants, Children, and Adolescents: IV: Initial: 15 mg/kg/dose every 6 hours (Ref). Higher initial doses have been recommended for patients with serious MRSA infection with normal renal function, though dosing based on studies and models that were not specific to meningitis (Ref). See "MRSA infection, serious; treatment".MRSA infection, serious; treatmentMRSA infection, serious; treatment: Note: Doses should be adjusted based on patient-specific serum concentrations to a target AUC24 of 400 mg•hour/L, but potentially up to 600 mg•hour/L, based on adult data. In pediatric patients, an AUC24 of ≥400 mg•hour/L has been associated with trough concentrations of 7 to 10 mg/L, though trough concentrations do not clearly predict AUC on an individual level and trough-only monitoring is not recommended (Ref). Some studies have indicated that doses on the lower end of the range (ie, 60 mg/kg/day divided every 6 hours) will achieve target AUC24 in most children (Ref). To minimize risk of acute kidney injury, maintain AUC24 <800 mg•hour/L and trough <15 mg/L. For obese patients, start with a one-time loading dose of 20 mg/kg (based on total body weight), then start maintenance dosing (Ref).Infants ≥3 months and Children <12 years: IV: Initial: 60 to 80 mg/kg/day in divided doses every 6 hours; initial maximum daily dose: 3,600 mg/day.Children ≥12 years and Adolescents: IV: Initial: 60 to 70 mg/kg/day in divided doses every 6 to 8 hours; initial maximum daily dose: 3,600 mg/day.PeritonitisPeritonitis (peritoneal dialysis) (Ref): Limited data available:Prophylaxis: Infants, Children, and Adolescents:Touch contamination of PD line (if known MRSA colonization): Intraperitoneal: 25 mg per liter.High-risk gastrointestinal procedures: Note: Use should be reserved for patients at high risk for MRSA: IV: 10 mg/kg administered 60 to 90 minutes before procedure; maximum dose: 1,000 mg.Treatment: Infants, Children, and Adolescents:Intermittent: Intraperitoneal: Initial dose: 30 mg/kg in the long dwell; subsequent doses: 15 mg/kg/dose every 3 to 5 days during the long dwell; Note: Increased clearance may occur in patients with residual renal function; subsequent doses should be based on serum concentration obtained 2 to 4 days after the previous dose; redosing should occur when serum concentration <15 mcg/mL.Continuous: Intraperitoneal: Loading dose: 1,000 mg per liter of dialysate; maintenance dose: 25 mg per liter.Pneumonia, community-acquiredPneumonia, community-acquired: Infants >3 months, Children, and Adolescents: IV: Initial: 40 to 60 mg/kg/day in divided doses every 6 to 8 hours; (Ref). Note: Higher doses may be necessary when treating MRSA infections; doses should be adjusted based on patient-specific serum concentrations to a target AUC24 of 400 mg•hour/L (Ref). See "MRSA infection, serious; treatment".Skin and skin structure infections, complicatedSkin and skin structure infections, complicated: Note: Duration of treatment should be individualized and is dependent on severity of infection, adequacy of source control, and clinical improvement. For necrotizing fasciitis, continue treatment until further debridement is not necessary, patient has clinically improved, and patient is afebrile for 48 to 72 hours.Necrotizing infections, mixed (non-MRSA): Infants, Children, and Adolescents: IV: Initial: 10 to 13 mg/kg/dose every 8 hours (Ref).Serious MRSA infection, including necrotizing infection and pyomyositis: Note: Dosage adjustment to target AUC24 of 400 mg•hour/L recommended for serious MRSA infections based on adult data. A loading dose of 20 mg/kg (based on total body weight) is recommended in obese patients (Ref).Infants ≥3 months and Children <12 years: IV: Initial: 60 mg/kg/day in divided doses every 6 hours; maximum daily dose: 3,600 mg/day (Ref). Based on pharmaco*kinetic modeling studies, doses up to 80 mg/kg/day may be necessary to achieve target AUC24 (Ref).Children ≥12 years and Adolescents: IV: Initial: 60 mg/kg/day in divided doses every 6 to 8 hours; maximum daily dose: 3,600 mg/day (Ref). Based on pharmaco*kinetic modeling studies, doses up to 70 mg/kg/day may be necessary to achieve target AUC24 (Ref).Surgical prophylaxisSurgical (perioperative) prophylaxis: Infants, Children, and Adolescents: IV: 15 mg/kg/dose within 120 minutes prior to surgical incision. May be administered in combination with other antibiotics depending upon the surgical procedure (Ref).VentriculitisVentriculitis (including health care-associated ventriculitis and cerebrospinal fluid [CSF] shunt infections):Infants, Children, and Adolescents: Limited data available: Intraventricular or intrathecal: Use a preservative-free preparation: 5 to 20 mg/day; usual dose: 10 or 20 mg/day (Ref); due to the smaller CSF volume in infants, some guidelines recommend decreasing the infant dose; adult dosage recommendations are based on ventricle size (Ref).Continuous infusion dosing: Limited data available; optimal dosing unknown:Infants, Children, and Adolescents: IV: Loading dose: 10 to 15 mg/kg/dose administered over 1 to 2 hours, followed by maintenance infusion of 40 to 60 mg/kg/day; adjust dose to achieve target serum concentration (Ref). Note: Required dose to achieve target concentration varies significantly between patients and depending on age, renal function, and target concentration; total daily doses of 30 to 110 mg/kg/day have been reported (Ref). Pediatric patients with cancer or who are critically ill may require higher doses to achieve target concentrations (Ref). Note: When transitioning from intermittent to continuous infusion, an initial loading dose may not be required; the total daily dose will likely need reduced depending on patient-specific factors, concentrations achieved during intermittent dosing, and clinical considerations (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricOral: There are no dosage adjustments provided in manufacturer's labeling; however, dosage adjustment unlikely due to low systemic absorption.IV: Note: Vancomycin levels should be monitored in patients with any renal impairment:Infants, Children, and Adolescents: The following adjustments have been recommended (Ref): Note: Renally-adjusted dose recommendations are based on intravenous doses of 10 mg/kg/dose every 6 hours or 15 mg/kg/dose every 8 hours.GFR 30 to 50 mL/minute/1.73 m2: 10 mg/kg/dose every 12 hours.GFR 10 to 29 mL/minute/1.73 m2: 10 mg/kg/dose every 18 to 24 hours.GFR <10 mL/minute/1.73 m2: 10 mg/kg/dose; redose based on serum concentrations.Intermittent hemodialysis: 10 mg/kg/dose; redose based on serum concentrations.Peritoneal dialysis (PD): 10 mg/kg/dose; redose based on serum concentrations.Continuous renal replacement therapy (CRRT): 10 mg/kg/dose every 12 to 24 hours; monitor serum concentrations.Dosing: Hepatic Impairment: PediatricOral: There are no dosage adjustments provided in the manufacturer's labeling; however, dosage adjustment unlikely needed due to low systemic absorption.IV: There are no dosage adjustments provided in the manufacturer's labeling; however, degrees of hepatic dysfunction do not affect the pharmaco*kinetics of vancomycin (Ref).Dosing: Older AdultRefer to adult dosing.Dosing: Obesity: AdultThe recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.Example of dosing regimen:Class 1, 2, or 3 obesity (BMI ≥30 kg/m2):Loading dose: Note: Consider utilizing a loading dose when rapid attainment of target concentrations is necessary (eg, sepsis, documented/suspected methicillin-resistant S. aureus infection) (Ref).Initial: IV: 20 to 25 mg/kg using actual body weight; maximum loading dose: 3 g. After administration of the loading dose, initiate maintenance dose at the next dosing interval (Ref). In critically ill patients, may consider loading doses of 20 to 35 mg/kg using actual body weight; maximum loading dose: 3 g (Ref).Maintenance dose: IV: Use actual body weight and the following clearance (CL) equations to calculate a maintenance dose; empiric maintenance doses >4.5 g/day are unlikely to be necessary (Ref). Note: If vancomycin therapy is continued, individualize vancomycin dose using early Bayesian approach (ie, 2 serum concentrations within first 24 to 48 hours) to achieve target AUC (Ref).1. Calculate estimated vancomycin CL (Ref).Estimate CL (L/hour): 9.656 – [0.078 × age] – [2.009 × SCr] + [0.04 × actual body weight0.75] + [1.09 × sex].Where adult age is in years; SCr is serum creatinine in mg/dL; actual body weight in kg scaled to an exponent of 0.75; and sex is 1 if male and 0 if female.2. Calculate empiric vancomycin maintenance regimen (Ref).Estimate daily dose (rounded to nearest 250 mg): Estimated CL (L/hour) × 500 mg•hour/L.Where 500 mg•hour/L is the mid-range AUC target selected for a minimum inhibitory concentration (MIC) of 1 mg/L. When the vancomycin CL is estimated to be ≤3 L/hour, administer the dose every 24 hours or divide the daily dose every 12 hours. If CL is estimated to be >3 L/hour, divide the daily dose and administer every 6 to 12 hours (Ref).Rationale for recommendations:Vancomycin is a hydrophilic antimicrobial with a low to medium Vd and CL that is proportional to glomerular filtration rate. Vancomycin Vd correlates with actual body weight but does not increase proportionately with increasing body size (Ref) and has been reported to be lower in patients with obesity compared to individuals who are not obese (0.3 to 0.5 L/kg vs 0.68 L/kg) (Ref). Because vancomycin loading doses are dependent on Vd, lower loading doses are generally needed in patients with obesity and the dose can be capped once a threshold dose is reached (Ref). Vancomycin CL can be estimated by variables used to estimate kidney function. Estimated vancomycin CL in patients with obesity is ~6 L/hour and rarely exceeds 9 L/hour. The empiric maintenance daily dose can be calculated by an estimate of CL and the AUC/MIC target of 400 to 600 (Ref). Using a targeted AUC approach may reduce the total daily dose (TDD) of vancomycin versus a target trough concentration; lower TDD may reduce the risk of acute kidney injury (Ref). Optimal dosing and monitoring regimens are uncertain; refer to institutional protocol.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productCapsule, Oral, as hydrochloride: Vancocin: 125 mg, 250 mg [contains fd&c blue #2 (indigotine)]Generic: 125 mg, 250 mgKit, Intravenous, as hydrochloride: Vancosol Pack: 1 g/100 mL in NaCl 0.9% [DSC]Solution, Intravenous, as hydrochloride: Generic: 750 mg/150 mL (150 mL); 1000 mg/200 mL (200 mL); 1250 mg/250 mL (250 mL); 1500 mg/300 mL (300 mL); 1750 mg/350 mL (350 mL)Solution, Intravenous, as hydrochloride [preservative free]: Generic: 500 mg/100 mL (100 mL); 2000 mg/400 mL (400 mL); 1 g/200 mL in Dextrose 5% (200 mL); 1 g/200 mL in NaCl 0.9% (200 mL); 500 mg/100 mL in Dextrose 5% (100 mL); 750 mg/150 mL in Dextrose 5% (150 mL)Solution Reconstituted, Intravenous [preservative free]: Generic: 1.25 g (1 ea)Solution Reconstituted, Intravenous, as hydrochloride: Generic: 500 mg (1 ea); 1 g (1 ea); 1.5 g (1 ea); 10 g (1 ea)Solution Reconstituted, Intravenous, as hydrochloride [preservative free]: Generic: 250 mg (1 ea [DSC]); 500 mg (1 ea); 750 mg (1 ea); 1 g (1 ea); 1.5 g (1 ea); 5 g (1 ea); 10 g (1 ea); 100 g (1 ea)Solution Reconstituted, Oral, as hydrochloride: Firvanq: 25 mg/mL (150 mL, 300 mL); 50 mg/mL (150 mL, 300 mL) [contains fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10), sodium benzoate; grape flavor]Firvanq: 50 mg/mL (150 mL, 300 mL) [contains fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10), sodium benzoate; white grape flavor]Generic: 250 mg/5 mL (80 mL, 150 mL, 300 mL)Generic Equivalent Available: USYesDosage Forms ConsiderationsFirst-Vancomycin oral solution is a compounding kit. Refer to manufacturer’s labeling for compounding instructions.Dosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral, as hydrochloride: Vancocin: 125 mg, 250 mg [contains fd&c blue #2 (indigotine)]Generic: 125 mg, 250 mgSolution, Intravenous, as hydrochloride: Generic: 1 g/200 mL in NaCl 0.9% (200 mL)Solution Reconstituted, Intravenous, as hydrochloride: Generic: 500 mg (1 ea, 10 mL); 1000 mg (1 ea); 1 g (1 ea, 20 mL, 30 mL); 5 g (1 ea); 10 g (1 ea)Administration: AdultIntravenous: Administer vancomycin with a final concentration not to exceed 5 mg/mL by IV intermittent infusion over at least 60 minutes (recommended infusion period of ≥30 minutes for every 500 mg administered (Ref)); in adult patients in need of fluid restriction, a concentration up to 10 mg/mL may be used, but risk of infusion-related reactions is increased. Not for IM administration.If a maculopapular rash appears on the face, neck, trunk, and/or upper extremities (vancomycin infusion reaction [formerly “red man syndrome”]), slow the infusion rate to over 11/2 to 2 hours and increase the dilution volume (Ref). Hypotension, shock, and cardiac arrest (rare) have also been reported with too rapid of infusion. Administration of antihistamines prior to infusion may prevent or minimize this reaction (Ref).Irritant; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Information conflicts regarding the use of dry cold or dry warm compresses (Ref); however, dry warm compresses may be of benefit in increasing local blood flow to enhance drug removal from the extravasation site. Intradermal hyaluronidase may be considered for refractory cases (Ref).Hyaluronidase: Intradermal: Inject a total of 1 mL (15 units/mL) as 5 separate 0.2 mL injections (using a tuberculin syringe) along injection site and edematous area (Ref).Antibiotic lock technique (off-label use): Instill prepared vancomycin lock solution into each lumen of the catheter access port using a volume sufficient to fill the catheter (2 to 5 mL) with a dwell time of 48 to 72 hours (dependent on frequency of catheter use). Withdraw lock solution prior to catheter use; replace with fresh vancomycin lock solution after catheter use (Ref).Intraventricular (off-label route): Use preservative-free preparations only. May be administered intraventricularly with a final concentration of 2.5 to 10 mg/mL for the treatment of CSF shunt infections. When administered through a ventricular drain, clamp drain for 15 to 60 minutes before opening the drain to allow vancomycin solution to equilibrate in the CSF (Ref).Intravitreal (off-label route): May administer vancomycin intravitreally with a final concentration of 1 mg/0.1 mL NS or sterile water (Ref).Oral:Solution (Firvanq): Shake reconstituted oral solution well before each use.Injection: Reconstituted powder for injection (not premixed solution) may be diluted and used for oral administration; common flavoring syrups may be added to improve taste. The unflavored, diluted solution may also be administered via nasogastric tube.Rectal (off-label route): May be administered as a retention enema per rectum (Ref); 500 mg in 100 to 500 mL of NS, volume may depend on length of segment being treated. If sodium chloride causes hyperchloremia could use solution with lower chloride concentration (eg, LR) (Ref).Administration: PediatricOral:Oral solution (Firvanq): Shake reconstituted oral solution well before each use.Powder for injection: Reconstituted powder for injection (not premixed solution) may be diluted and used for oral administration; common flavoring syrups may be added to improve taste. The unflavored, diluted solution may also be administered via nasogastric tube.Parenteral:IV:Intermittent: Administer intermittent IV infusion over 60 minutes. Vancomycin infusion reaction (formerly "red man syndrome") may occur if the infusion is too rapid. It is not an allergic reaction, but may be characterized by hypotension and/or a maculopapular rash appearing on the face, neck, trunk, and/or upper extremities; if this should occur, slow the infusion rate to administer dose over 90 to 120 minutes (Ref) and increase the dilution volume; the reaction usually dissipates in 30 to 60 minutes; administration of antihistamines just before the infusion may also prevent or minimize this reaction.Continuous: After loading dose, administer over 24 hours (Ref).Irritant; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation. If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity. Information varies regarding the use of dry cold or dry warm compresses (Ref); however, dry warm compresses may be of benefit in increasing local blood flow to enhance drug removal from the extravasation site. Intradermal hyaluronidase may be considered for refractory cases (Ref).Intrathecal/Intraventricular: Use preservative-free preparations only. Administer as diluted solution (1 to 10 mg/mL) over 1 to 2 minutes (Ref). When administered through a ventricular drain, clamp drain for 15 to 60 minutes to allow vancomycin solution to equilibrate in the cerebrospinal fluid (CSF) (Ref).Intracatheter (vascular); antibiotic lock technique: Instill prepared vancomycin lock solution into each lumen of the catheter access port using a volume sufficient to fill the catheter with a dwell time of ≥8 to 12 hours and up to 72 hours (dependent on frequency of catheter use). Withdraw lock solution prior to catheter use; replace with fresh vancomycin lock solution after catheter use (Ref).Rectal: Instill vancomycin enema solution via rectal foley; retain for 1 hour. In pediatric patients the optimal doses have not been established; suggested volumes for pediatric patients: 1 to 3 years of age: 50 mL; 4 to 9 years of age: 75 mL; >10 years of age: 100 mL (Ref).Use: Labeled IndicationsClostridioides difficile infection, treatment (oral): Treatment of C. difficile infection (CDI) in adults and pediatric patients <18 years of age.Endocarditis (injection):Corynebacteria (diphtheroids): Treatment of diphtheroid endocarditis in combination with either rifampin, an aminoglycoside, or both in early-onset prosthetic valve endocarditis caused by diphtheroids.Enterococcal: Treatment of endocarditis caused by enterococci (eg, Enterococcus faecalis), in combination with an aminoglycoside.Staphylococcal: Treatment of staphylococcal endocarditis.Streptococcal: Treatment of endocarditis due to Streptococcus viridans or Streptococcus bovis, as monotherapy or in combination with an aminoglycoside.Enterocolitis (oral): Treatment of enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) in adults and pediatric patients <18 years of age. Note: Staphylococcal enterocolitis is uncommon; the disease and treatment are not well described in the literature (Iwata 2014; Lin 2010).Staphylococcal infections (injection): Treatment of serious or severe infections (eg, bloodstream infections, bone infections, lower respiratory tract infections, skin and skin structure infections) caused by susceptible strains of methicillin-resistant (beta-lactam-resistant) staphylococci; empiric therapy of infections when methicillin-resistant staphylococci are suspected.Use: Off-Label: AdultCatheter-related bloodstream infection, antibiotic lock technique (catheter-salvage therapy); Cerebrospinal fluid shunt infection; Clostridioides difficile infection, prophylaxis; Clostridioides difficile infection, treatment (rectal administration); Cystic fibrosis, acute pulmonary exacerbation; Diabetic foot infection, moderate to severe; Endophthalmitis, treatment; Intra-abdominal infection, health care–associated; Intracranial abscess (brain abscess, intracranial epidural abscess) or spinal epidural abscess; Meningitis, bacterial; Peritonitis, treatment (peritoneal dialysis patients); Prosthetic joint infection; Streptococcus (group B), maternal prophylaxis for prevention of neonatal disease; Surgical prophylaxisMedication Safety IssuesSound-alike/look-alike issues: IV vancomycin may be confused with INVanzVancomycin may be confused with clindamycin, gentamicin, tobramycin, valACYclovir, vecuronium, VibramycinHigh alert medication:The Institute for Safe Medication Practices (ISMP) includes this medication (intrathecal administration) among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.Adverse Reactions (Significant): ConsiderationsAnaphylaxisVancomycin may rarely cause life-threatening immune-mediated anaphylaxis, which may present as generalized and extensive pruritus and/or erythema of skin, respiratory distress, bronchospasm, hypoxia, and hypotension. Clinical presentation is similar to vancomycin infusion reaction (a nonimmune-mediated anaphylactoid infusion-related reaction; formerly called “red man syndrome”), making it difficult for clinicians to distinguish between the 2 reactions (Ref).Mechanism: Non-dose-related; immunologic; IgE-mediated with specific antibodies formed against a drug allergen following initial exposure (immunologically mediated) or result in direct mast cell stimulation (Ref). IgE binding and cross-linking of the high affinity IgE receptor (FcεRI) on the surface of mast cells causes release of histamine and other mediators that can result in urticaria, flushing, airway obstruction, hypotension, and tachycardia (Ref).Onset: Rapid; IgE-mediated reactions generally occur within 1 hour of administration but may occur up to 6 hours after exposure (Ref). In a systematic review analyzing 7 case reports of vancomycin-induced anaphylaxis, the median time to onset of signs/symptoms was 2 minutes (range: 1 to 35 minutes) (Ref).Risk factors:• Previous exposure to vancomycin (necessary for IgE-mediated anaphylaxis) (Ref)Clostridioides difficile infectionAlthough oral vancomycin is used for the treatment of Clostridioides difficile infection (CDI), Clostridioides difficile-associated diarrhea and Clostridioides difficile colitis have been reported with intravenous vancomycin (Ref). Clinical symptoms range from mild diarrhea to life-threatening colitis, toxic megacolon, and sepsis. In patients with severe CDI, frequent symptoms include watery diarrhea, abdominal pain, fever, nausea, anorexia, and malaise (Ref).Mechanism: Non-dose-related; antibiotics disrupt the indigenous gut microbiota which promotes C. difficile spore germination, growth, and toxin production, leading to epithelial damage and colitis (Ref).Onset: Varied; may start on the first day of antibiotic therapy or up to 3 months postantibiotic (Ref).Risk factors:• Antibiotic exposure (highest risk factor); antibiotics most frequently associated with C. difficile include clindamycin, fluoroquinolones, and third-/fourth-generation cephalosporins (Ref)• Long durations in a hospital or other health care setting (recent or current) (Ref)• Advanced age (Ref)• Immunocompromised conditions or a serious underlying condition (Ref)• GI surgery/manipulation (Ref)• Antiulcer medications, such as proton pump inhibitors and H2 blockers (suggested risk factors) (Ref)• Chemotherapy (suggested risk factor) (Ref)Drug-induced immune thrombocytopeniaDrug-induced immune thrombocytopenia (DITP) has been associated with use. Vancomycin-induced ITP has been associated with severe bleeding characterized by petechial hemorrhages, ecchymoses, and oozing from the buccal mucosa. Rarely, acutely-ill patients have experienced gross hematuria, lower GI hemorrhage, intrapulmonary hemorrhage, and excessive bleeding from venipuncture sites (Ref).Mechanism: Non-dose-related; immunologic; platelet-reactive antibodies of the IgG class, the IgM class, or both, have been detected in patients with thrombocytopenia while receiving vancomycin. These antibodies reacted with platelets only in the presence of vancomycin, suggesting that the mechanism is similar to quinine-induced thrombocytopenia rather than a hapten-specific antibody (Ref).Onset: Varied; DITP; typically occurs within 1 to 2 weeks after initiating therapy or longer in patients with intermittent exposure (Ref). In case reports, the mean time to platelet nadir count was ~8 days following first exposure. However, there are rare case reports describing a rapid onset (within 24 hours) of acute severe thrombocytopenia, primarily in settings of reexposure to vancomycin (Ref).Hypersensitivity reactions (delayed)Maculopapular rash and severe cutaneous adverse reactions (SCARs), including drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrosis (TEN), Stevens-Johnson syndrome (SJS), and acute generalized exanthematous pustulosis (AGEP), have occurred rarely with use and may be life-threatening (Ref). In addition, vancomycin-induced dermatologic disorder (linear IgA bullous dermatosis [LABD]) has been reported rarely and clinical presentation may mimic TEN, making it difficult to distinguish (Ref). Other reactions include erythema multiforme, exfoliative dermatitis, and hypersensitivity angiitis (Ref).Mechanism: Non-dose-related; immunologic. Delayed hypersensitivity reactions are mediated by T-cells or antibodies other than IgE (eg, IgG-mediated, such as some cytopenias) (Ref). SCARs are delayed type IV hypersensitivity reactions involving a T-cell mediated drug-specific immune response (Ref). The mechanism behind vancomycin-induced LABD is unknown; LABD is a rare immune-mediated blistering disorder resulting in linear deposition of IgA at the basem*nt membrane zone (Ref).Onset: Delayed; type IV reactions are delayed hypersensitivity reactions that typically occur days to weeks after drug exposure but may occur more rapidly (usually within 1 to 4 days) upon reexposure (Ref). DRESS usually does not develop until after 2 weeks of administration (Ref). In a systematic case review, a median onset of 9 days and 21 days was observed for SJS/TEN and DRESS, respectively (Ref). In vancomycin-induced LABD, lesions typically appear 1 to 15 days after the first vancomycin dose (Ref); a median latency of 7 days was observed in a systematic review (Ref).Risk factors:• Patients with end-stage renal disease (suggested risk factor) (Ref)• In DRESS, a strong association was observed for patients with the HLA-A*32:01 allele in a study involving predominantly European ancestry (Ref)• Cross-reactivity with teicoplanin (Ref)NephrotoxicitySystemic exposure is associated with nephrotoxicity (usually reversible), which may result in acute kidney injury (or acute renal failure), predominantly occurring in patients with multiple risk factors (Ref). Cases of systemic absorption and nephrotoxicity with oral vancomycin have been reported (Ref).Mechanism: Non-dose-related; most commonly attributed to acute tubular necrosis (or renal tubular necrosis), resulting from direct oxidative stress on proximal tubule cells or obstructive tubular cast formation. In addition, acute interstitial nephritis has also been described, characterized by tubular and interstitial inflammation, resulting from an immunologically mediated (non-IgE) process (Ref).Onset: Intermediate; usually occurs 5 to 7 days and up to 14 days following monotherapy (Ref). Acute interstitial nephritis was observed at a median onset of 26 days in a systematic case review (Ref).Risk factors:• Vancomycin exposure (trough levels ≥15 mg/L, larger AUC [>650 to 1,300 mg-h/L], high daily doses [>4 g/day]) (Ref)• Duration of therapy >7 days (Ref)• Obesity (Ref)• Preexisting kidney dysfunction (Ref)• Critical illness (Ref)• Concurrent nephrotoxin therapy or concurrent prolonged use of piperacillin/tazobactam (Ref)• Older adults >65 years:• Parenteral: Less commonly associated risk factor (Ref)• Oral: Increases the risk of systemic absorption from oral vancomycinNeutropenia/pancytopeniaNeutropenia (severe) and agranulocytosis have been observed in numerous case reports and case series; in some cases, drug fever also accompanied the neutropenia (Ref). Reversible pancytopenia has also been reported in case reports (Ref).Mechanism: Non-dose-related; available data suggest a peripheral mechanism mediated by antibodies and direct toxicity to the bone marrow (Ref).Onset: Varied; usually occurs after 7 to 12 days of treatment, with most cases occurring after 20 days (Ref). However, 1 case report described an onset of 8 weeks following discontinuation of a 3-week course, and then upon rechallenge, neutropenia recurred 3 days following reinitiation (Ref).Risk factors:• Prolonged exposure (ie, >7 days) (Ref)• Teicoplanin: In patients experiencing neutropenia who were switched to teicoplanin (another glycopeptide), 50% of these patients also developed teicoplanin-induced neutropenia (Ref)OtotoxicityVancomycin is infrequently associated with ototoxicity, manifested as tinnitus, sensorineural hearing loss, dizziness, or vertigo; some cases have reported irreversible hearing loss (Ref). Of note, vancomycin has not been found to be ototoxic in animal models (Ref).Mechanism: Non-dose-related; proposed to be via direct damage to the auditory branch of the eighth cranial nerve, although data are conflicting and unclear if ototoxicity is directly attributable to vancomycin or to other confounding factors (Ref).Risk factors:• Older adults (Ref)• Coadministration with ototoxic agents (eg, aminoglycosides) (Ref)• Kidney dysfunction (potential risk factor) (Ref)Vancomycin infusion reactionVancomycin infusion reaction, a non-IgE-mediated drug reaction most often characterized by an erythematous rash, generalized flushing, and pruritus, may occur. Severe reactions, which are uncommon, may also include hypotension, chest pain, and dyspnea. Rarely, vancomycin infusion reaction may be life-threatening and cause severe hypotension and cardiac arrest or cardiovascular collapse. Clinical presentation can be similar to IgE-mediated anaphylaxis making it difficult for clinicians to distinguish between the 2 reactions (Ref). Reactions usually cease promptly after infusion is stopped.Mechanism: Non-IgE-mediated drug reaction caused by histamine release from mast cells and basophils found in the skin, lung, GI tract, myocardium, and vascular system (Ref). The mast cell receptor MRGPRX2 has also been identified as a cause of non-IgE-mediated drug reactions (Ref).Onset: Rapid; usually occurs 4 to 10 minutes after the start of the infusion with the first dose but may also occur at any time (Ref).Risk factors:• Typically caused by rapid IV infusion (<1 hour) of large doses (Ref)• Concomitant medications that also induce histamine release including ciprofloxacin; barbiturates; opioids (except fentanyl which rarely induces histamine); certain neuromuscular antagonists (atracurium, cisatracurium, doxacurium, mivacurium, succinylcholine, tubocurarine); propofol; plasma expanders (dextran, polygeline); and radiocontrast agents (Ref).Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.IV:Frequency not defined:Cardiovascular: Chest pain, flushing, hypotension, shock, vasculitisDermatologic: Bullous dermatitis, erythema of skin, exfoliative dermatitis (Forrence 1990), pruritus, Stevens-Johnson syndrome (Lin 2014)Hematologic & oncologic: Agranulocytosis (di Fonzo 2018), eosinophilia, leukopenia, thrombocytopeniaHypersensitivity: Hypersensitivity reaction (Kupstaite 2010)Local: Injection site phlebitis, irritation at injection site, pain at injection siteNervous system: Chills, dizziness, malaise, vertigoNeuromuscular & skeletal: MyalgiaOtic: Hearing loss (Klibanov 2003), ototoxicity (Forouzesh 2009), tinnitus (Traber 1981)Renal: Increased blood urea nitrogen (Bergman 1988), increased serum creatinine, interstitial nephritis (Bergman 1988), renal tubular necrosis (Shah-Khan 2011)Respiratory: Dyspnea, wheezingMiscellaneous: Fever (Smith 1999)Postmarketing:Cardiovascular: Hypersensitivity angiitis (rare: <1%) (Pingili 2017)Dermatologic: Acute generalized exanthematous pustulosis (rare: <1%) (Mawri 2015), dermatologic disorder (linear IgA bullous dermatosis) (rare: <1%) (Tashima 2014), erythema multiforme (rare: <1%) (Khicher 2019), maculopapular rash (Marik 1997), toxic epidermal necrolysis (rare: <1%) (Changela 2013)Gastrointestinal: Clostridioides difficile associated diarrhea (rare: <1%) (Hecht 1989), Clostridioides difficile colitis (rare: <1%) (Hecht 1989), peritonitis (following intraperitoneal administration during CAPD) (Freiman 1992)Hematologic & oncologic: Henoch-Schonlein purpura (Min 2017), immune thrombocytopenia (Al Jafar 2015; Mohammadi 2017), neutropenia (reversible) (literature suggests an incidence ranging from 2% to 12%) (Black 2011; di Fonzo 2018), pancytopenia (rare: <1%) (Carmichael 1986)Hypersensitivity: Anaphylaxis (rare: <1%) (Anne 1994), fixed drug eruption (Gilmore 2004), vancomycin infusion reaction (literature suggests an incidence ranging from 4% to as high as 47%) (Alvarez-Arango 2021; Austin 2020; Symons 1985; Wazny 2001)Immunologic: Drug reaction with eosinophilia and systemic symptoms (rare: <1%) (Cacoub 2011)Renal: Acute kidney injury (Sawada 2018), nephrotoxicity (common: ≥10%) (Lodise 2009)Oral:>10%:Endocrine & metabolic: Hypokalemia (13%)Gastrointestinal: Abdominal pain (15%), nausea (17%)1% to 10%:Cardiovascular: Peripheral edema (6%)Gastrointestinal: Diarrhea (9%), flatulence (8%), vomiting (9%)Genitourinary: Urinary tract infection (8%)Nervous system: Fatigue (5%), headache (7%)Neuromuscular & skeletal: Back pain (6%)Renal: Nephrotoxicity (5%)Miscellaneous: Fever (9%)Frequency not defined:Cardiovascular: HypotensionGastrointestinal: Clostridioides difficile colitis, constipationHematologic & oncologic: AnemiaNervous system: Depression, insomniaRenal: Increased serum creatinine, renal failure syndrome, renal insufficiencyPostmarketing:Cardiovascular: VasculitisDermatologic: Acute generalized exanthematous pustulosis, dermatologic disorder (linear IgA bullous dermatosis) (Tashima 2014), exfoliative dermatitis (rare: <1%) (Forrence 1990), pruritus, skin rash, Stevens-Johnson syndrome (rare: <1%) (An 2011), toxic epidermal necrolysis (rare: <1%) (An 2011), urticariaHematologic & oncologic: Eosinophilia, thrombocytopeniaHypersensitivity: Anaphylaxis, flushing (Arroyo-Mercado 2019), nonimmune anaphylaxisImmunologic: Drug reaction with eosinophilia and systemic symptoms (Cacoub 2011)Nervous system: Chills, dizziness, drug fever, pain, vertigoNeuromuscular & skeletal: Muscle spasm (chest and back)Otic: TinnitusRespiratory: Dyspnea, wheezingContraindicationsHypersensitivity to vancomycin or any component of the formulationWarnings/PrecautionsConcerns related to adverse effects:• Extravasation and thrombophlebitis: IV vancomycin is an irritant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation. Pain, tenderness, and necrosis may occur with extravasation. If thrombophlebitis occurs, slow infusion rates, dilute solution (eg, 2.5 to 5 g/L) and rotate infusion sites.• Superinfection: Prolonged use may result in fungal or bacterial superinfection.Disease-related concerns:• Inflammatory bowel disease: Clinically significant serum concentrations have been reported in patients with inflammatory disorders of the intestinal mucosa who have taken oral vancomycin (multiple doses) for the treatment of C. difficile-associated diarrhea. Although use may be warranted, the risk for adverse reactions may be higher in this situation; consider monitoring serum trough concentrations in patients with renal insufficiency, severe colitis, and a prolonged course (IDSA/SHEA [McDonald 2018]; Pettit 2015).• Renal impairment: Use with caution in patients with renal impairment or those receiving other nephrotoxic drugs; dosage modification required and close monitoring is recommended in patients with preexisting renal impairment and those at high risk for renal impairment. Accumulation may occur after multiple oral doses of vancomycin in patients with renal impairment; consider monitoring serum concentrations in this circ*mstance.Other warnings/precautions:• Appropriate use: Oral vancomycin is only indicated for the treatment of CDI or enterocolitis due to S. aureus and is not effective for systemic infections; parenteral vancomycin is not effective for the treatment of enterocolitis.• Intraocular administration (off-label route): Hemorrhagic occlusive retinal vasculitis (HORV), including permanent visual loss, has been reported in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery.• Intraperitoneal administration (off-label route): Use caution when administering intraperitoneally (IP); in some continuous ambulatory peritoneal dialysis (CAPD) patients, chemical peritonitis (cloudy dialysate, fever, severe abdominal pain) has occurred. Symptoms are self-limited and usually clear after vancomycin discontinuation.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Aminoglycosides: Vancomycin may enhance the nephrotoxic effect of Aminoglycosides. Vancomycin may enhance the neurotoxic effect of Aminoglycosides.Management: Consider avoiding coadministration of aminoglycosides and vancomycin unless clinically indicated. If coadministered, monitor closely for signs of nephrotoxicity and neurotoxicity. Risk D: Consider therapy modificationBacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii.Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modificationBCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization).Risk C: Monitor therapyBile Acid Sequestrants: May diminish the therapeutic effect of Vancomycin. Management: Avoid concurrent administration of oral vancomycin and bile acid sequestrants when possible.If use of both agents is necessary, consider separating doses by at least 2 hours to minimize the significance of the interaction. Risk D: Consider therapy modificationCholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine.Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combinationColistimethate: Vancomycin may enhance the nephrotoxic effect of Colistimethate.Management: Avoid coadministration of colistimethate and vancomycin whenever possible due to the potential for additive or synergistic nephrotoxicity. If coadministration cannot be avoided, closely monitor renal function. Risk D: Consider therapy modificationImmune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Risk C: Monitor therapyLactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol.Risk C: Monitor therapyNeuromuscular-Blocking Agents: Vancomycin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents.Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Vancomycin. Risk C: Monitor therapyPiperacillin: May enhance the nephrotoxic effect of Vancomycin. Risk C: Monitor therapySodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate.Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modificationTaurolidine: Vancomycin may diminish the therapeutic effect of Taurolidine.Risk C: Monitor therapyTyphoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected.Management: Avoid use of live attenuated typhoid vaccine (Ty21a)in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modificationReproductive ConsiderationsPregnancy status should be evaluated in patients who may become pregnant prior to using the IV formulation containing the excipients polyethylene glycol (PEG 400) and N-acetyl D-alanine (NADA).Pregnancy ConsiderationsVancomycin crosses the placenta and can be detected in fetal serum, amniotic fluid, and cord blood (Bourget 1991; Reyes 1989). Adverse fetal effects, including sensorineural hearing loss or nephrotoxicity, have not been reported following maternal use during the second or third trimesters of pregnancy.The pharmaco*kinetics of vancomycin may be altered during pregnancy and pregnant patients may need a higher dose of vancomycin. Maternal half-life is unchanged, but the volume of distribution and the total plasma clearance may be increased (Bourget 1991). Individualization of therapy through serum concentration monitoring may be warranted.Vancomycin is recommended for the treatment of mild, moderate, or severe Clostridioides difficile infections in pregnant patients. Standard doses should be used (ACG [Surawicz 2013]).Vancomycin is recommended as an alternative option to prevent the transmission of group B streptococcal (GBS) disease from mothers to newborns. Untreated asymptomatic GBS disease can result in maternal urinary tract infection, intraamniotic infection, endometritis, preterm labor, and/or stillbirth. Vertical transmission from the mother can cause sepsis, pneumonia, or meningitis in the newborn. Vancomycin IV is recommended for use in women who are at high risk for anaphylaxis to penicillin (or whose risk is unknown), and the GBS isolate is resistant to clindamycin. Dose and rate of infusion should be based on maternal weight and renal function, similar to nonpregnant patients (ACOG 2020).In patients known to be colonized with methicillin-resistant S. aureus (MRSA), a single dose of vancomycin is recommended as part of the antibiotic regimen for prophylactic use prior to cesarean delivery. Monotherapy with vancomycin does not provide sufficient coverage for cesarean delivery surgical prophylaxis (ACOG 2018).Based on limited data, vancomycin is considered likely compatible with pregnancy when used for the treatment of airway diseases, such as cystic fibrosis (ERS/TSANZ [Middleton 2020]).The formulation of vancomycin injection containing the excipients polyethylene glycol (PEG 400) and N-acetyl D-alanine (NADA) has caused fetal malformations in animal reproduction studies. If use of vancomycin is needed during the first or second trimesters of pregnancy, use other available formulations of vancomycin.Breastfeeding ConsiderationsVancomycin is present in breast milk following IV administration.Information related to the presence of vancomycin in breast milk is available from a mother who received vancomycin 1 g IV every 12 hours during pregnancy and for at least 1 week prior to sampling. Vancomycin 12.7 mcg/mL was detected in breast milk 4 hours after a maternal dose (Reyes 1989).Vancomycin exhibits minimal oral absorption; therefore, the amount available to pass into the milk would be limited following oral administration and unlikely to provide clinically relevant exposure to an infant exposed via breast milk.In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush or diarrhea (WHO 2002).Vancomycin is recommended for the treatment of Clostridioides difficile infections in breastfeeding women (ACG [Surawicz 2013]) and is considered compatible with breastfeeding when used for the treatment of airway diseases, such as cystic fibrosis (ERS/TSANZ [Middleton 2020]). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.Dietary ConsiderationsMay be taken with food.Monitoring ParametersIV: Periodic renal function tests, CBC, pregnancy test prior to use for formulation containing PEG 400 and NADA excipients, serial auditory function testing may be helpful to minimize risk of ototoxicity, serum trough vancomycin concentrations in select patients (eg, aggressive dosing, life-threatening infection, seriously ill, unstable renal function, concurrent nephrotoxins, prolonged courses).AUC monitoring: Frequency of AUC monitoring should be based on clinical judgement; frequent or daily monitoring may be appropriate for hemodynamically unstable patients; hemodynamically stable patients may only require once-weekly monitoring (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Trough monitoring:Hemodynamically stable patients: Draw trough concentrations at least once weekly (ASHP/IDSA/SIDP [Rybak 2009]).Hemodynamically unstable patients: Draw trough concentrations more frequently or in some instances daily (ASHP/IDSA/SIDP [Rybak 2009]).Prolonged courses (>3 to 5 days): Draw at least one steady-state trough concentration; repeat as clinically appropriate (ASHP/IDSA/SIDP [Rybak 2009]).Note: Drawing >1 trough concentration prior to the fourth dose for short course (<3 days) or lower intensity dosing (target trough concentrations <15 mg/L) is not recommended. For patients with uncomplicated skin and soft tissue infections who are not obese and have normal renal function, serum trough monitoring is generally not needed (IDSA [Liu 2011]).Oral/rectal therapy: Serum sample monitoring is not typically required; systemic absorption of enteral vancomycin may occur in patients with mucosal disruption due to colitis, especially in patients with renal failure. Monitoring serum vancomycin levels may be considered for patients with renal failure who have severe colitis and require a prolonged course of enteral vancomycin (IDSA/SHEA [McDonald 2018]; Pettit 2015).Reference RangeIV:Timing of serum samples:First-order pharmaco*kinetic analytic equations or Bayesian software to estimate AUC: Requires collection of 2 serum concentrations, postdistributional peak concentration (Cmax) drawn 1 to 2 hours after infusion and trough concentration (Cmin) drawn at the end of the dosing interval. It is preferable that a near steady-state postdistributional peak and trough concentration within the same dosing interval (if possible) are used with the equation-based method. Bayesian-derived AUC monitoring does not require steady-state serum concentrations (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Trough monitoring: Draw trough concentration just before the administration of a dose at steady-state conditions. Steady-state conditions generally occur approximately after the third dose; therefore, may begin monitoring vancomycin trough concentrations before the fourth dose (usually within 1 hour of administration). More specific recommendations for timing of serum samples may be found in "Monitoring Parameters" (Alvarez 2016; ASHP/IDSA/SIDP [Rybak 2009]).Target concentrations:Intermittent infusion:AUC/minimum inhibitory concentration determined by broth microdilution (MICBMD): 400 to 600, assuming MICBMD of 1 mg/L. When MICBMD is >1 mg/L, probability of attaining an AUC/MIC target of ≥400 is low with conventional dosing; higher doses may risk unnecessary toxicity. When MICBMD is <1 mg/L, decreasing the dose to achieve the AUC/MIC target is not recommended (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Trough: 10 to 20 mg/L; target within this range depends on site and severity of infection, as well as clinical response. For pathogens with a minimum inhibitory concentration (MIC) ≤1 mg/L, the minimum trough concentration should be 15 mg/L to meet target AUC/MIC of ≥400. For complicated infections (eg, bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia caused by S. aureus) or infections associated with severe sepsis or septic shock, trough concentrations of 15 to 20 mg/L are recommended to improve penetration and improve clinical outcomes (ASHP/IDSA/SIDP [Rybak 2009]; Liu 2011). The American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines for hospital-acquired pneumonia and the IDSA meningitis guidelines also recommend trough concentrations of 15 to 20 mg/L (Kalil 2016; Tunkel 2004; Tunkel 2017).Continuous infusion: Target steady-state concentration: 20 to 25 mg/L (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Concentrations associated with toxicity: Serum concentration >80 mg/L.Intraventricular (off-label route): Limited data available (IDSA [Tunkel 2004; Tunkel 2017]; Smetana 2018): Prior to administration of the next intraventricular dose, withdraw a sample of cerebrospinal fluid (CSF). This trough CSF concentration divided by the vancomycin MIC for the isolated bacterial pathogen (inhibitory quotient) should exceed 10 to 20.Mechanism of ActionInhibits bacterial cell wall synthesis by blocking glycopeptide polymerization through binding tightly to D-alanyl-D-alanine portion of cell wall precursorPharmaco*kineticsAbsorption: Oral: Poor; Rectal: significant absorption through inflamed colonic mucosa may occur; Intraperitoneal (IP): 60% of an IP dose absorbed in 6 hours.Distribution: Distributes widely in body tissue and fluids, except for cerebrospinal fluid (CSF).Vd:Neonates, term: 0.57 to 0.69 L/kg (de Hoog 2004).Infants: 0.56 L/kg (Rainkie 2015).Children ≤6 years of age: 0.61 L/kg (Rainkie 2015).Children >6 years of age: 0.47 L/kg (Rainkie 2015).Adolescents: 0.49 L/kg (Rainkie 2015).Adults: 0.4 to 1 L/kg (ASHP/IDSA/SIDP [Rybak 2009]); 0.3 to 0.5 L/kg in patients who are morbidly obese (Adane 2015; Bauer 1998; Hong 2015).Relative diffusion from blood into CSF: Good only with inflammation (exceeds usual MICs).Children:CSF concentrations: 0.2 to 17.3 mg/L (de Hoog 2004).CSF:blood level ratio: Normal meninges: Nil; Inflamed meninges: 7.1% to 68% (de Hoog 2004).Adults:Uninflamed meninges: 0 to 4 mg/L; serum concentration dependent (ASHP/IDSA/SIDP [Rybak 2009]).Inflamed meninges: 6 to 11 mg/L; serum concentration dependent (ASHP/IDSA/SIDP [Rybak 2009]).CSF:serum level ratio: Normal meninges: Nil; Inflamed meninges: ~80% (Shokouhi 2014).Protein binding: ~55%.Metabolism: No apparent metabolism.Half-life elimination: Biphasic: Terminal:Preterm neonates (GA: 32 to 34 weeks); PNA ~3 to 5 days: 5.9 to 9.8 hours (Schaad 1980).Term neonates; PNA ~2 to 3 days: 6.7 hours (Schaad 1980).Infants: 2.8 hours (Rainkie 2015).Children <6 years of age: 2.4 hours (Rainkie 2015).Children ≥6 years of age: 2.9 hours (Rainkie 2015).Adolescents: 3.2 hours (Rainkie 2015).Adults: 4 to 6 hours; significantly prolonged with renal impairment.End-stage renal disease: 7.5 days.Time to peak, serum: IV: Immediately after completion of infusion.Excretion: Primarily via glomerular filtration; IV: Urine (75% as unchanged drug in the first 24 hours); Oral: Primarily feces.Clearance: presence of malignancy in children is associated with an increase in vancomycin clearance.Neonates: 0.63 to 1.5 mL/minute/kg; dependent on GA and/or PMA (de Hoog 2004).Pediatric patients: Median: 1.1 mL/minute/kg (range: 0.33 to 1.87 mL/minute/kg) (Marsot 2012).Adults: 1.6 to 6.2 L/hour (Matzke 1984); patients who are obese: ~6 L/hour (rarely exceeds 9 L/hour) (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Pharmaco*kinetics: Additional ConsiderationsPediatric: Extracorporeal membrane oxygenation (ECMO): Reported pharmaco*kinetic parameters in pediatric patients receiving ECMO vary widely based on ECMO circuitry/filters, age, weight, kidney function, and underlying diseases. In general, volume of distribution may be increased and clearance may be increased or decreased; reported parameters vary significantly; elimination half-life appears to be dependent upon renal function (Amaker 1996; Buck 1998; Cies 2017; Moffett 2018; Mulla 2005; Zylbersztajn 2018).Older adult: Total systemic and renal clearance may be reduced.Anti-infective considerations:Parameters associated with efficacy: Note: Ratios, including the minimum inhibitory concentration (MIC), depend upon the methodology used; MIC determined by E-test is typically 1.5 to 2 times MIC determined by broth microdilution (ASHP/IDSA/PIDS/SIDP [Rybak 2020]).Staphylococcus aureus: AUC/MICBMD ≥400 mg•hour/L (ASHP/IDSA/PIDS/SIDP [Rybak 2020]; Kullar 2011; Lodise 2014; Moise-Broder 2004); specific cutoff for efficacy has varied slightly between studies.Enterococcus spp.: AUC/MICEtest ≥389 (Jumah 2018).Coagulase-negative staphylococci (neonates): AUC24 ≥300 mg•hour/L in first 24 hours of therapy or AUC24 ≥424 mg•hour/L in the second 24 hours of therapy (Gwee 2022).Parameters associated with toxicity: Nephrotoxicity: AUC ≥600 to 650 mg•hour/L (adults); ≥800 mg•hour/L (pediatrics); risk continues to increase along AUC continuum (Aljefri 2019; ASHP/IDSA/PIDS/SIDP [Rybak 2020]; Fiorito 2018; Le 2015; Lodise 2020); Cmin ≥15 mg/L (ASHP/IDSA/PIDS/SIDP [Rybak 2020]; van Hal 2013).Postantibiotic effect: A short postantibiotic effect has been observed in E. faecalis (0.5 to 1 hour) and S. aureus (0.6 to 2 hours); slightly longer in S. epidermidis (4.3 to 6.5 hours) (Hanberger 1991; Löwdin 1998).Pricing: USCapsules (Vancocin Oral)125 mg (per each): $103.35250 mg (per each): $190.55Capsules (Vancomycin HCl Oral)125 mg (per each): $31.31250 mg (per each): $57.72Solution (Vancomycin HCl in Dextrose Intravenous)1GM/200ML 5% (per mL): $0.16500 mg/100 mL 5% (per mL): $0.09750MG/150ML 5% (per mL): $0.10Solution (Vancomycin HCl in NaCl Intravenous)1GM/200ML 0.9% (per mL): $0.14500 mg/100 mL 0.9% (per mL): $0.09750MG/150ML 0.9% (per mL): $0.10Solution (Vancomycin HCl Intravenous)500 mg/100 mL (per mL): $0.11750 mg/150 mL (per mL): $0.101000 mg/200 mL (per mL): $0.101250 mg/250 mL (per mL): $0.091500MG/300ML (per mL): $0.091750MG/350ML (per mL): $0.092000MG/400ML (per mL): $0.08Solution (reconstituted) (Firvanq Oral)25 mg/mL (per mL): $0.9050 mg/mL (per mL): $1.14Solution (reconstituted) (Vancomycin HCl Intravenous)1 g (per each): $4.14 - $19.541.25 g (per each): $24.121.5 g (per each): $28.94 - $29.225 g (per each): $19.72 - $108.3110 g (per each): $39.18 - $260.68100 g (per each): $600.00500 mg (per each): $2.96 - $9.79750 mg (per each): $8.02 - $11.81Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAekovan (PH);Alvarcin (CR, DO, GT, HN, NI, PA, SV);Celovan (HK);Citerin (MX);Covan (BD);Covancin (IN);Cytovan (IN);Dhacocin (MY, SG);Edicin (BG, CZ, EE, RO, RU, SK, TH, TR, UA);Estavam (MX);Forstaf (IN);Icoplax (AR, PE);Kovan (CL);Levovanox (IT);Mersa (PH);Normedia (SE);Riveran (AR, PE);Vacsol (MX);Vagran (VE);Vamysin (BE);Vanauras (MX);Vanaurus (CR, DO, EC, GT, HN, NI, PA, SV);Vancard (BD);Vancep (ID);Vancin (BD);Vancin-S (TH);Vanco (TW);Vanco-SAAR (DE);Vanco-Teva (IL);Vancoavenir (IL);Vancobac (BD);Vancobact (EG);Vancocid (TH);Vancocin (AE, AT, AU, BB, BG, HU, IE, JO, LB, LK, MT, NL, RU, SA, SI, VN, ZA);Vancocin CP (CN, IN, MX, PK, TW);Vancocin HCl (BF, BJ, CH, CI, DK, ET, GB, GH, GM, GN, HK, KE, LR, MA, ML, MR, MU, MW, NE, NG, PH, SC, SD, SE, SL, SN, TN, TW, TZ, UG, ZM, ZW);Vancocina (IT);Vancocine (FR);Vancodex (ID);Vancoled (AE, KR, KW, VN);Vancolon (AE, BH, EG, ET, KW, LB, PH, QA, SA);Vancomax (PE, PY);Vancomet (PH);Vanconix (BD);Vancorin (TR);Vancorus (RU);Vancosam (LK);Vancosan (BR, FI, IS, LT, LV);Vancotech (LK);Vancotek (AR);Vancotex (MY);Vancotrat (BR);Vancox (MX);Vancozin (EG, KR);Vanlyo (TW);Vanmicira (CZ);Vantocil (ID);Varedet (AR, PE, PY, UY);Vivocin (MY);Voncon (GR);Vondem (GR);Voxin (GR)For country code abbreviations (show table)Adane ED, Herald M, Koura F. Pharmaco*kinetics of vancomycin in extremely obese patients with suspected or confirmed Staphylococcus aureus infections. Pharmacotherapy. 2015;35(2):127-139. doi:10.1002/phar.1531 [PubMed 25644478]Al-Jafar H, Al-Yousef A, Al-Shatti S, Al-Banwan K. Drug-immune thrombocytopenia with thrombosis versus heparin-induced thrombocytopenia: a critical clinical controversy. Case Rep Nephrol Dial. 2015;5(2):152‐159. doi:10.1159/000435806 [PubMed 26266247]Aljefri DM, Avedissian SN, Rhodes NJ, Postelnick MJ, Nguyen K, Scheetz MH. Vancomycin area under the curve and acute kidney injury: a meta-analysis. Clin Infect Dis. 2019;69(11):1881-1887. doi:10.1093/cid/ciz051 [PubMed 30715208]Al-Jeraisy M, Phelps SJ, Christensen ML, Einhaus S. Intraventricular vancomycin in pediatric patients with cerebrospinal fluid shunt infections. J Pediatr Pharmacol Ther. 2004;9(1):36-42.Álvarez R, López Cortés LE, Molina J, Cisneros JM, Pachón J. Optimizing the clinical use of vancomycin. 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CloseZiprasidone: Drug informationZiprasidone: Drug information(For additional information see "Ziprasidone: Patient drug information" and see "Ziprasidone: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningIncreased mortality in elderly patients with dementia-related psychosis:Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Ziprasidone is not approved for the treatment of patients with dementia-related psychosis.Brand Names: USGeodonBrand Names: CanadaAuro-Ziprasidone;ZeldoxPharmacologic CategoryAntimanic Agent;Second Generation (Atypical) AntipsychoticDosing: AdultNote: Oral dose needs to be taken with a meal (≥500 calories) to be adequately absorbed (Gandelman 2009; Lincoln 2010). Safety: Dose-dependent QTc interval prolongation; consider monitoring ECG during therapy (baseline and after dose increases), particularly in patients with risk factors for QTc prolongation (eg, preexisting QT prolongation, other cardiovascular disease, uncorrected electrolyte abnormalities, concurrent use with other drugs that prolong QT interval) (Camm 2012; Shah 2014). Some experts recommend checking baseline ECG in patients with schizophrenia, regardless of risk factors (APA [Keepers 2020]).Agitation/Aggression associated with psychiatric disorders, substance intoxications, or other organic causesAgitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia [labeled use], bipolar disorder [off-label use]), substance intoxications (off-label use), or other organic causes (off-label use) (alternative agent): Note: Antipsychotics are appropriate when psychosis is suspected to be the primary cause of agitation/aggression. Other agents are used preferentially in agitation associated with certain intoxications (eg, anticholinergic substances, stimulants) or alcohol withdrawal. Depending on presentation, may combine with a benzodiazepine (Moore 2020; WFSBP [Hasan 2012]; Wilson 2012). For cooperative patients able to take oral medication, use an alternative antipsychotic that does not need to be taken with a meal.IM: 10 mg every 2 hours or 20 mg every 4 hours (maximum: 40 mg/day). Oral therapy should replace IM administration as soon as possible.Bipolar disorderBipolar disorder:Acute manic episodes with or without mixed features (labeled use) and acute hypomania, monotherapy (off-label use) (alternative agent):Oral: Initial: 40 mg twice daily with meal; on day 2 of treatment, may increase to 60 or 80 mg twice daily; subsequently adjust dose based on response and tolerability. Usual dosage: 40 to 80 mg twice daily (CANMAT [Yatham 2018]; Stovall 2021; manufacturer's labeling).Note: For some patients, doses up to 240 mg/day may be necessary and tolerated (Stovall 2021). Combining with lithium or valproate for acute episode does not provide additional benefit (Sachs 2012; Scherk 2007).Maintenance treatment, monotherapy (off-label use) or adjunctive with antimanic therapy (labeled use): Monotherapy: Oral: Continue dose that was used to achieve control of the acute episode (CANMAT [Yatham 2018]).Adjunctive with antimanic therapy:Oral: 40 or 80 mg twice daily with meal (manufacturer's labeling).Note: Despite lack of added benefit for ziprasidone plus lithium or valproate in acute episodes, maintenance treatment with combination treatment may delay time to relapse (Bowden 2010; manufacturer's labeling).Delirium in the ICU, hyperactive, treatmentDelirium in the ICU, hyperactive, treatment (alternative agent) (off-label use):Note: Nonpharmacologic interventions and treatment of underlying conditions are initial steps to prevent and manage delirium. Antipsychotics may be used as short-term adjunctive treatment if distressing symptoms (eg, agitation, anxiety) are present (SCCM [Devlin 2018]). Reassess daily for continued need; consider discontinuation and/or taper as symptoms resolve, especially at transitions of care, to prevent unnecessary continuation of therapy (D’Angelo 2019; Marshall 2016; Tietze 2020). Although data are limited, some experts use the following:IM: 10 mg, then may repeat every 2 hours if needed or 20 mg, then may repeat once in 4 hours if needed; maximum total daily dose: 40 mg (Tietze 2020).Oral: 20 to 40 mg every 12 hours with meal, if possible; maximum total daily dose: 80 mg (Girard 2010; Tietze 2020).Delusional infestationDelusional infestation (delusional parasitosis) (off-label use): Oral: Initial: 20 mg twice daily with meal; gradually increase every few weeks to lowest effective daily dose in range of 20 to 80 mg twice daily (De Berardis 2013; Freudenmann 2008). After achieving adequate response, maintain for ≥1 to 3 months before attempting to taper and discontinue (Suh 2020).Major depressive disorder, treatment resistantMajor depressive disorder, treatment resistant (unipolar, nonpsychotic) (adjunctive therapy with antidepressant) (alternative agent) (off-label use):Note: Also can be used for initial treatment of major depression with psychotic features (ie, not necessarily treatment resistant) in combination with an antidepressant (Rothschild 2020).Oral: Initial: 20 mg twice daily with meal; may increase daily dose based on response and tolerability in increments of 40 mg every week up to 160 mg/day in 2 divided doses (Dunner 2007; Papakostas 2015).SchizophreniaSchizophrenia:Oral: Initial: 20 to 40 mg twice daily with meal; may increase dose based on response and tolerability every 2 days or more. Usual dosage: 20 to 80 mg twice daily; maximum dose: 80 mg twice daily (Stroup 2022; manufacturer's labeling).Note: For IM administration in acute agitation associated with schizophrenia, refer to "Agitation/Aggression (Severe, Acute) Associated with Psychiatric Disorders, (eg, Schizophrenia [Labeled Use], Bipolar Disorder [Off-Label Use]), Substance Intoxications (Off-Label Use), or Other Organic Causes (Off-Label Use)."Discontinuation of therapy: In the treatment of chronic psychiatric disease, switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (eg, over several weeks to months) is advised to detect a reemergence of symptoms and to avoid withdrawal reactions (ie, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (APA [Keepers 2020]; Lambert 2007; Moncrieff 2020; Post 2021).Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Stroup 2022).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultOral: No dosage adjustment necessary.IM: No dosage adjustment necessary. Cyclodextrin, an excipient in the IM formulation, is cleared by renal filtration; use with caution.Ziprasidone is not removed by hemodialysis.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling; however, drug undergoes extensive hepatic metabolism and systemic exposure may be increased.Use with caution.Dosing: Pediatric(For additional information see "Ziprasidone: Pediatric drug information")Acute agitationAcute agitation (schizophrenia): Limited data available:Weight-directed dosing: Children ≥5 years and Adolescents: IM: 0.2 mg/kg; maximum dose: 20 mg/dose; a retrospective review of 40 patients (age range: 5 to 18 years) presenting to the ED with acute agitation showed a significant (p=0.03) response with a mean initial single dose of 0.19 ± 0.1 mg/kg amongst responders compared to a mean initial dose of 0.13 ± 0.06 mg/kg in nonresponders (Nguyen 2018)Fixed dosing (Barzman 2007; Khan 2006; Staller 2004):Children 5 to 11 years: IM: 10 mgChildren ≥12 years and Adolescents: IM: 10 to 20 mg; one study (n=59; age range: 5 to 19 years) reported that 69% of 20 mg doses surpassed the desired calming therapeutic effect and caused varying degrees of sedation (4% of patients were unable to be aroused) (Barzman 2007)Autistic disorders or Pervasive Developmental Disorder-Not Otherwise Specified; irritabilityAutistic disorders or Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS); irritability: Limited data available: Children ≥6 years and Adolescents: Oral: Reported final dose range: 20 to 240 mg/day divided twice daily; see the following for initial doses and titration reported (Dominick 2015; Malone 2007; McDougle 2002)A prospective, open-labeled study of 12 patients (12 to 18 years) used the following individually titrated doses (Malone 2007):Patient weight ≤35 kg: Initial: 20 mg every other day at bedtime for 2 doses; then increase dose in weekly increments based on clinical response and tolerability: Week 1: 10 mg twice daily (20 mg/day); Week 2: 20 mg twice daily (40 mg/day); Week 3: 40 mg twice daily (80 mg/day); Week 4: 80 mg twice daily (160 mg/day)Patient weight >35 kg: Initial: 20 mg/day at bedtime for 3 doses; then increase dose in weekly increments based on clinical response and tolerability: Week 1: 20 mg twice daily (40 mg/day); Week 2: 40 mg twice daily (80 mg/day); Week 4: 80 mg twice daily (160 mg/day)A retrospective trial evaluated 42 pediatric patients (mean age: 11.8 ± 3.9 years; range: 5.9 to 18.7 years) and reported treatment response in 40% of subjects based on improvement in Clinical Global Impressions-Improvement Scale (CGI-I) scores at a mean final dose: 98.7 ± 52 mg/day (1.7 ± 1.1 mg/kg/day), reported range: 20 to 240 mg/day (Dominick 2015). A case series of 12 patients (8 to 20 years) initiated therapy at 20 mg/day administered at bedtime and then increased by 10 to 20 mg/week divided twice daily based on clinical response and tolerability; final ziprasidone dosage ranged between 20 to 120 mg/day (mean: ~60 mg/day) divided twice daily (McDougle 2002).Bipolar I disorderBipolar I disorder: Note: In June 2009, an FDA advisory panel advised that ziprasidone is effective in patients 10 to 17 years of age for the treatment of mixed and manic episodes of bipolar disorder, but did not conclude that it was safe due to large number of subjects lost to follow-up and ambiguity within QTc prolongation data. Since then, prescribing of ziprasidone has decreased similarly for pediatric and adult patients after the FDA non-approval (Wang 2016).Fixed dosing: Limited data available (DelBello 2008a; DelBello 2008b; Elbe 2008; Findling 2008; Findling 2013; Mechcatie 2009): Children and Adolescents 10 to 17 years: Oral: Initial dose: 20 mg/day; titrate dose upwards as tolerated, using twice daily dosing over a 2-week period to the weight-based target range: 60 to 80 mg/day (weight <45 kg) divided into twice daily doses or 120 to 160 mg/day (weight ≥45 kg) divided into twice daily doses (Findling 2013).Weight-directed dosing: Limited data available: Children ≥6 years and Adolescents: An open-label, 8-week study of 21 patients (6 to 17 years [mean: 10.3 years]) with bipolar disorder and comorbid conditions (eg, ADHD, depression, conduct disorder) used the following weight-based dosing regimen (Biederman 2007):Initial dose: 1 mg/kg/day divided twice daily; increase to 1.5 mg/kg/day divided twice daily by Week 2 and increase to 2 mg/kg/day divided twice daily by Week 3 if tolerated; maximum dose: 160 mg/day; Note: Only 14 of the 21 patients completed the study; five dropped out due to lack of efficacy; two dropped out due to adverse reactions; patients experienced a high incidence of sedation (46%) and headaches (38%).Tourette syndrome, tic disorderTourette syndrome, tic disorder: Very limited data available: Children and Adolescents 7 to 16 years: Oral: Initial dose: 5 mg/day for 3 days then using twice daily dosing, titrate dose as tolerated up to 40 mg/day divided twice daily. Dosing is based on a double-blind, placebo-controlled pilot study (n=28), mean daily dose at the end of trial: 28.2 + 9.6 mg/day (Sallee 2000).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricOral: There are no pediatric-specific recommendations; based on experience in adult patients, no adjustment may be necessaryIM: There are no pediatric-specific recommendations; cyclodextrin, an excipient in the IM formulation, is cleared by renal filtration; use with cautionZiprasidone is not removed by hemodialysis.Dosing: Hepatic Impairment: PediatricNo dosage adjustment is recommended; however, drug undergoes extensive hepatic metabolism and systemic exposure may be increased. Use with caution.Dosing: Older AdultRefer to adult dosing. Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia or psychosis. Titrate dosage slowly and monitor carefully (Howard 2000).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral, as hydrochloride: Geodon: 20 mg, 40 mg, 60 mg, 80 mgGeneric: 20 mg, 40 mg, 60 mg, 80 mgSolution Reconstituted, Intramuscular, as mesylate [strength expressed as base]: Generic: 20 mg (1 ea)Solution Reconstituted, Intramuscular, as mesylate [strength expressed as base, preservative free]: Geodon: 20 mg (1 ea)Generic: 20 mg (1 ea)Generic Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Capsule, Oral, as hydrochloride: Zeldox: 20 mg, 40 mg, 60 mg, 80 mgGeneric: 20 mg, 40 mg, 60 mg, 80 mgAdministration: AdultOral: Administer capsule with food (≥500 calories [Lincoln 2010]). Swallow capsule whole; do not open, crush, or chew capsules.Injection: For IM administration only.Administration: PediatricOral: Administer capsule with food (in adults, ≥500 calories [Lincoln 2010]). Swallow capsule whole; do not open, crush, or chew capsules.Parenteral: For IM use only; do not administer IVHazardous Drugs Handling ConsiderationsHazardous agent (NIOSH 2016 [group 3]).Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.NIOSH recommends single gloving for administration of intact tablets or capsules. If manipulating tablets/capsules (eg, to prepare an oral suspension), NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration. For IM preparation, double gloves, a protective gown, and ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator) are recommended. Double gloving and a protective gown are required during IM administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).Use: Labeled IndicationsAgitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia, bipolar disorder), substance intoxications, or other organic causes (IM only): Treatment of acute agitation in patients with schizophrenia for whom treatment with ziprasidone is appropriate and who need IM antipsychotic medication for rapid control of agitation. May be used off label for the treatment of acute agitation associated with bipolar disorder (CANMAT [Yatham 2018]) and substance intoxication (Wilson 2012).Bipolar disorder: Monotherapy for the acute treatment of manic episodes with or without mixed features associated with bipolar disorder; for the maintenance treatment of bipolar disorder (manic or mixed episodes) as monotherapy (off label) or as an adjunct to lithium or valproate. May be used off label for the treatment of hypomania (CANMAT [Yatham 2018]).Schizophrenia: Treatment of schizophrenia.Use: Off-Label: AdultDelirium in the ICU, hyperactive, treatment; Delusional infestation (delusional parasitosis); Major depressive disorder, treatment resistant (unipolar, nonpsychotic)Medication Safety IssuesSound-alike/look-alike issues:Ziprasidone may be confused with TraZODoneOlder Adult: High-Risk Medication:Beers Criteria: Antipsychotics are identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2019]).Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequencies represent oral administration unless otherwise indicated. Note: Although minor QTc prolongation (mean: 10 msec at 160 mg/day) may occur more frequently (incidence not specified), clinically relevant prolongation (>500 msec) was rare (0.06%) and less than placebo (0.23%).>10%:Central nervous system: Drowsiness (oral and IM: 8% to 31%; may be dose-related), extrapyramidal reaction (oral: 1% to 31%), headache (oral and IM: 5% to 18%), dizziness (oral and IM: 3% to 16%; includes lightheadedness; may be dose-related)Gastrointestinal: Nausea (oral and IM: 8% to 12%)1% to 10%:Cardiovascular: Orthostatic hypotension (IM: ≤5%, oral: ≥1%; may be dose-related), chest pain (3%), hypertension (oral and IM: 1% to 3%), tachycardia (1% to 2%), bradycardia (oral and IM: ≤2%), facial edema (≥1%), angina pectoris (≤1%), peripheral edema (≤1%)Central nervous system: Akathisia (oral: 8% to 10%; IM: ≤2%), anxiety (oral: 5%; may be dose-related), hypoesthesia (1% to 2%), agitation (oral: ≥1%, IM: ≤2%), personality disorder (IM: ≤2%), speech disturbance (oral and IM: ≤2%), amnesia (≥1%), ataxia (≥1%), chills (≥1%), confusion (≥1%), delirium (≥1%), dystonia (≥1%; may be dose-related), falling (≥1%), flank pain (≥1%), hostility (≥1%), hypothermia (≥1%), vertigo (≥1%), withdrawal syndrome (≥1%), anorg*smia (≤1%), atrial fibrillation (≤1%), male sexual disorder (≤1%), paralysis (≤1%), insomniaDermatologic: Skin rash (1% to 5%; may be dose-related), fungal dermatitis (1% to 2%), diaphoresis (IM: ≤2%), furunculosis (IM: ≤2%), skin photosensitivity (≥1%), alopecia (≤1%), contact dermatitis (≤1%), ecchymoses (≤1%), eczema (≤1%), exfoliative dermatitis (≤1%), maculopapular rash (≤1%), urticaria (≤1%), vesiculobullous dermatitis (≤1%)Endocrine & metabolic: Weight gain (4% to 16%), albuminuria (≤1%), amenorrhea (≤1%), dehydration (≤1%), glycosuria (≤1%), hypercholesterolemia (≤1%), hyperglycemia (≤1%), hypermenorrhea (≤1%), hypokalemia (≤1%), increased lactate dehydrogenase (≤1%), increased thirst (≤1%)Gastrointestinal: Constipation (oral: 9%, IM: ≤2%), dyspepsia (oral: 8%, IM: 2% to 3%), vomiting (oral and IM: 1% to 5%), xerostomia (oral: 4% to 5%; may be dose-related), diarrhea (oral and IM: ≤5%), sialorrhea (4%; may be dose-related), abdominal pain (oral and IM: ≤2%), anorexia (oral and IM: ≤2%; may be dose-related), dysmenorrhea (IM: ≤2%), dysphagia (≤2%), buccoglossal syndrome (≥1%)Genitourinary: Hematuria (≤1%), impotence (≤1%), lactation (female: ≤1%), priapism (IM: ≤1%), urinary retention (≤1%)Hematologic & oncologic: Rectal hemorrhage (oral and IM: ≤2%), anemia (≤1%), eosinophilia (≤1%), leukocytosis (≤1%), leukopenia (≤1%), lymphadenopathy (≤1%)Hepatic: Increased serum alkaline phosphatase (≤1%), increased serum transaminases (≤1%)Hypersensitivity: Tongue edema (≤3%)Local: Pain at injection site (IM: 7% to 8%)Neuromuscular & skeletal: Weakness (oral: 5% to 6%; may be dose-related), myalgia (1% to 2%), paresthesia (oral and IM: ≤2%), abnormal gait (≥1%), akinesia (≥1%), choreoathetosis (≥1%), dysarthria (≥1%), dyskinesia (≥1%), hyperkinesia (≥1%), hypokinesia (≥1%), hypotonia (≥1%), neuropathy (≥1%), tremor (≥1%; may be dose-related), twitching (≥1%), cogwheel rigidity (oral: ≥1%), hypertonia (≥1%), increased creatine phosphokinase (≤1%), tenosynovitis (≤1%)Ophthalmic: Visual disturbance (3% to 6%; may be dose-related), diplopia (≥1%), oculogyric crisis (≥1%), blepharitis (≤1%), cataract (≤1%), conjunctivitis (≤1%), photophobia (≤1%), xerophthalmia (≤1%)Otic: Tinnitus (≤1%)Renal: Polyuria (≤1%)Respiratory: Respiratory tract infection (8%), rhinitis (oral: 4%), cough (3%), pharyngitis (3%), dyspnea (1% to 2%), flu-like symptoms (oral: ≥1%), epistaxis (≤1%), pneumonia (≤1%)Miscellaneous: Accidental injury (4%), fever (≥1%), motor vehicle accident (≥1%)<1%, postmarketing, and/or case reports: Agranulocytosis, angioedema, arthralgia, basophilia, bundle branch block, cardiomegaly, cerebral infarction, cerebrovascular accident, cholestatic jaundice, decreased glucose tolerance, deep vein thrombophlebitis, diabetic coma, DRESS syndrome, ejacul*tory disorder, facial droop, fecal impaction, female sexual disorder, first degree atrioventricular block, galactorrhea, gingival hemorrhage, gout, granulocytopenia, gynecomastia, hematemesis, hemophthalmos, hemoptysis, hepatitis, hepatomegaly, hyperchloremia, hyperkalemia, hyperreflexia, hypersensitivity reaction (including allergic dermatitis, orofacial edema), hyperthyroidism, hyperuricemia, hypocalcemia, hypochloremia, hypocholesterolemia, hypochromic anemia, hypoglycemia, hypomagnesemia, hypomania, hyponatremia, hypoproteinemia, hypothyroidism, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased monocytes, increased serum creatinine, increased serum prolactin, jaundice, keratitis, keratoconjunctivitis, ketosis, laryngismus, liver steatosis, lymphedema, lymphocytosis, mania, melena, myocarditis, myoclonus, myopathy, neuroleptic malignant syndrome, neutropenia, nocturia, nystagmus, oliguria, opisthotonos, oral leukoplakia, oral paresthesia, phlebitis, polycythemia, prolonged QT interval on ECG, pulmonary embolism, respiratory alkalosis, seizure, serotonin syndrome (with or without serotonergic medications), sleep apnea syndrome (obstructive) (Health Canada 2016, Shirani 2011), Stevens-Johnson syndrome, swollen tongue, syncope, tardive dyskinesia, thrombocythemia, thrombocytopenia, thrombophlebitis, thyroiditis, torsades de pointes, torticollis, trismus, urinary incontinence, vagin*l hemorrhage, venous thromboembolism, visual field defectContraindicationsHypersensitivity to ziprasidone or any component of the formulation; history of (or current) prolonged QT; congenital long QT syndrome; recent myocardial infarction;uncompensated heart failure; concurrent use of other QTc-prolonging agents including arsenic trioxide, chlorpromazine, class Ia antiarrhythmics (eg, disopyramide, quinidine, procainamide), class III antiarrhythmics (eg, amiodarone, dofetilide, ibutilide, sotalol), dolasetron, droperidol, gatifloxacin, halofantrine, levomethadyl, mefloquine, mesoridazine, moxifloxacin, pentamidine, pimozide, probucol, sparfloxacin, tacrolimus, and thioridazine Warnings/PrecautionsConcerns related to adverse effects:• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.• Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of olanzapine for the unapproved use in elderly patients with dementia-related psychosis.• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).• Dermatologic reactions: Use has been associated with a fairly high incidence of rash and/or urticaria (5%) that was dose- and possibly duration-related; discontinue if alternative etiology is not identified. Cases of dermatologic reactions (including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported; may be fatal. Symptoms of DRESS include a combination of three or more of the following: Severe skin eruption (rash or exfoliative dermatitis), fever, lymphadenopathy, eosinophilia and one or more systemic complications (eg, hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis). Discontinue use if DRESS or other severe cutaneous reactions are suspected.• Dyslipidemia: Has been reported with atypical antipsychotics; risk profile may differ between agents. Compared to other antipsychotics, the risk of dyslipidemia with ziprasidone is minimal to low (Solmi 2017).• Esophageal dysmotility/Aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (ie, Alzheimer disease), particularly in patients >75 years (Herzig 2017; Maddalena 2004).• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Keeper 2020]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability.• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Compared to other antipsychotics, the risk of hyperglycemia with ziprasidone is minimal to low (Solmi 2017).• Hyperprolactinemia: May increase prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown.• Neuroleptic malignant syndrome (NMS): Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability.• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).• Priapism: Rare cases of priapism have been reported.• QT prolongation: May result in QTc prolongation (dose related), which has been associated with the development of malignant ventricular arrhythmias (torsades de pointes) and sudden death. Observed prolongation was greater than with other atypical antipsychotic agents (risperidone, olanzapine, quetiapine), but less than with thioridazine. Avoid hypokalemia, hypomagnesemia. Use caution in patients with bradycardia. Discontinue in patients found to have persistent QTc intervals >500 msec. Patients with symptoms of dizziness, palpitations, or syncope should receive further cardiac evaluation. Also see Contraindications.• Suicidal ideation: The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI. Compared to other antipsychotics, the risk of weight gain with ziprasidone is minimal to low (Solmi 2017).Disease-related concerns:• Cardiovascular disease: Use is contraindicated in patients with recent acute myocardial infarction (MI), QT prolongation, or uncompensated heart failure. Avoid use in patients with a history of cardiac arrhythmias; use with caution in patients with history of MI or unstable heart disease.• Dementia: [US Boxed Warning]: Elderly patients with dementia-related behavioral disorders treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death (APA [Reus 2016]). Ziprasidone is not approved for the treatment of dementia-related psychosis.• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.• Hepatic impairment: Use with caution in patients with hepatic disease or impairment.• Renal impairment: Use the intramuscular formulation with caution in patients with renal impairment.• Seizures: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.Dosage form specific issues:• Intramuscular formulation: Use the intramuscular formulation with caution in patients with renal impairment; formulation contains cyclodextrin, an excipient which may accumulate in renal insufficiency, although the clinical significance of this finding is uncertain (Luke 2010).Other warnings/precautions:• Discontinuation of therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).Warnings: Additional Pediatric ConsiderationsIn June 2009, an FDA advisory panel advised that ziprasidone is effective in patients 10 to 17 years of age for the treatment of mixed and manic episodes of bipolar disorder, but did not conclude that it was safe due to large number of subjects lost to follow-up and ambiguity within QTc prolongation data. Since then, prescribing of ziprasidone has decreased similarly for pediatric and adult patients after the FDA non-approval (Wang 2016). Observed QTc prolongation with ziprasidone was greater than with other atypical antipsychotic agents (eg, risperidone, olanzapine, quetiapine), but less than with thioridazine. A prospective study followed 20 children (mean age: 13.2 years) for an average of 4.6 months and reported significant QTc prolongation at relatively low ziprasidone doses (mean daily dose: 30 mg ± 13 mg/day); the authors suggest the effect is not dose dependent in children unlike adults and recommend reserving ziprasidone use as second- or third-line for patients at risk for QTc prolongation or when using doses >40 mg/day (Blair 2005); monitor ECG with use. Use with caution during diarrheal illnesses; monitor electrolytes closely, particularly potassium and magnesium (Blair 2004). May cause hyperprolactinemia; use with caution in children and adolescents; adverse effects due to increased prolactin concentrations have been observed; long-term effects on growth or sexual maturation have not been evaluated.An increased risk for the development of type 2 diabetes mellitus (DM) was observed in pediatric patients 10 to 18 years receiving second-generation antipsychotics (SGA) at mean exposure duration of: 17.2 months. For patients initiated on SGA: 0.4% incidence with mean exposure at time type 2 DM diagnosed: 13.5 months; for SGA noniniators (patients receiving another agent prior to SGA initiation): 0.2% incidence with mean exposure at time of type 2 DM diagnosed: 14.6 months. Amongst specific SGAs, the risk was highest for aripiprazole (p=0.001) and ziprasidone (p=0.06) compared to risperidone as the reference group but not quetiapine or olanzapine (Rubin 2015).Pediatric psychiatric disorders are frequently serious mental disorders which present with variable symptoms that do not always match adult diagnostic criteria. Conduct a thorough diagnostic evaluation and carefully consider risks of psychotropic medication before initiation in pediatric patients. Medication therapy for pediatric patients with bipolar disorder is indicated as part of a total treatment program that frequently includes educational, psychological, and social interventions. A systematic review and meta-analysis of trials (n=2,158, age range: 8 to 19 years old) reported inferior efficacy of ziprasidone compared to other agents (aripiprazole, asenapine, paliperidone, risperidone, quetiapine, olanzapine, molindone) for youth with early-onset schizophrenia (Pagsberg 2017). Another systematic review evaluating the effect and safety of atypical antipsychotics for treatment of disruptive behavior disorders in children and youths noted a lack of evidence to support ziprasidone in children ≥5 years and youth and no evidence for children <5 years of age (Loy 2017).Similar to adult experience, the American Academy of Child and Adolescent Psychiatry (AACAP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (AACAP [McClellan 2007]).Metabolism/Transport EffectsSubstrate of CYP1A2 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapyAgents With Seizure Threshold Lowering Potential: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased. Risk C: Monitor therapyAlcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).Risk C: Monitor therapyAlizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyAmifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine.Risk C: Monitor therapyAmiodarone: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Amiodarone.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationAmisulpride (Oral): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Amisulpride (Oral).Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even greater risk. Risk D: Consider therapy modificationAmphetamines: Antipsychotic Agents may enhance the adverse/toxic effect of Amphetamines. Antipsychotic Agents may diminish the stimulatory effect of Amphetamines.Risk C: Monitor therapyAntidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.Risk C: Monitor therapyAnti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist).Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modificationAntipsychotic Agents: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased.Risk C: Monitor therapyArsenic Trioxide: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Arsenic Trioxide.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationAstemizole: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Astemizole.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationAzelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationAzithromycin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Azithromycin (Systemic).Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationBedaquiline: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Bedaquiline.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationBlonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin.Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modificationBlood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapyBrexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone.Risk C: Monitor therapyBrimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combinationBromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBuprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine.Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modificationBuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapyCabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combinationCannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.Risk C: Monitor therapyCarbetocin: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationChlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modificationChloroquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Chloroquine.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationChlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapyChlorproMAZINE: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of ChlorproMAZINE.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationCisapride: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Cisapride.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationCitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Citalopram.Risk X: Avoid combinationClarithromycin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clarithromycin.Risk X: Avoid combinationClofazimine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Clofazimine.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationClomiPRAMINE: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationCloZAPine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of CloZAPine.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationCNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of Ziprasidone. Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase the serum concentration of Ziprasidone. Risk C: Monitor therapyDabrafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationDaridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationDasatinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Dasatinib.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationDelamanid: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Delamanid.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationDeutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapyDexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine.Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modificationDexmethylphenidate-Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined.Risk C: Monitor therapyDifelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDomperidone: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Domperidone.Risk X: Avoid combinationDoxepin-Containing Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Doxepin-Containing Products.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationDoxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants isnot recommended. Risk C: Monitor therapyDronedarone: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Dronedarone.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationDroperidol: May enhance the QTc-prolonging effect of Ziprasidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk X: Avoid combinationEncorafenib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationEntrectinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combinationEscitalopram: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Escitalopram.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationEsketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyEtelcalcetide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationFexinidazole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combinationFingolimod: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias (including TdP) with a continuous overnight ECG when fingolimod is combined with QT prolonging drugs. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyFlecainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flecainide.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationFluconazole: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluconazole. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationFlunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine.Risk X: Avoid combinationFlunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modificationFluorouracil Products: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Fluorouracil Products.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationFlupentixol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Flupentixol.Risk X: Avoid combinationGadobenate Dimeglumine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationGemifloxacin: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationGilteritinib: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this combination. If use is necessary, monitor for QTc interval prolongation and arrhythmias. Risk D: Consider therapy modificationGuanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine.Risk C: Monitor therapyHalofantrine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Halofantrine.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationHaloperidol: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Haloperidol.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationHydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modificationIboga: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationImipramine: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationInotuzumab Ozogamicin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Inotuzumab Ozogamicin.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationIohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased.Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modificationIomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased.Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modificationIopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased.Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modificationKava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyKratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationLemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modificationLevofloxacin-Containing Products (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationLevoketoconazole: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Levoketoconazole.Risk X: Avoid combinationLithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapyLofexidine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Lofexidine.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationMagnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMeglumine Antimoniate: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationMequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine.Management: Consider alternatives to one of these agents when possible.While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modificationMethadone: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationMethotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modificationMetoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combinationMetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE.Risk C: Monitor therapyMetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapyMidostaurin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Midostaurin.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationMinocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMoxifloxacin (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Moxifloxacin (Systemic).Risk X: Avoid combinationNilotinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Nilotinib.Risk X: Avoid combinationOLANZapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of OLANZapine.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationOlopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOndansetron: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ondansetron.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationOpioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists.Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOrphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine.Risk X: Avoid combinationOsimertinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Osimertinib.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationOxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products.Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modificationOxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE.Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOxytocin: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationPacritinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pacritinib.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPapaverine: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of Papaverine.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationParaldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde.Risk X: Avoid combinationPAZOPanib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of PAZOPanib.Risk X: Avoid combinationPentamidine (Systemic): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic).Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationPerampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyPilsicainide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pilsicainide.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationPimozide: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Pimozide.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk X: Avoid combinationPiperaquine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Piperaquine.Risk X: Avoid combinationPiribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents.Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid combinationProbucol: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Probucol.Risk X: Avoid combinationProcarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyPropafenone: May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationPropofol: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Agents (Indeterminate Risk - Avoid): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Agents (Indeterminate Risk - Caution): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk).Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Risk X: Avoid combinationQUEtiapine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of QUEtiapine.Risk X: Avoid combinationQuinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide.Risk C: Monitor therapyQuiNINE: QT-prolonging Miscellaneous Agents (Highest Risk) may enhance the QTc-prolonging effect of QuiNINE.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationRibociclib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Ribociclib.Risk X: Avoid combinationRisperiDONE: QT-prolonging Agents (Highest Risk) may enhance the CNS depressant effect of RisperiDONE. QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of RisperiDONE.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationRopeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased.Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modificationRufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapySerotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapySertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Risk X: Avoid combinationSodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities.Risk C: Monitor therapySparfloxacin: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Sparfloxacin.Risk X: Avoid combinationSulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride.Risk X: Avoid combinationSUNItinib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of SUNItinib.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationSuvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant.Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary.Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationTerfenadine: May enhance the QTc-prolonging effect of Ziprasidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationTetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapyThalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide.Risk X: Avoid combinationThioridazine: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Thioridazine.Risk X: Avoid combinationToremifene: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Toremifene.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationTrimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyValerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyVemurafenib: QT-prolonging Agents (Highest Risk) may enhance the QTc-prolonging effect of Vemurafenib.Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modificationZolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem.Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg formen who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modificationFood InteractionsAdministration with a meal containing at least 500 calories increases serum levels ~80%. Management: Administer with a meal containing at least 500 calories (Lincoln 2010).Reproductive ConsiderationsZiprasidone may cause hyperprolactinemia, which may cause a reversible reduction of reproductive function in females.If treatment is needed in a woman planning a pregnancy, use of an agent other than ziprasidone may be preferred (Grunze 2018; Larsen 2015).Pregnancy ConsiderationsAntipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.The American College of Obstetricians and Gynecologists recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy are limited and routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to a typical antipsychotic that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008). If treatment is initiated during pregnancy, use of an agent other than ziprasidone may be preferred (Grunze 2018; Larsen 2015).Health care providers are encouraged to enroll women 18 to 45 years of age exposed to ziprasidone during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388 or https://www.womensmentalhealth.org/pregnancyregistry).Breastfeeding ConsiderationsZiprasidone is present in breast milk (Schlotterbeck 2009).According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Monitor infants exposed to ziprasidone via breast milk for excess sedation, irritability, poor feeding, and extrapyramidal symptoms. Until additional information is available, use of agents other than ziprasidone in breastfeeding women may be preferred (Larsen 2015).Dietary ConsiderationsCapsule: Take with food.Monitoring ParametersFrequency of Antipsychotic Monitoringa,bMonitoring parameterFrequency of monitoringCommentsa For all monitoring parameters, it is appropriate for check at baseline and when clinically relevant (based on symptoms or suspected adverse reactions) in addition to the timeline.b ADA 2004; APA [Keepers 2020]; De Hert 2011; Gugger 2011; manufacturer's labeling.c Cardiac risk factors include congenital long QT syndrome, structural or functional cardiac disease, bradycardia, family history of sudden cardiac death.d Risk factors for extrapyramidal symptoms (EPS) include prior history of EPS, high doses of antipsychotics, young age (children and adolescents at higher risk than adults), and dopaminergic affinity of individual antipsychotic.e Risk factors for tardive dyskinesia include age >55 years; females; White or African ethnicity; presence of a mood disorder, intellectual disability, or CNS injury; past or current EPS.AdherenceEvery visitBlood chemistries (electrolytes, renal function, liver function, TSH)AnnuallyCorrect electrolyte imbalances (hypokalemia) prior to administration; may prolong QT intervalCBCAs clinically indicatedCheck frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropeniaECGAs clinically indicatedCheck after significant dose increase or new QTc prolonging medication if there are cardiac risk factorscExtrapyramidal symptomsEvery visit; 4 weeks after initiation and dose change; annually. Use a formalized rating scale at least annually or every 6 months if high risk.dFall riskEvery visitFasting plasma glucose/HbA1c12 weeks after initiation and dose change; annuallyCheck more frequently than annually if abnormal. Follow diabetes guidelines.Lipid panel12 weeks after initiation and dose change; annuallyCheck more frequently than annually if abnormal. Follow lipid guidelines.Mental status and alertnessEvery visitMetabolic syndrome historyAnnuallyEvaluate for personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular diseaseProlactinAsk about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported.Hyperprolactinemia symptoms: Changes in menstruation, libido, gynecomastia, development of galactorrhea, and erectile and ejacul*tory functionTardive dyskinesiaEvery visit; annually. Use a formalized rating scale at least annually or every 6 months if high risk.eVital signs (BP, orthostatics, temperature, pulse, signs of infection)Every visit (at least weekly during first 3 to 4 weeks of treatment); 4 weeks after dose change.Weight/Height/BMI8 and 12 weeks after initiation and dose change; quarterlyConsider monitoring waist circumference at baseline and annually, especially in patients with or at risk for metabolic syndrome.Consider changing antipsychotic if BMI increases by ≥1 unit.Some experts recommend checking weight and height at every visit.Reference RangeTiming of serum samples: Draw trough just before next dose (Hiemke 2018).Therapeutic reference range: 50 to 200 ng/mL (SI: 127.5 to 510 nmol/L) (Hiemke 2018). Note: Dosing should be based on therapeutic response as opposed to serum concentrations; however, therapeutic drug monitoring can be used to confirm adherence (APA [Keepers 2020]).Laboratory alert level: 400 ng/mL (SI: 1,020 nmol/L) (Hiemke 2018).Mechanism of ActionZiprasidone is a benzylisothiazolylpiperazine antipsychotic. The exact mechanism of action is unknown. However, in vitro radioligand studies show that ziprasidone has high affinity for D2, D3, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT1D, and alpha1-adrenergic; moderate affinity for histamine H1 receptors; and no appreciable affinity for alpha2-adrenergic receptors, beta-adrenergic, 5-HT3, 5-HT4, cholinergic, mu, sigma, or benzodiazepine receptors. Ziprasidone functions as an antagonist at the D2, 5-HT2A, and 5-HT1D receptors and as an agonist at the 5-HT1A receptor. Ziprasidone moderately inhibits the reuptake of serotonin and norepinephrine.Pharmaco*kineticsOnset of action:Agitation: IM: Initial effects within 15 minutes; adequate sedation within 30 minutes (Martel 2005).Bipolar disorder, acute mania: Oral: Initial effects may be observed within days of treatment with continued improvements over 1 to 2 weeks (Goikolea 2013; Tohen 2000; Welten 2016).Major depressive disorder, unipolar: Oral: Initial effects may be observed within 1 week with continued improvements over 6 to 12 weeks (Wen 2014).Schizophrenia: Oral: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).Absorption: Well absorbed; administration with 500 calorie meals increases serum levels ~80% (Lincoln 2010).Distribution: Vd: 1.5 L/kg.Protein binding: >99%, primarily to albumin and alpha-1 acid glycoprotein.Metabolism: Extensively hepatic, primarily chemical and enzymatic reductions via glutathione and aldehyde oxidase, respectively; less than 1/3 of total metabolism via CYP3A4 and CYP1A2 (minor).Bioavailability: Oral (with food): 60%; IM: 100%.Half-life elimination:Oral: Mean terminal half-life:Children: Mean: 3.3 to 4.1 hours (Sallee 2006).Adults: 7 hours.IM: Mean half-life: 2 to 5 hours.Time to peak:Oral: Children: Mean: 5 to 5.5 hours (Sallee 2006); Adults: 6 to 8 hours.IM: ≤60 minutes.Excretion: Feces (~66%; <4% of total dose as unchanged drug); urine (~20%; <1% of total dose as unchanged drug).Clearance:Children: Mean: 11.5 to 13.1 mL/minute/kg (Sallee 2006).Adults: Mean: 7.5 mL/minute/kg.Pharmaco*kinetics: Additional ConsiderationsHepatic function impairment: Increases the AUC of ziprasidone.Pricing: USCapsules (Geodon Oral)20 mg (per each): $25.4040 mg (per each): $26.6460 mg (per each): $30.8280 mg (per each): $30.82Capsules (Ziprasidone HCl Oral)20 mg (per each): $8.00 - $8.9640 mg (per each): $8.00 - $8.9660 mg (per each): $9.83 - $10.8880 mg (per each): $9.83 - $10.88Solution (reconstituted) (Geodon Intramuscular)20 mg (per each): $65.60Solution (reconstituted) (Ziprasidone Mesylate Intramuscular)20 mg (per each): $23.89 - $56.40Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAzona (IN);Dolextaci (EG);Geodon (BB, BR, BZ, CO, CR, DO, GR, GT, HN, IE, IL, MX, NI, PA, SV, TR, TW, VE, ZA);Ypsila (HU);Zeldox (AE, AR, AT, AU, BG, BH, CL, CN, CZ, DE, DK, EE, EG, ES, FI, HK, HR, IS, JO, KR, KW, LB, LT, LV, MY, NO, NZ, PE, PH, PL, PT, QA, RO, RU, SE, SG, SI, SK, TH, UA, UY, VN);Zepradon (VN);Zipradon (BD);Zipramyl (PL);Zipsi (CZ);Zipsila (PL, RU);Zipsydon (BD, IN);Zipwell (HU, MT);Zypsilan (CZ, ES)For country code abbreviations (show table)2019 American Geriatrics Society Beers Criteria Update Expert Panel. 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Accessed July 27, 2020.Nguyen T, Stanton J, Foster R. Intramuscular ziprasidone dosing for acute agitation in the pediatric emergency department: an observational study. J Pharm Pract. 2018;31(1):18-21. [PubMed 28205446]Pagsberg AK, Tarp S, Glintborg D, et al. Acute antipsychotic treatment of children and adolescents with schizophrenia-spectrum disorders: a systematic review and network meta-analysis. J Am Acad Child Adolesc Psychiatry. 2017;56(3):191-202. [PubMed 28219485]Papakostas GI, Fava M, Baer L, et al. Ziprasidone augmentation of escitalopram for major depressive disorder: efficacy results from a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2015;172(12):1251-1258. doi:10.1176/appi.ajp.2015.14101251 [PubMed 26085041]Politte LC, McDougle CJ. Atypical antipsychotics in the treatment of children and adolescents with pervasive developmental disorders. Psychopharmacology (Berl). 2014;231(6):1023-1036. [PubMed 23552907]Post RM. Bipolar disorder in adults: Choosing maintenance treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 30, 2021.Remington G, Chue P, Stip E, Kopala L, Girard T, Christensen B. The crossover approach to switching antipsychotics: what is the evidence? Schizophr Res. 2005;76(2-3):267-272. doi:10.1016/j.schres.2005.01.009 [PubMed 15949658]Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry. 2016;173(5):543-546. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2015.173501. Accessed May 26, 2016. doi:10.1176/appi.ajp.2015.173501 [PubMed 27133416]Rothschild AJ. Unipolar major depression with psychotic features: acute treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 4, 2020Rubin DM, Kreider AR, Matone M, et al. Risk for incident diabetes mellitus following initiation of second-generation antipsychotics among Medicaid-enrolled youths. JAMA Pediatr. 2015;169(4):e150285. [PubMed 25844991]Sachs GS, Vanderburg DG, Karayal ON, Kolluri S, Bachinsky M, Cavus I. Adjunctive oral ziprasidone in patients with acute mania treated with lithium or divalproex, part 1: results of a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2012;73(11):1412-1419. doi:10.4088/JCP.11m07388 [PubMed 23218157]Sallee FR, Kurlan R, Goetz CG, et al, “Ziprasidone Treatment of Children and Adolescents With Tourette's Syndrome: A Pilot Study,” J Am Acad Child Adolesc Psychiatry, 2000, 39(3):292-9.Sallee FR, Miceli JJ, Tensfeldt T, Robarge L, Wilner K, Patel NC. Single-dose pharmaco*kinetics and safety of ziprasidone in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006;45(6):720-728. [PubMed 16721322]Scherk H, Pajonk FG, Leucht S. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Arch Gen Psychiatry. 2007;64(4):442-455. doi:10.1001/archpsyc.64.4.442 [PubMed 17404121]Schlotterbeck P, Saur R, Hiemke C, et al. Low concentration of ziprasidone in human milk: a case report. Int J Neuropsychopharmacol. 2009;12(3):437‐438. doi:10.1017/S1461145709009936 [PubMed 19203410]Scott LK, Green R, McCarthy PJ, et al, "Agitation and/or Aggression After Traumatic Brain Injury in the Pediatric Population Treated With Ziprasidone. Clinical Article," J Neurosurg Pediatr, 2009, 3(6):484-7. [PubMed 19485732]Shah AA, Aftab A, Coverdale J. QTc prolongation with antipsychotics: is routine ECG monitoring recommended? J Psychiatr Pract. 2014;20(3):196-206. doi:10.1097/01.pra.0000450319.21859.6d [PubMed 24847993]Shirani A, Paradiso S, Dyken ME. The impact of atypical antipsychotic use on obstructive sleep apnea: a pilot study and literature review. 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CloseZileuton: Drug informationZileuton: Drug information(For additional information see "Zileuton: Patient drug information" and see "Zileuton: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USZyflo;Zyflo CR [DSC]Pharmacologic Category5-Lipoxygenase InhibitorDosing: AdultAsthmaAsthma:Immediate release: Oral: 600 mg 4 times dailyExtended release: Oral: 1,200 mg twice dailyDosing: Kidney Impairment: AdultNo dosage adjustment necessary.Dosing: Hepatic Impairment: AdultUse is contraindicated in patients with active liver disease or persistent transaminase elevations ≥3 times the upper limit of normal.Dosing: Pediatric(For additional information see "Zileuton: Pediatric drug information")AsthmaAsthma: Note: Current guidelines do not describe a role for zileuton in the management of asthma (GINA 2018); not routinely used. Children ≥12 years and Adolescents:Immediate release: Oral: 600 mg 4 times daily; maximum daily dose: 2,400 mg/dayExtended release: Oral: 1,200 mg twice daily; maximum daily dose: 2,400 mg/dayDosing: Kidney Impairment: PediatricNo dosage adjustment necessary in renal impairment or with hemodialysis; dialysis: <0.5% removed by hemodialysis.Dosing: Hepatic Impairment: PediatricContraindicated in patients with active liver disease or persistent transaminase elevations ≥3 times the upper limit of normal.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productTablet, Oral: Zyflo: 600 mg [scored]Tablet Extended Release 12 Hour, Oral: Zyflo CR: 600 mg [DSC]Generic: 600 mgGeneric Equivalent Available: USMay be product dependentAdministration: AdultImmediate release: Administer without regard to meals.Extended release: Swallow tablet whole; do not crush, cut, or chew; administer within 1 hour after morning and evening meals.Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet formulation is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.Administration: PediatricOral:Immediate release: May administer daily doses at meals and bedtime.Extended release: Do not crush, cut, or chew tablet; administer within 1 hour after morning and evening meals. If dose is missed, it does not need administered; at the next scheduled time administer the next dose; do not double the dose.Use: Labeled IndicationsAsthma: Prophylaxis and chronic treatment of asthma in adults and children ≥12 years of ageLimitations of use: Not indicated for relief of acute bronchospasmAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%: Central nervous system: Headache (23% to 25%)1% to 10%:Cardiovascular: Chest painCentral nervous system: Pain (8%), dizziness, drowsiness, hypertonia, insomnia, malaise, nervousnessDermatologic: Pruritus, skin rashGastrointestinal: Dyspepsia (8%), nausea (5% to 6%), abdominal pain (5%), diarrhea (5%), constipation, flatulence, vomitingGenitourinary: Urinary tract infection, vaginitisHematologic & oncologic: Leukopenia (1% to 3%), lymphadenopathyHepatic: Increased serum ALT (≥3 x ULN: 2% to 5%), hepatotoxicityHypersensitivity: Hypersensitivity reactionNeuromuscular & skeletal: Myalgia (7%), weakness (4%), arthralgia, neck pain, neck stiffnessOphthalmic: ConjunctivitisRespiratory: Upper respiratory tract infection (9%), sinusitis (7%), pharyngolaryngeal pain (5%)Miscellaneous: Fever<1%, postmarketing, and/or case reports: Behavioral changes, hepatic failure, hepatitis, hyperbilirubinemia, jaundice, mood changes, sleep disorder, suicidal tendencies, urticariaContraindicationsHypersensitivity to zileuton or any component of the formulation; active liver disease or transaminase elevations ≥3 times ULNWarnings/PrecautionsConcerns related to adverse effects:• Hepatotoxicity: There have been reports of hepatic adverse effects (elevated transaminase levels); serum ALT should be monitored. Females >65 years and patients with pre-existing elevated transaminases may be at greater risk. Discontinue therapy and follow transaminases until normal if patients develop clinical signs/symptoms of liver dysfunction or with transaminase levels >5 times ULN; use caution with history of liver disease and/or in those patients who consume substantial quantities of ethanol.• Neuropsychiatric events: Postmarketing reports of behavioral changes and sleep disorders have been noted.Concurrent drug therapy issues:• Sedatives: CNS effects may be potentiated when used with other sedative drugs or ethanol.Special populations: • Older adult: Females >65 years of age may be at increased risk for ALT elevations. Pharmaco*kinetics were similar in older adults (≥65 years) compared to younger adults.• Pediatric: Due to the risk of hepatotoxicity, the manufacturer does not recommend use of zileuton in children <12 years of age.Other warnings/precautions:• Reversal of bronchospasm: Not indicated for the reversal of bronchospasm in acute asthma attacks, including status asthmaticus; therapy may be continued during acute asthma exacerbations.Metabolism/Transport EffectsSubstrate of CYP1A2 (minor), CYP2C9 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak)Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine.Risk C: Monitor therapyLomitapide: Zileuton may increase the serum concentration of Lomitapide.Management: Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half with concurrent zileuton; the lomitapide dose may then be increased to a max adult dose of 30 mg/day (patients on lomitapide 5 mg/day may continue that dose). Risk D: Consider therapy modificationLoxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine.Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation.This does not apply to non-inhaled formulations of loxapine. Risk X: Avoid combinationPropranolol: Zileuton may increase the serum concentration of Propranolol.Risk C: Monitor therapyTheophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives.Risk C: Monitor therapyTiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine.Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modificationWarfarin: Zileuton may increase the serum concentration of Warfarin.Risk C: Monitor therapyFood InteractionsZyflo CR: Improved absorption when administered with food. Management: Administer with food.Pregnancy ConsiderationsUncontrolled asthma is associated with adverse events in pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low birth weight infants, cesarean delivery, and the development of gestational diabetes). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Maternal treatment improves pregnancy outcomes by reducing the risk of some adverse events (eg, preterm birth, gestational diabetes). Maternal asthma symptoms should be monitored monthly during pregnancy. Agents other than zileuton are preferred for the treatment of asthma during pregnancy (ERS/TSANZ [Middleton 2020]; GINA 2021).Data collection to monitor pregnancy and infant outcomes associated with asthma and the medications used to treat asthma in pregnancy is ongoing. Health care providers are encouraged to enroll exposed pregnant patients in the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (877-311-8972 or https://mothertobaby.org). Patients may also enroll themselves.Breastfeeding ConsiderationsIt is not known if zileuton is present in breast milk.According to the manufacturer, due to the potential tumorigenicity of zileuton in animal studies, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.Dietary ConsiderationsImmediate release: Take without regard to meals.Extended release:Take with food. Monitoring ParametersHepatic transaminases (prior to initiation and during therapy), specifically monitor serum ALT (prior to initiation, once-a-month for the first 3 months, every 2 to 3 months for the remainder of the first year, and periodically thereafter for patients receiving long-term therapy)Mechanism of ActionSpecific 5-lipoxygenase inhibitor which inhibits leukotriene formation. Leukotrienes augment neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction (which contribute to inflammation, edema, mucous secretion, and bronchoconstriction in the airway of the asthmatic).Pharmaco*kineticsAbsorption: Well-absorbedDistribution: 1.2 L/kg Protein binding: 93%, primarily albuminMetabolism: Hepatic and gastrointestinal; zileuton and N-dehydroxylated metabolite can be metabolized by CYP1A2, 2C9, and 3A4Half-life elimination: ~3 hoursTime to peak: Immediate release: 1.7 hours Excretion: Urine (~95% primarily as metabolites); feces (~2%)Pharmaco*kinetics: Additional ConsiderationsHepatic function impairment: The mean apparent plasma clearance of zileuton in subjects with hepatic impairment was approximately half the value of the healthy subjects. The percent binding of zileuton to plasma proteins after multiple dosing was significantly reduced in patients with moderate hepatic impairment.Pricing: USTablet, 12-hour (Zileuton ER Oral)600 mg (per each): $32.18 - $33.83Tablets (Zyflo Oral)600 mg (per each): $37.59Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention (2018 update). http://www.ginasthma.org. Updated 2018. Accessed January 10, 2019.Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-final-_wms.pdf. Updated 2020. Accessed May 6, 2020.Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf. Updated 2021. Accessed May 28, 2021.Middleton PG, Gade EJ, Aguilera C, et al. ERS/TSANZ task force statement on the management of reproduction and pregnancy in women with airways diseases. Eur Respir J. 2020;55(2):1901208. doi:10.1183/13993003.01208-2019 [PubMed 31699837]National Asthma Education and Prevention Program (NAEPP). Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma. Clinical Practice Guidelines, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Publication No. 08-4051. Published August 2007. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.Zileuton extended-release tablets [prescribing information]. Upper Saddle River, NJ: DASH Pharmaceuticals LLC; November 2020.Zyflo (zileuton) [prescribing information]. Cary, NC: Chiesi USA, Inc; January 2017.Zyflo CR (zileuton) [prescribing information]. Cary, NC: Chiesi USA, Inc; March 2019.Topic 10054 Version 177.0

CloseTravoprost: Drug informationTravoprost: Drug information(For additional information see "Travoprost: Patient drug information" and see "Travoprost: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USTravatan ZBrand Names: CanadaAPO-Travoprost Z;Izba;SANDOZ Travoprost;TEVA-Travoprost Z [DSC];Travatan ZPharmacologic CategoryOphthalmic Agent, Antiglaucoma;Prostaglandin, OphthalmicDosing: AdultOcular hypertension/glaucomaOcular hypertension/glaucoma (open-angle): Ophthalmic: Instill 1 drop into affected eye(s) once daily in the evening; do not exceed once-daily dosing (may decrease intraocular pressure-lowering effect).Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling; dosage adjustments are unlikely due to low systemic absorption.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling; dosage adjustments are unlikely due to low systemic absorption.Dosing: Pediatric(For additional information see "Travoprost: Pediatric drug information")Elevated intraocular pressureElevated intraocular pressure (IOP): Ophthalmic: Infants ≥2 months, Children, and Adolescents: Limited data available: 1 drop into affected eye(s) once daily in the evening (Dixon 2017; Yanovitch 2008). Note: Do not exceed once-daily dosing (may decrease IOP-lowering effect).Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling; however, dosage adjustments are unlikely due to low systemic absorption.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling; however, dosage adjustments are unlikely due to low systemic absorption.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Ophthalmic: Travatan Z: 0.004% (2.5 mL, 5 mL) [contains propylene glycol]Travatan Z: 0.004% (2.5 mL [DSC], 5 mL [DSC]) [benzalkonium free; contains cremophor el, propylene glycol]Generic: 0.004% (2.5 mL, 5 mL)Generic Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution, Ophthalmic: Izba: 0.003% (2.5 mL, 5 mL) [contains propylene glycol]Travatan Z: 0.004% (2.5 mL, 5 mL) [contains propylene glycol]Generic: 0.004% (2.5 mL, 5 mL)Administration: AdultOphthalmic: May be used with other eye drops to lower intraocular pressure. If using more than one ophthalmic product, wait at least 5 minutes in between application of each medication. Remove contact lenses prior to administration and wait 15 minutes (after administration) before reinserting. Minimize contamination by not touching the eyelids or surrounding areas with the dropper tip; keep bottle tightly closed when not in use. Use eyelid closure or nasolacrimal occlusion when applying topical medications to reduce systemic absorption.Administration: PediatricFor ophthalmic use only. Travoprost may be used with other eye drops to lower intraocular pressure. If using more than one ophthalmic product, wait at least 5 minutes in between application of each medication. Apply gentle pressure to lacrimal sac immediately following instillation (1 minute) or instruct patient to gently close eyelid after administration to decrease systemic absorption of ophthalmic drops (Urtti 1993; Zimmerman 1984). Remove contact lenses prior to administration and wait 15 minutes (after administration) before reinserting. Avoid contact of bottle tip with skin or eye; ocular solutions can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may occur from using contaminated solutionsUse: Labeled IndicationsOcular hypertension/glaucoma (open-angle): Reduction of elevated intraocular pressure in patients ≥16 years of age.Medication Safety IssuesSound-alike/look-alike issues: Travatan may be confused with XalatanAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%: Ophthalmic: Ocular hyperemia (30% to 50%)1% to 10%:Cardiovascular: Angina pectoris (1% to 5%), bradycardia (1% to 5%), chest pain (1% to 5%), hypertension (1% to 5%), hypotension (1% to 5%)Central nervous system: Foreign body sensation of eye (5% to 10%), anxiety (1% to 5%), depression (1% to 5%), headache (1% to 5%), pain (1% to 5%)Dermatologic: Hyperpigmentation of eyelashes, increased growth in number of eyelashesEndocrine & metabolic: Hypercholesterolemia (1% to 5%)Gastrointestinal: Dyspepsia (1% to 5%), gastrointestinal distress (1% to 5%)Genitourinary: Prostatic disease (1% to 5%), urinary incontinence (1% to 5%), urinary tract infection (1% to 5%)Hypersensitivity: Hypersensitivity reaction (1% to 5%)Infection: Infection (1% to 5%)Neuromuscular & skeletal: Arthritis (1% to 5%), back pain (1% to 5%)Ophthalmic: Decreased visual acuity (5% to 10%), eye discomfort (5% to 10%), eye pain (5% to 10%), eye pruritus (5% to 10%), blepharitis (1% to 4%), blurred vision (1% to 4%), cataract (1% to 4%), conjunctivitis (1% to 4%), corneal staining (1% to 4%), crusting of eyelid (1% to 4%), dry eye syndrome (1% to 4%), hyperpigmentation of eyelids (periorbital; 1% to 4%), iris discoloration (1% to 4%), keratitis (1% to 4%), lacrimation (1% to 4%), ophthalmic inflammation (1% to 4%), photophobia (1% to 4%), subconjunctival hemorrhage (1% to 4%), visual disturbance (1% to 4%), increased eyelash length, increased eyelash thicknessRespiratory: Bronchitis (1% to 5%), flu-like symptoms (1% to 5%), sinusitis (1% to 5%)<1%, postmarketing, and/or case reports: Abdominal pain, arthralgia, asthma, bacterial keratitis (due to solution contamination), cardiac arrhythmia, chest discomfort, corneal edema, cystoid macular edema, diarrhea, dyspnea, dysuria, enophthalmos, epistaxis, erythema of skin, insomnia, iritis, macular edema, musculoskeletal pain, nausea, prostate specific antigen increase, pruritus, tachycardia, tinnitus, uveitis, vomitingContraindicationsThere are no contraindications listed in the US manufacturer’s labeling.Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to travoprost or any component of the formulation; pregnancy or women attempting to become pregnant.Warnings/PrecautionsConcerns related to adverse effects:• Bacterial keratitis: Inadvertent contamination of multiple-dose ophthalmic solutions has caused bacterial keratitis.• Eye color changes: May change/increase brown pigmentation of the iris, the eyelid skin, and eyelashes; length and/or number of eyelashes may also be increased. Pigmentation of the iris is likely to be permanent although iris color change may not be noticeable for months to years; pigmentation of the periorbital tissue and eyelash changes may be reversible following discontinuation of therapy. Long-term consequences and potential injury to eye are not known.• Ocular inflammation: Intraocular inflammation and exacerbation of inflammation may occur; use with caution in patients with a history of intraocular inflammation (eg, iritis/uveitis) and generally avoid use in patients with active intraocular inflammation.Disease-related concerns:• Aphakia or pseudoaphakia: Topical prostaglandin analogues have been associated with the occurrence/exacerbation of macular edema. Carefully examine the macula in these patients especially those with an open posterior capsule.• Herpetic keratitis: Use with caution in patients with a history of herpes simplex keratitis; reactivation may occur. Avoid use in patients with active herpes simplex keratitis.• Uveitis: Use cautiously in patients with intraocular inflammation as topical prostaglandins may worsen inflammation.Special populations:• Contact lens wearers: Remove contact lens prior to instillation; may reinsert 15 minutes following administration.• Pediatric: Use in pediatric patients (<16 years of age) is not recommended by the manufacturer due to possible safety issues of increased pigmentation following long-term chronic use.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents (Ophthalmic): May diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents (Ophthalmic) may enhance the therapeutic effect of Prostaglandins (Ophthalmic). Risk C: Monitor therapyReproductive ConsiderationsOphthalmic prostaglandins, such as travoprost, have a theoretical risk of miscarriage. To decrease this risk, agents other than travoprost may be preferred for the treatment of glaucoma in patients planning to become pregnant (Strelow 2020).Pregnancy ConsiderationsOphthalmic prostaglandins, such as travoprost, are generally avoided during pregnancy due to a theoretical risk of miscarriage and premature labor. Agents other than travoprost may be preferred for the treatment of glaucoma during pregnancy, especially during the first trimester. In general, if ophthalmic agents are needed in pregnancy, the minimum effective dose should be used in combination with punctal occlusion to decrease exposure to the fetus (Belkin 2020; Prum 2016; Strelow 2020).Breastfeeding ConsiderationsIt is not known if travoprost is present in breast milk.According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Due to their short half-lives, ophthalmic prostaglandins such as travoprost are considered compatible with breastfeeding; administering after breastfeeding may help decrease potential exposure to the infant via breast milk (Belkin 2020; Prum 2016; Strelow 2020).Monitoring ParametersOphthalmic exams (optic nerve and visual field assessment), serial measurement of intraocular pressure (IOP). Frequency of follow up based upon whether target IOP achieved, if there is any progression of damage, and how long disease has been controlled (AAO 2019).Mechanism of ActionA selective FP prostanoid receptor agonist which lowers intraocular pressure by increasing trabecular meshwork and outflowPharmaco*kineticsOnset of action: ~2 hours.Peak effect: 12 hours.Absorption: Absorbed via cornea; plasma levels <10 pg/mL within 1 hour.Metabolism: Hydrolyzed by esterases in the cornea to active free acid; systemically; the free acid is metabolized to inactive metabolites.Half-life elimination: 45 minutes (range: 17 to 86 minutes).Excretion: Urine (<2% as metabolites).Pharmaco*kinetics: Additional ConsiderationsRace/ethnicity: The intraocular pressure (IOP)-lowering effect of travoprost was shown to be 7 to 8 mm Hg among patients with a baseline pressure of 25 to 27 mm Hg in clinical studies. The mean IOP reduction was up to 1.8 mm Hg greater in Black patients, although it is not known if this increase can be attributed to race or to heavily pigmented irides.Pricing: USSolution (Travatan Z Ophthalmic)0.004% (per mL): $97.77Solution (Travoprost (BAK Free) Ophthalmic)0.004% (per mL): $79.34 - $83.84Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAvatan (LK);Avost (BD);Avro (BD);Bondulc (CZ);Fredomat (CZ);Izba (HR, IE, MY, NL, NO, PL, SE, TH, TW);Lupitros (IN);Tekliva (EG);Trapost (BD);Travamed (BR);Travatan (AE, AR, AT, AU, BE, BG, BH, BO, BR, CH, CL, CN, CO, CR, CY, DE, DK, DO, EC, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HU, ID, IE, IL, IS, IT, JO, KR, KW, LB, LK, LT, LU, LV, MT, MX, MY, NI, NL, NO, NZ, PA, PE, PH, PK, PL, PR, PT, PY, QA, RO, RU, SA, SE, SG, SI, SK, SV, TH, TR, TW, UA, UY, VE, VN, ZA, ZW);Travatanz (JP);Travotan (BD);Vitron (VE);Vizitrav (ES, NL)For country code abbreviations (show table)American Academy of Ophthalmology (AAO) PPP Glaucoma Panel, Hoskins Center for Quality Eye Care. Glaucoma summary benchmarks-2019, October 2019. Available online: https://www.aao.org/summary-benchmark-detail/glaucoma-summary-benchmarks-2019#PrimaryOpen-AngleGlaucoma(InitialEvaluation). Last accessed December 23, 2019.Belkin A, Chen T, DeOliveria AR, et al. A practical guide to the pregnant and breastfeeding patient with glaucoma. OphthalmolGlaucoma. 2020;3:79-89.Center for Drug Evaluation and Research. Clinical pharmacology and biopharmaceutics review(s). US Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204822Orig1s000ClinPharmR.pdf. Published August 21, 2013. Accessed December 23, 2019.Center for Drug Evaluation and Research. Pharmacology review. US Food and Drug Administration website.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/21257_Travatan_pharmr_P1.pdf. Published August 21, 2013. Accessed December 23, 2019.Dixon ER, Landry T, Venkataraman S, et al. A 3-month safety and efficacy study of travoprost 0.004% ophthalmic solution compared with timolol in pediatric patients with glaucoma or ocular hypertension. J AAPOS. 2017;21(5):370-374.e1. [PubMed 28887006]European Medicines Academy. Summary of product characteristics - travatan. https://www.ema.europa.eu/en/documents/product-information/travatan-epar-product-information_en.pdf Accessed December 23, 2019.Gupta N, Aung T, Congdon, Dada R, et al. International Council of Ophthalmology guidelines for glaucoma eye care. 2017. Available online: http://www.icoph.org/downloads/ICOGlaucomaGuidelines.pdf. Last accessed December 13, 2019.Izba (travoprost) [prescribing information]. Fort Worth, TX: Alcon Laboratories Inc; June 2021.Izba (travoprost) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada; September 2017.Prum BE Jr, Rosenberg LF, Gedde SJ, et al. Primary open-angle glaucoma preferred practice pattern(®) guidelines. Ophthalmology. 2016;123(1):P41-P111. doi:10.1016/j.ophtha.2015.10.053 [PubMed 26581556]Strelow B, Fleischman D. Glaucoma in pregnancy: an update. Curr Opin Ophthalmol. 2020;31(2):114-122. doi:10.1097/ICU.0000000000000641 [PubMed 31922978]Travatan Z (travoprost) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; May 2020.Travatan Z (travoprost) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; February 2019.Travoprost ophthalmic solution [prescribing information]. Princeton, NJ: Sandoz Inc; September 2017.Urtti A, Salminen L. Minimizing systemic absorption of topically administered ophthalmic drugs. Surv Ophthalmol. 1993;37(6):435-456. [PubMed 8100087]Yanovitch TL, Enyedi LB, Schotthoeffer EO, Freedman SF. Travoprost in children: adverse effects and intraocular pressure response. J AAPOS. 2009;13(1):91-93. [PubMed 19233013]Zimmerman TJ, Kooner KS, Kandarakis AS, Ziegler LP. Improving the therapeutic index of topically applied ocular drugs. Arch Ophthalmol. 1984; 102(4):551-553. [PubMed 6704011]Topic 10055 Version 198.0

CloseZolpidem: Drug informationZolpidem: Drug information(For additional information see "Zolpidem: Patient drug information" and see "Zolpidem: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningComplex sleep behaviors:Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following the use of zolpidem. Some of these events may result in serious injuries, including death. Discontinue zolpidem immediately if a patient experiences a complex sleep behavior.Brand Names: USAmbien;Ambien CR;Edluar;Intermezzo [DSC];ZolpimistBrand Names: CanadaAPO-Zolpidem ODT;MINT-Zolpidem ODT;PMS-Zolpidem ODT;SublinoxPharmacologic CategoryHypnotic, Miscellaneous;Nonbenzodiazepine Benzodiazepine Receptor AgonistDosing: AdultInsomniaInsomnia: Note: Limit long-term use (>4 weeks) to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (ACP [Qaseem 2016]; ESRS [Riemann 2017]). Use of the higher dose can increase the risk of next-day impairment of driving and activities requiring full alertness.Sleep-onset insomnia: ER tablet: Oral: Initial: 6.25 mg (females) or 6.25 to 12.5 mg (males) immediately before bedtime with ≥7 to 8 hours of planned sleep before waking. Use lowest effective dose, not to exceed 12.5 mg.IR tablet, spray, sublingual tablet: Oral: Initial: 5 mg (females) or 5 to 10 mg (males) immediately before bedtime with ≥7 to 8 hours of planned sleep before waking. Use lowest effective dose, not to exceed 10 mg.Sleep-maintenance insomnia, 7 to 8 hours planned sleep:ER tablet: Oral: Initial: 6.25 mg (females) or 6.25 to 12.5 mg (males) immediately before bedtime with ≥7 to 8 hours of planned sleep before waking. Use lowest effective dose, not to exceed 12.5 mg.IR tablet, spray, sublingual tablet (off-label use): Oral: Initial: 5 mg (females) or 5 to 10 mg (males) immediately before bedtime with ≥7 to 8 hours of planned sleep before waking. Use lowest effective dose, not to exceed 10 mg.Sleep-maintenance insomnia, awakening with 4 hours planned sleep: IR sublingual tablet: Oral: 1.75 mg (females) or 1.75 to 3.5 mg (males) once per night upon awakening in the middle of the night with ≥4 hours of planned sleep remaining.Discontinuation of therapy: Reduce by the smallest available dosage form every week or every other week; ER tablets cannot be split. For patients taking higher doses of zolpidem (eg, 10 to 12.5 mg/day) for an extended period, tapering zolpidem even more slowly in conjunction with cognitive behavioral therapy for insomnia is encouraged (Bélanger 2009). Because the ER tablets cannot be split, the taper is generally done with IR tablets.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Fillastre 1993; manufacturer's labeling).Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Fillastre 1993; manufacturer's labeling): No supplemental dose or dosage adjustment necessary (expert opinion).Peritoneal dialysis: Unlikely to be significantly dialyzed: No dosage adjustment necessary (expert opinion).Dosing: Hepatic Impairment: AdultER tablet:Mild to moderate impairment: 6.25 mg immediately before bedtime.Severe impairment: Avoid use.IR tablet:Mild to moderate impairment: 5 mg immediately before bedtime.Severe impairment: Avoid use.Oral spray: 5 mg immediately before bedtime.Sublingual tablet:Edluar: 5 mg immediately before bedtime.Intermezzo: Females and males: 1.75 mg once per night as needed. Note: Take in bed only if ≥4 hours left before waking and there is difficulty in returning to sleep.Sublinox [Canadian product]:Mild to moderate impairment: 5 mg immediately before bedtime.Severe impairment: Use is contraindicated.Dosing: Pediatric(For additional information see "Zolpidem: Pediatric drug information")Note: The lowest effective dose should be used; higher doses may be more likely to impair next-morning activities.InsomniaInsomnia:Children and Adolescents ≤17 years: Limited data available; efficacy results variable and have not been demonstrated in randomized placebo-controlled trials (Anand 2017). Oral: Immediate-release tablets: Usual reported dose: 0.25 mg/kg at bedtime; maximum dose: 10 mg/dose (Blumer 2008; Blumer 2009; Hanna 2018); dosing based on reported experience from an open-label, dose escalation pharmaco*kinetic evaluation showed zolpidem was well-tolerated in pediatric patients 2 to 18 years of age and recommended a dose of 0.25 mg/kg at bedtime for evaluation in future efficacy trials (Blumer 2008). However, zolpidem has not been shown to be effective in a randomized placebo-controlled trial (n=201) of children aged 6 to 17 years with ADHD-associated insomnia; zolpidem 0.25 mg/kg/dose (maximum dose: 10 mg) administered nightly did not decrease sleep latency; in addition, hallucinations occurred in 7.4% of patients (Blumer 2009). A comparative, randomized controlled trial of zolpidem and haloperidol in pediatric burn patients (n=40, mean age: 9.4 ± 0.7 years) showed zolpidem dosed at 0.5 mg/kg nightly for 1 week (maximum dose: 20 mg) minimally increased Stage 3/4 sleep and REM but not total sleep time; the authors no longer use zolpidem to try to improve sleep in their pediatric burn patients (Armour 2008). A retrospective study compared effectiveness of zolpidem (no dose noted in study) in pediatric burn patients (n=46, mean age: 11 ± 3.7 years) with and without ADHD and found that sleep dysfunction was similar between the groups and those with ADHD required a sleep medication change sooner, concluding that zolpidem was not an effective drug in managing sleep in pediatric burn patients with or without ADHD (Cronin 2015). A prospective, randomized double-blind clinical trial of children between ages 2 to 9 years reported that zolpidem at 0.25 mg/kg (maximum dose: 10 mg/dose) was similar to midazolam with regards to anxiety scoring and inferior with regard to mask acceptance score when used as premedication for perioperative anxiety (Hanna 2018).Adolescents ≥18 years (non-debilitated patients): Note: The lowest effective dose should be used; higher doses may be more likely to impair next morning activities.Oral:Immediate-release tablet (eg, Ambien), spray (Zolpimist): 5 mg (females) or 5 to 10 mg (males) immediately before bedtime; maximum dose: 10 mg/dose.Extended-release tablet (eg, Ambien CR): 6.25 mg (females) or 6.25 to 12.5 mg (males) immediately before bedtime; maximum dose: 12.5 mg/dose.Sublingual tablet:Edluar: 5 mg (females) or 5 to 10 mg (males) immediately before bedtime; maximum daily dose: 10 mg/day.Intermezzo: Note: Should be taken if patient awakens in middle of night, has difficulty returning to sleep, and has at least 4 hours left before waking.Females: 1.75 mg once per night as needed; maximum dose: 1.75 mg/night.Males: 3.5 mg once per night as needed; maximum dose: 3.5 mg/night.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no pediatric-specific recommendations; based on experience in adult patients, no adjustment may be necessary.Hemodialysis: Not dialyzable.Dosing: Hepatic Impairment: PediatricAdolescents ≥ 18 years:Immediate-release tablet:Mild to moderate impairment: 5 mg immediately before bedtimeSevere impairment: Avoid useExtended-release tablet:Mild to moderate impairment: 6.25 mg immediately before bedtimeSevere impairment: Avoid useOral spray: 5 mg immediately before bedtimeSublingual tablet:Edluar: 5 mg immediately before bedtimeIntermezzo: Females and males: 1.75 mg once per night as needed. Note: Take in bed only if ≥4 hours left before waking and there is difficulty in returning to sleep.Dosing: Older AdultAvoid use (Beers Criteria [AGS 2019]).Discontinuation of therapy: Refer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Oral, as tartrate: Zolpimist: 5 mg/actuation (4.5 mL [DSC], 7.7 mL [DSC]) [contains benzoic acid, propylene glycol]Zolpimist: 5 mg/actuation (4.5 mL, 7.7 mL) [contains benzoic acid, propylene glycol; cherry flavor]Tablet, Oral, as tartrate: Ambien: 5 mg [contains fd&c red #40 (allura red ac dye), polysorbate 80]Ambien: 10 mgGeneric: 5 mg, 10 mgTablet Extended Release, Oral, as tartrate: Ambien CR: 6.25 mgAmbien CR: 12.5 mg [contains fd&c blue #2 (indigotine)]Generic: 6.25 mg, 12.5 mgTablet Sublingual, Sublingual, as tartrate: Edluar: 5 mg, 10 mg [contains saccharin sodium]Intermezzo: 1.75 mg [DSC]Generic: 1.75 mg, 3.5 mgGeneric Equivalent Available: USMay be product dependentDosage Forms ConsiderationsZolpimist oral spray 4.5 mL containers contain 30 actuations and 7.7 mL containers contain 60 actuations.Dosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet Sublingual, Sublingual, as tartrate: Sublinox: 5 mg, 10 mg [contains saccharin sodium]Generic: 5 mg, 10 mgControlled SubstanceC-IVMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Ambien: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/019908s40s044s047lbl.pdf#page=24Ambien CR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021774s021s025s028lbl.pdf#page=27Edluar: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021997s011lbl.pdf#page=23Intermezzo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022328s008lbl.pdf#page=20Zolpidem tablets:https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/Zolpidem.pdfZolpimist: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022196s012lbl.pdf#page=19Administration: AdultOral: Administer immediately before bedtime due to rapid onset of action. Regardless of dosage form, do not administer with or immediately after a meal (may delay onset). With the exception of Intermezzo, zolpidem should be taken as a single dose at bedtime with at least 7 to 8 hours remaining before planned time of awakening and should not be readministered during the same night. Intermezzo should be taken in bed if patient awakes in the middle of the night (ie, if ≥4 hours left before waking) and there is difficulty in returning to sleep.ER tablet: Swallow tablet whole; do not divide, crush, or chew.Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet, sublingual tablet, and oral spray formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.Sublingual tablet: Place sublingual tablet under the tongue and allow to disintegrate; do not swallow or administer Edluar or Sublinox with water.Oral spray: Spray directly into the mouth over the tongue. Prior to initial use, prime pump by spraying 5 times. If pump is not used for at least 14 days, reprime pump with 1 spray.Administration: PediatricOral:All formulations: Regardless of dosage form, do not administer with or immediately after a meal (may delay onset). With the exception of Intermezzo, zolpidem should be taken as a single dose immediately before bedtime (due to rapid onset) with at least 7 to 8 hours remaining before planned time of awakening and should not be readministered during the same night. Intermezzo should be taken in bed if patient awakens in the middle of the night (ie, if ≥4 hours left before waking) and there is difficulty in returning to sleep.Extended-release tablets (Ambien CR): Swallow whole; do not divide, crush, or chew.Sublingual tablets (Edluar, Intermezzo): Examine blisterpack before use; do not use if blisters are broken, torn, or missing. Separate individual blisters at perforation; peel off top layer of paper; push tablet through foil. Place under the tongue and allow to disintegrate; do not swallow or administer with water.Oral spray (Zolpimist): Spray directly into the mouth over the tongue. Prior to initial use, pump should be primed by spraying 5 times. If pump is not used for at least 14 days, reprime pump with 1 spray.Use: Labeled IndicationsInsomnia:IR and sublingual tablets (Edluar only) and oral spray: Short-term treatment of insomnia with difficulty of sleep onset.ER tablet: Short-term treatment of insomnia with difficulty of sleep onset and/or sleep maintenance.Sublingual tablet (Intermezzo only): As-needed treatment of insomnia when middle-of-the-night awakening is followed by difficulty returning to sleep and the patient has ≥4 hours of sleep time remaining.Sublingual tablet (Sublinox only [Canadian product]): Short-term treatment of insomnia (with difficulty of sleep onset, frequent awakenings, and/or early awakenings).Medication Safety IssuesSound-alike/look-alike issues:Ambien may be confused with Abilify, Ativan, Ambi 10Sublinox may be confused with SuboxoneZolpidem may be confused with lorazepam, zaleplon, ZyloprimOlder Adult: High-Risk Medication:Beers Criteria: Zolpidem, a nonbenzodiazepine benzodiazepine-receptor agonist hypnotic, is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to adverse events similar to benzodiazepines in older adults (eg, delirium, falls, fractures) and an increase in emergency room visits, hospitalizations, and motor vehicle crashes. In addition, improvement in sleep latency and duration is minimal (Beers Criteria [AGS 2019]).Pharmacy Quality Alliance (PQA): Zolpidem (when cumulative day supply is >90 days) is identified as a high-risk medication in patients 65 years and older on the PQA’s, Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (PQA 2017).International issues:Ambien [US, Argentina, Israel] may be confused with Amyben brand name for amiodarone [Great Britain]Adverse Reactions (Significant): ConsiderationsCNS depressionSedative-hypnotic agents, including zolpidem, are associated with next-day drowsiness, and decreased mental alertness (Ref). In patients taking zolpidem, these effects have led to impaired driving, accidental injury, and trauma, such as motor vehicle accidents, falling, bone fracture (including femoral neck fracture), and intracranial injuries (Ref). Patients may feel fully awake, despite this impairment in mental alertness. Zolpidem is included in the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (Ref).Mechanism: Serum concentration-related; related to the pharmacologic action (ie, sedative-hypnotic effects).Onset: Rapid; occurs within 24 hours after dose; may occur after the first dose (Ref).Risk factors:• Conditions or states leading to increased serum concentrations (eg, age ≥65 years, females) (Ref)• Concurrent CNS depressants (eg, medications, alcohol)• Concurrent drugs that increase zolpidem concentrations (eg, CYP 3A4 inhibitors)• Extended-release formulation (Ref)• Sleeping less than 7 to 8 hours after zolpidem administrationComplex sleep behaviorsComplex sleep-related disorder may occur, including somnambulism, and eating, driving, cooking, and having sex while sleeping have been reported (Ref). Patients usually have no recollection of these sleep-related behaviors (Ref). In some cases, these behaviors led to serious injury or death (Ref). Non-fatal effects were reversible upon drug discontinuation (Ref).Mechanism: Dose-related; idiosyncratic (Ref).Onset: Varied; typically occurs 30 minutes after a single dose (Ref). May occur after years of therapy (Ref).Risk factors:• Dose: May occur at any dose; more likely with higher doses (Ref)• Females (Ref)• Concurrent use of serotonergic antidepressants (Ref)• Concurrent use of alcohol or CNS depressants (Ref)• Concurrent use of CYP3A4 inhibitors (Ref)• Preexisting sleep disorder (eg, obstructive sleep apnea, restless leg syndrome) (Ref)• Administration earlier than immediately before sleep (Ref)• Substance use disorder (Ref)Other psychiatric/behavioral effectsVarious other psychiatric and behavioral effects (aside from complex sleep-related disorder; see above for more information) have been reported, including hallucination (visual and auditory), delirium, abnormality in thinking, increased aggressive behavior, disinhibition, bizarre behavior, agitation, amnesia, anxiety, and worsening of depression in pediatric and adult patients (Ref). These effects have occurred unpredictably in patients with and without previously diagnosed psychiatric illness or risk factors. Hallucination was reported more frequently with zolpidem than placebo in pediatric patients treated for insomnia associated with attention-deficit/hyperactivity disorder (ADHD) (Ref). These effects were reversible upon discontinuation (Ref).Mechanism: Dose-related; idiosyncratic (Ref).Onset: Varied; typically occurs within 15 to 30 minutes after initial dose (Ref).Risk factors:• Dose: May occur at any dose; more likely with higher doses (Ref)• Females (Ref)• Age ≥65 years (Ref)• Concurrent psychoactive medications (eg, SSRIs, opioids, other anti-anxiety or insomnia medications) (Ref)• Concurrent alcohol (Ref)• Concurrent ADHD, neurodevelopmental disorder, or other underlying psychiatric illness (Ref)• Substance use disorder (Ref)Suicidal ideation and behaviorSuicidal ideation and suicidal tendencies have occurred in patients with and without previously diagnosed psychiatric illness (Ref). May be related to zolpidem-induced “dream-like” confusion, bizarre behavior, hallucination, or paranoia (Ref). Some reports have been connected to complex sleep-related disorder (see above for more information) (Ref).Mechanism: Dose-related; idiosyncratic (Ref).Onset: Intermediate; typically occurs within the first 7 days of therapy (Ref).Risk factors:• Dose: May occur at any dose; more likely with higher doses (Ref)• History of psychiatric illness (eg, anxiety, bipolar disorder, depression, schizophrenia) (Ref)• Concurrent alcohol or illicit drug use (Ref)WithdrawalWithdrawal symptoms following discontinuation of GABA-mediate (GABAergic) medications are generally mild and infrequent (Ref). Transient rebound sleep disturbances (eg, longer sleep-onset latency and increased awakenings) may occur for 1 to 2 days after discontinuation (Ref). Less commonly, a withdrawal syndrome, with symptoms including abdominal cramps, anxiety, disorientation, dysphoria, insomnia, irritability, muscle cramps, restlessness, seizures, sweating, tremor, and vomiting may occur, especially after rapid dose decreases or abrupt discontinuation of chronic supratherapeutic doses (Ref). Withdrawal syndrome symptoms generally resolve within a few weeks of drug discontinuation or with resumption of therapy (Ref).Mechanism: Withdrawal; long-term therapy induces changes in the GABAA benzodiazepine receptor that decrease the effects of endogenous GABA after drug discontinuation (Ref). Chronic use of supratherapeutic zolpidem doses may result in loss of receptor selectivity and benzodiazepine-like drug effects (Ref). Therefore, rapid dose decreases or abrupt discontinuation may mimic benzodiazepine withdrawal.Onset: Rapid; typically occurs within 48 hours of rapid dose decrease or abrupt drug discontinuation (Ref).Risk factor:• Chronic administration of supratherapeutic doses (eg, >100 mg/day for months to years) (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported with oral administration, unless otherwise noted.>10%: Nervous system: Dizziness (1% to 12%) (Blumer 2009), drowsiness (2% to 15%) (table 1)Drowsiness, headache (oral: 7% to 19%; sublingual: 3%)Zolpidem: Adverse Reaction: DrowsinessDrug (Zolpidem)Placebo DoseDosage FormNumber of Patients (Zolpidem)Number of Patients (Placebo)15%2%12.5 mgExtended-release oral1021108%5%≤10 mgImmediate-release oral1521612%0%≤10 mgImmediate-release oral6854731% to 10%:Cardiovascular: Chest discomfort (1%), chest pain (1%), edema (≤1%), hypertension (≤1%), increased blood pressure (1%), orthostatic hypotension (≤1%), palpitations (2%), syncope (≤1%), tachycardia (≤1%)Dermatologic: Diaphoresis (≤1%), pallor (≤1%), pruritus (≤1%), skin rash (1% to 2%), urticaria (≤1%), wrinkling of skin (1%)Endocrine & metabolic: Heavy menstrual bleeding (1%), hyperglycemia (≤1%), increased thirst (≤1%), menstrual disease (≤1%)Gastrointestinal: Abdominal distress (1%), abdominal tenderness (1%), anorexia (≤1%), change in appetite (1%), constipation (2%), diarrhea (1% to 3%), dysgeusia (≤1%), dyspepsia (>1%), dysphagia (≤1%), flatulence (≤1%), frequent bowel movements (1%), gastroenteritis (1%) (Blumer 2009), gastroesophageal reflux disease (1%), hiccups (>1%), nausea (7%), vomiting (1%), xerostomia (3%)Genitourinary: Cystitis (≤1%), urinary incontinence (≤1%) (Blumer 2009), urinary tract infection (>1%), vaginitis (≤1%)Hematologic & oncologic: Bruise (1%)Hepatic: Abnormal hepatic function tests (≤1%)Hypersensitivity: Hypersensitivity reaction (4%)Infection: Infection (≤1%), influenza (3%)Nervous system: Abnormal dreams (1%), agitation (≤1%), amnesia (1%) (table 2)Amnesia, anxiety (2% to 6%) (table 3)Anxiety, ataxia (1%) (table 4)Ataxia, balance impairment (2%) (table 5)Balance Impairment, cerebrovascular disease (≤1%), cognitive dysfunction (≤1%), confusion (>1%), depersonalization (1%), depression (2%) (table 6)Depression, disinhibition (1%) (table 7)Disinhibition, disorientation (3%), disturbance in attention (2%) (table 8)Disturbance in Attention, dysarthria (≤1%), eating disorder (1%; binge eating), emotional lability (≤1%), euphoria (>1%), falling (≤1%), fatigue (oral: 3%; sublingual: 1%) (table 9)Fatigue, hallucination (4%), hypoesthesia (2%), illusion (≤1%), increased body temperature (1%), insomnia (>1%), intoxicated feeling (3%), lethargy (3%), malaise (≤1%), memory impairment (3%), migraine (≤1%), nervousness (≤1%), paresthesia (1%), psychom*otor impairment (2%), sleep disorder (1%), speech disturbance (≤1%), stress (1%), stupor (≤1%), vertigo (2%)Zolpidem: Adverse Reaction: AmnesiaDrug (Zolpidem)Placebo DoseDosage FormNumber of Patients (Zolpidem)Number of Patients (Placebo)1%0%≤10 mgImmediate-release oral152161Zolpidem: Adverse Reaction: AnxietyDrug (Zolpidem)Placebo DoseDosage FormNumber of Patients (Zolpidem)Number of Patients (Placebo)6%3%12.5 mgExtended-release oralN/AN/A2%0%12.5 mgExtended-release oral102110Zolpidem: Adverse Reaction: AtaxiaDrug (Zolpidem)Placebo DoseDosage FormNumber of Patients (Zolpidem)Number of Patients (Placebo)1%0%12.5 mgExtended-release oral102110Zolpidem: Adverse Reaction: Balance ImpairmentDrug (Zolpidem)Placebo DoseDosage FormNumber of Patients (Zolpidem)Number of Patients (Placebo)2%0%12.5 mgExtended-release oral102110Zolpidem: Adverse Reaction: DepressionDrug (Zolpidem)Placebo DoseDosage FormNumber of Patients (Zolpidem)Number of Patients (Placebo)2%0%12.5 mgExtended-release oral1021102%1%≤10 mgImmediate-release oral152161Zolpidem: Adverse Reaction: DisinhibitionDrug (Zolpidem)Placebo DoseDosage FormNumber of Patients (Zolpidem)Number of Patients (Placebo)1%0%12.5 mgExtended-release oral102110Zolpidem: Adverse Reaction: Disturbance in AttentionDrug (Zolpidem)Placebo DoseDosage FormNumber of Patients (Zolpidem)Number of Patients (Placebo)2%0%12.5 mgExtended-release oral102110Zolpidem: Adverse Reaction: FatigueDrug (Zolpidem)Placebo DoseDosage FormNumber of Patients (Zolpidem)Number of Patients (Placebo)3%2%12.5 mgExtended-release oral1021101%0%3.5 mgSublingual150145Neuromuscular & skeletal: Arthralgia (>1%), arthritis (≤1%), asthenia (1%), back pain (3% to 4%), lower limb cramp (≤1%), myalgia (4%), neck pain (1%), tremor (≤1%)Ophthalmic: Asthenopia (1%), blurred vision (2%), diplopia (>1%), eye irritation (≤1%), eye pain (≤1%), eye redness (2%), scleritis (≤1%), visual disturbance (1% to 3%; including altered depth perception)Otic: Labyrinthitis (1%), tinnitus (1%)Respiratory: Bronchitis (≤1%), cough (≤1%), dyspnea (≤1%), flu-like symptoms (1% to 2%), lower respiratory tract infection (>1%), pharyngitis (3%), rhinitis (≤1%), sinusitis (4%), throat irritation (1%), upper respiratory tract infection (>1%)Miscellaneous: Fever (≤1%), trauma (≤1%)<1%:Cardiovascular: Acute myocardial infarction, angina pectoris, arteritis, cardiac arrhythmia, circulatory shock, exacerbation of hypertension, extrasystoles, facial edema, flushing, hypotension, phlebitis, pulmonary embolism, thrombosis, varicose veins, ventricular tachycardiaDermatologic: Acne vulgaris, bullous rash, dermatitis, furunculosis, skin photosensitivityEndocrine & metabolic: Decreased libido, gout, hot flash, hypercholesteremia, hyperlipidemia, weight lossGastrointestinal: Alteration of saliva, dental caries, enteritis, eructation, esophageal spasm, gastritis, hemorrhoids, increased appetite, intestinal obstruction, sialorrhea, tenesmusGenitourinary: Breast fibroadenosis, dysuria, impotence, mastalgia, nocturia, urinary frequency, urinary retentionHematologic & oncologic: Anemia, breast neoplasm, hyperhemoglobinemia, increased erythrocyte sedimentation rate, leukopenia, lymphadenopathy, macrocytic anemia, purpuric disease, rectal hemorrhageHepatic: Hyperbilirubinemia, increased serum alkaline phosphataseHypersensitivity: Anaphylactic shockInfection: Abscess, herpes simplex infection, herpes zoster infectionNervous system: Abnormal gait, abnormality in thinking, aggressive behavior, altered sense of smell, apathy, delusion, dementia, drug dependence, dysphasia, hypotonia, hysteria, manic reaction, myasthenia, neuralgia, neuritis, neuropathy, neurosis, numbness of tongue, pain, panic disorder, paresis, personality disorder, restless leg syndrome, rigors, sciatica, strange feeling, yawningNeuromuscular & skeletal: Hypokinesia, osteoarthritis, tendinopathy, tetanyOphthalmic: Abnormal lacrimation, accommodation disturbance, conjunctivitis, corneal ulcer, glaucoma, periorbital edema, photopsiaOtic: Otitis externa, otitis mediaRenal: Acute kidney injury, polyuria, pyelonephritis, renal painRespiratory: Bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia, pulmonary edema, respiratory depressionPostmarketing:Hepatic: Cholestatic hepatitis, hepatocellular hepatitisHypersensitivity: Anaphylaxis, angioedemaNervous system: Complex sleep-related disorder (Harbourt 2020), delirium (Inagaki 2010), somnambulism (Inagaki 2010), suicidal ideation, suicidal tendencies, withdrawal syndrome (Wilson 2019)Neuromuscular & skeletal: Bone fracture (Treves 2018), femoral neck fracture (Wang 2001)Miscellaneous: Accidental injury (Chung 2013)ContraindicationsHypersensitivity to zolpidem or any component of the formulation; patients who have experienced complex sleep behaviors after taking zolpidemCanadian labeling: Additional contraindications (not in US labeling): Significant obstructive sleep apnea syndrome and acute and/or severe impairment of respiratory function; myasthenia gravis; severe hepatic impairment; personal or family history of sleepwalkingWarnings/PrecautionsDisease-related concerns:• Depression: Use with caution in patients with depression, particularly if suicidal risk may be present.• Drug abuse: Use with caution in patients with a history of drug dependence. Risk of abuse is increased in patients with a history or family history of alcohol or drug abuse or mental illness.• Hepatic impairment: GABA agonists, including zolpidem, have been associated with precipitation of hepatic encephalopathy in patients with hepatic impairment. Patients with hepatic impairment do not clear zolpidem as rapidly as patients with normal hepatic function. Use with caution in patients with mild to moderate hepatic impairment; dose adjustment recommended. Avoid use of immediate and extended-release tablets in patients with severe hepatic impairment; may result in encephalopathy.• Myasthenia gravis: Use with caution in patients with myasthenia gravis.• Respiratory disease: Use with caution in patients with respiratory compromise, COPD, or sleep apnea.Special populations:• Debilitated: Use with caution in debilitated patients; potential for oversedation, impaired coordination, and confusion with use; dosage adjustment recommended.• Older adult: Use with caution in older adult patients; dose adjustment recommended. Monitor for impaired cognitive and/or motor performance, confusion, and potential for falling.• Females: Dosage adjustment is recommended for females; pharmaco*kinetic studies involving zolpidem showed a significant increase in maximum concentration and exposure in females compared to males at the same dose.• Pediatric: When studied for the unapproved use of insomnia associated with ADHD in children, a higher incidence (~7%) of hallucinations was reported. In addition, sleep latency did not decrease compared to placebo.Dosage form specific issues:• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.Other warnings/precautions:• Appropriate use: Symptomatic treatment of insomnia should be initiated only after careful evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 10 days may indicate the need for psychiatric and/or medical illness reevaluation. Long-term use is not recommended; reevaluation of patient’s status should occur before extending treatment due to risk of abuse and dependence.• Rapid onset: Because of the rapid onset of action, administer Intermezzo immediately prior to bedtime, after the patient has gone to bed and is having difficulty falling asleep, or during the middle of the night when at least 4 hours are left before waking.Warnings: Additional Pediatric ConsiderationsSome dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).Metabolism/Transport EffectsSubstrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyAzelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBlonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin.Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modificationBrimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBuprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine.Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modificationCannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.Risk C: Monitor therapyChlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modificationChlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapyCiprofloxacin (Systemic): May increase the serum concentration of Zolpidem. Management: Consider avoiding the combination of ciprofloxacin and zolpidem if possible. If combined, monitor for signs of zolpidem toxicity (eg, somnolence, dizziness, lethargy). Risk D: Consider therapy modificationClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCNS Depressants: May enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg formen who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modificationCYP3A4 Inducers (Moderate): May decrease the serum concentration of Zolpidem. Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of Zolpidem. Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase the serum concentration of Zolpidem. Risk C: Monitor therapyDaridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationDexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine.Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modificationDifelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDroperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modificationFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFlunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine.Risk X: Avoid combinationFlunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modificationFluvoxaMINE: May enhance the CNS depressant effect of Zolpidem. FluvoxaMINE may increase the serum concentration of Zolpidem. Risk C: Monitor therapyFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationHydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modificationKava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyKratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationLemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modificationLisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyLofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMagnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMelatonin: May enhance the sedative effect of Hypnotics (Nonbenzodiazepine). Risk C: Monitor therapyMethotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modificationMetoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE.Risk C: Monitor therapyMinocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyOlopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOrphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine.Risk X: Avoid combinationOxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOxybate Salt Products: Hypnotics (Nonbenzodiazepine) may enhance the CNS depressant effect of Oxybate Salt Products.Risk X: Avoid combinationOxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE.Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationParaldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde.Risk X: Avoid combinationPiribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil.Risk C: Monitor therapyPramipexole: CNS Depressants may enhance the sedative effect of Pramipexole.Risk C: Monitor therapyProcarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyRopeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased.Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modificationROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole.Risk C: Monitor therapyRotigotine: CNS Depressants may enhance the sedative effect of Rotigotine.Risk C: Monitor therapyRufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapySt John's Wort: May decrease the serum concentration of Zolpidem. Risk X: Avoid combinationSuvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant.Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary.Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationThalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide.Risk X: Avoid combinationValerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyFood InteractionsMaximum plasma concentration and bioavailability are decreased with food; time to peak plasma concentration is increased; half-life remains unchanged. Management: Do not administer with (or immediately after) a meal.Pregnancy ConsiderationsZolpidem crosses the placenta (Juric 2009; Saito 2021).According to product labeling, severe neonatal respiratory depression (requiring artificial ventilation or intratracheal intubation) and sedation have been reported following maternal use late in the third trimester. Exposed neonates should be monitored for excess sedation, hypotonia, and respiratory depression. Additional adverse effects, including low birth weight or preterm delivery, have been observed in some studies (Juric 2009; Sharma 2011; Wang 2010; Wikner 2011).Breastfeeding ConsiderationsZolpidem is present in breast milk (Pons 1989).Data related to the presence of zolpidem in breast milk are available following administration of a single oral dose of IR zolpidem 20 mg to 5 breastfeeding women, 3 or 4 days following delivery. The amount of zolpidem recovered in milk samples 3 hours postadministration ranged from 0.76 to 3.88 mcg (0.004% to 0.019% of the administered maternal dose). Zolpidem was undetectable at 13 and 16 hours postadministration in all women. Infants in this study were not breastfed (Pons 1989).Data are also available from a case report. Zolpidem 5 to 10 mg (IR) was administered daily throughout pregnancy and postpartum. Breast milk was sampled at random times once daily for the first 3 days after delivery. Breast milk concentrations of zolpidem ranged from 6.4 ng/mL (9.1 hours after the maternal dose) to 26.5 ng/mL (2.2 hours after the maternal dose). Authors of this study calculated the estimated exposure of zolpidem to the breastfeeding infant to be 4 mcg/kg/day (relative infant dose [RID] 2.7% based on a weight-adjusted maternal dose of 0.15 mg/kg/day). This patient was taking ramelteon for 5 days in addition to zolpidem; adverse events were not observed in the infant who was partially breastfed (Saito 2021). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).Excess sedation in breastfed infants has been reported. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Monitor the infant for excess sedation, hypotonia, and respiratory depression. Consider pumping and discarding breast milk during treatment and for 23 hours after the last dose to minimize exposure to the infant.Dietary ConsiderationsDo not administer with or immediately after a meal (may delay onset).Monitoring ParametersDaytime alertness; fall risk, respiratory rate (patients with compromised respiration); behavior profile; tolerance, abuse, and dependence; reevaluate if insomnia persists after 7 to 10 days of use.Mechanism of ActionZolpidem, an imidazopyridine hypnotic that is structurally dissimilar to benzodiazepines, enhances the activity of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), via selective agonism at the benzodiazepine-1 (BZ1) receptor; the result is increased chloride conductance, neuronal hyperpolarization, inhibition of the action potential, and a decrease in neuronal excitability leading to sedative and hypnotic effects. Because of its selectivity for the BZ1 receptor site over the BZ2 receptor site, zolpidem exhibits minimal anxiolytic, myorelaxant, and antiseizure properties (effects largely attributed to agonism at the BZ2 receptor site).Pharmaco*kineticsOnset of action: Immediate release: 30 minutes.Duration: Immediate release: 6 to 8 hours.Absorption: Cmax and AUC is increased by ~45% in females compared to male subjects.Immediate release and sublingual: Rapid.Extended release: Biphasic absorption; rapid initial absorption (similar to immediate release product); then provides extended concentrations in the plasma beyond 3 hours postadministration.Distribution: Vd:Children 2 to 6 years: 1.8 ± 0.8 L/kg (Blumer 2008).Children >6 to 12 years: 2.2 ± 1.7 L/kg (Blumer 2008).Adolescents: 1.2 ± 0.4 L/kg (Blumer 2008).Adults: 0.54 L/kg after an IV dose (Holm 2000).Protein binding: ~93%.Metabolism: Hepatic methylation and hydroxylation via CYP3A4 (~60%), CYP2C9 (~22%), CYP1A2 (~14%), CYP2D6 (~3%), and CYP2C19 (~3%) to 3 inactive metabolites (Holm 2000).Bioavailability: Immediate release: 70% (Holm 2000).Half-life elimination:Children 2 to 6 years: Immediate release: 1.8 hours (Blumer 2008).Children >6 years and Adolescents: Immediate release: 2.3 hours (Blumer 2008).Adults:Immediate release, Extended release: ~2.5 hours (range: 1.4 to 4.5 hours); Cirrhosis: Up to 9.9 hours; Elderly: Prolonged up to 32%.Spray: ~3 hours (range: 1.7 to 8.4).Sublingual tablet: ~3 hours (range: 1.4 to 6.7 hours).Time to peak, plasma:Children 2 to 6 years: Immediate release: 0.9 hours (Blumer 2008).Children >6 to 12 years: Immediate release: 1.1 hours (Blumer 2008).Adolescents: Immediate release: 1.3 hours (Blumer 2008).Adults:Immediate release: 1.6 hours; 2.2 hours with food.Extended release: 1.5 hours; 4 hours with food.Spray: ~0.9 hours.Sublingual tablet: Edluar: ~1.4 hours, ~1.8 hours with food; Intermezzo: 0.6 to 1.3 hours, ~3 hours with food.Excretion: Urine (48% to 67%, primarily as metabolites); feces (29% to 42%, primarily as metabolites).Clearance, apparent:Children 2 to 6 years: 11.7 ± 7.9 mL/minute/kg (Blumer 2008).Children >6 to 12 years: 9.7 ± 10.3 mL/minute/kg (Blumer 2008).Adolescents: 4.8 ± 2 mL/minute/kg (Blumer 2008).Adults: Intermezzo: Males: 4 mL/minute/kg; Females: 2.7 mL/minute/kg.Pharmaco*kinetics: Additional ConsiderationsHepatic function impairment: Cmax and AUC were found to be 2 and 5 times higher, respectively, in hepatically compromised patients. The mean half-life in cirrhotic patients of 9.9 hours was greater than that observed in normal subjects of 2.2 hours.Older adult:Immediate release: Cmax, half-life, and AUC were significantly increased when compared with results in younger adults.Extended release: Mean Cmax and mean AUC are 70.6 ng/mL and 413 ng•h/mL, respectively, while the median Tmax is 2 hours.Sex: Cmax and AUC were higher when comparing the same dose in women with men. Women clear zolpidem from the body at a lower rate than men. In geriatric patients, clearance is similar between men and women.Pricing: USSolution (Zolpimist Oral)5 mg/ACT (per mL): $96.56Sublingual (Edluar Sublingual)5 mg (per each): $14.9610 mg (per each): $15.70Sublingual (Zolpidem Tartrate Sublingual)1.75 mg (per each): $10.043.5 mg (per each): $10.04Tablet, controlled release (Ambien CR Oral)6.25 mg (per each): $24.5612.5 mg (per each): $24.56Tablet, controlled release (Zolpidem Tartrate ER Oral)6.25 mg (per each): $1.61 - $6.1212.5 mg (per each): $1.61 - $6.12Tablets (Ambien Oral)5 mg (per each): $24.5610 mg (per each): $24.56Tablets (Zolpidem Tartrate Oral)5 mg (per each): $0.10 - $5.1410 mg (per each): $4.62 - $5.14Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAdorma (CZ);Ambien (BB, BM, BS, BZ, GY, IL, JM, PR, SR, TT);Ambien CR (AR);Ambulax-2 (IN);Conyx (KR);Dactive (PH);Dalparan (ES);Dormeben (CO);Dormizol (AU);Flazinil (EC);Fulsadem (AR);Hypnogen (EE);Ivadal (AT);Ivedal (ZA);Jonfa (VN);Le Tan (CN);Lioram (BR);Lunata (HR);Nidraj (BD);Nitrest (BD, CR, DO, GT, HN, IN, NI, PA, SV);Nocte (CR, DO, GT, HN, LK, NI, PA, SV);Nocte Sublingual (AR);Nottem (IT);Nuo Bin (CN);Nytamel (IE);Nyxe (ZA);Oniria (GR);Sanval (HR, RU);Sleepman (TW);Slepzol (ID);Somidem (AU, MY);Somit (AR, PY, UY);Somnil (CL, CO);Somno (PE);Sove (LK);Stildem (AU);Stilnix (IL);Stilnoct (BE, DK, FI, GB, IE, IS, LU, NL, NO, SE);Stilnox (AU, BF, BG, BJ, BR, CH, CI, CL, CN, CO, CR, CY, CZ, DE, DO, EE, ES, ET, FR, GH, GM, GN, GR, GT, HK, HN, HU, ID, IT, JO, KE, KR, KW, LB, LR, LT, LV, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NI, PA, PE, PH, PK, PL, PT, PY, QA, RO, SA, SC, SD, SK, SL, SN, SV, TN, TR, TW, TZ, UG, VE, VN, ZA, ZM);Stilnox CR (BR, CO, CR, DO, GT, HN, KR, MY, NI, PA, SG, SV);Sucedal (EC);Vicknox (HK);Ziohex (PH);Zodenox (MY);Zodium (EG);Zodorm (IL);Zoldem (AT, BD, DE, IE);Zoldorm (CH);Zoldox (TW);Zolep (HU);Zoliprex (LK);Zolmia (ID);Zolnod (IE);Zolnox (PY, UY);Zolpicin (TW);Zolpid (BD, KR);Zolpihexal (ZW);Zolpinox (DE);Zolpirest (PH);Zolpista (EG);Zolpitop (BE);Zolsana (BG);Zonoct (DK);Zopidem (TW);Zopim (MY);Zorimin (TW)For country code abbreviations (show table)2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi: 10.1111/jgs.15767. [PubMed 30693946]Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]Ambien (zolpidem tartrate tablet) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis US LLC; February 2022.Ambien CR (zolpidem tartrate extended-release tablet) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis US LLC; February 2022.American Academy of Pediatrics Committee on Drugs. "Inactive" ingredients in pharmaceutical products: update (subject review). Pediatrics. 1997;99(2):268-278. [PubMed 9024461]American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767 [PubMed 30693946]Anand S, Tong H, Besag FMC, Chan EW, Cortese S, Wong ICK. Safety, tolerability and efficacy of drugs for treating behavioural insomnia in children with attention-deficit/hyperactivity disorder: a systematic review with methodological quality assessment. Paediatr Drugs. 2017;19(3):235-250. [PubMed 28391425]Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. doi:10.1002/cpt.377 [PubMed 27060684]Armour A, Gottschlich MM, Khoury J, et al, "A Randomized, Controlled Prospective Trial of Zolpidem and Haloperidol for Use as Sleeping Agents in Pediatric Burn Patients," J Burn Care Res, 2008, 29(1):238-47. [PubMed 18182928]Bélanger L, Belleville G, Morin C. Management of hypnotic discontinuation in chronic insomnia. Sleep Med Clin. 2009;4(4):583-592. doi: 10.1016/j.jsmc.2009.07.011. [PubMed 20607118]Beyraghi N, Shamsi A, Farrokhian A. Detoxification of high-dose zolpidem using phenobarbital and gabapentin: two case reports. Archives of Psychiatry and Psychotherapy. 2016;4:16-19. doi:10.12740/APP/66307Blumer JL, Findling RL, Shih WJ, Soubrane C, Reed MD. Controlled clinical trial of zolpidem for the treatment of insomnia associated with attention-deficit/ hyperactivity disorder in children 6 to 17 years of age. Pediatrics. 2009;123(5):e770-e776. doi:10.1542/peds.2008-2945 [PubMed 19403468]Blumer JL, Reed MD, Steinberg F, et al, "Potential Pharmaco*kinetic Basis for Zolpidem Dosing in Children With Sleep Difficulties," Clin Pharmacol Ther, 2008, 83(4):551-8. [PubMed 17957186]Booth JN 3rd, Behring M, Cantor RS, et al. Zolpidem use and motor vehicle collisions in older drivers. Sleep Med. 2016;20:98-102. doi:10.1016/j.sleep.2015.12.004 [PubMed 27318232]Centers for Disease Control (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199.http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm [PubMed 6423951]Chang CM, Chen MJ, Tsai CY, et al. Medical conditions and medications as risk factors of falls in the inpatient older people: a case-control study. Int J Geriatr Psychiatry. 2011;26(6):602-607. doi:10.1002/gps.2569 [PubMed 21480377]Chen CS, Huang MF, Hwang TJ, et al. Clinical correlates of zolpidem-associated complex sleep-related behaviors: age effect. J Clin Psychiatry. 2014;75(11):e1314-e1318. doi:10.4088/JCP.13m08901 [PubMed 25470097]Chopra A, Selim B, Silber MH, Krahn L. Para-suicidal amnestic behavior associated with chronic zolpidem use: implications for patient safety. Psychosomatics. 2013;54(5):498-501. doi:10.1016/j.psym.2012.10.012 [PubMed 23352047]Chung SD, Lin CC, Wang LH, Lin HC, Kang JH. Zolpidem use and the risk of injury: a population-based follow-up study. PLoS One. 2013;8(6):e67459. doi:10.1371/journal.pone.0067459 [PubMed 23826304]Cronin SD, Gottschlich MM, Gose LM, Kagan RJ. Zolpidem and sleep in pediatric burn patients with attention deficit/hyperactivity disorder. Pediatr Nurs. 2015;41(3):132-134, 140. [PubMed 26201171]Cubala WJ, Gabrielsson A. Sleep related amnestic behaviors due to zolpidem. Bulletin of Clinical Psychopharmacology. 2014;24(2):188-194. doi:10.5455/bcp.20130527020102Edluar (zolpidem tartrate sublingual tablet) [prescribing information]. Somerset, NJ: Meda Pharmaceuticals Inc; September 2021.FDA Drug Safety Communication. Risk of next‐morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). Food and Drug Administration website. https://www.fda.gov/files/drugs/published/Drug-Safety-Communication--Risk-of-next-morning-impairment-after-use-of-insomnia-drugs--FDA-requires-lower-recommended-doses-for-certain-drugs-containing-zolpidem-%28Ambien--Ambien-CR--Edluar--and-Zolpimist%29.pdf. January 10, 2013. Accessed March 3, 2021.FDA Safety Alert. MedWatch. FDA adds Boxed Warnings for risk of serious injuries caused by sleepwalking with certain prescription insomnia medicines. Food and Drug Administration website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomnia. Accessed May 3, 2019.Fillastre JP, Geffroy-Josse S, Etienne I, et al. Pharmaco*kinetics and pharmacodynamics of zolpidem following repeated doses in hemodialyzed uraemic patients. Fundam Clin Pharmacol. 1993;7(1):1-9. doi:10.1111/j.1472-8206.1993.tb00212.x [PubMed 8458597]Greenblatt DJ, Legangneux E, Harmatz JS, et al. Dynamics and kinetics of a modified-release formulation of zolpidem: comparison with immediate-release standard zolpidem and placebo. J Clin Pharmacol. 2006;46(12):1469-1480. doi:10.1177/0091270006293303 [PubMed 17101746]Greenblatt DJ, Harmatz JS, Roth T, et al. Comparison of pharmaco*kinetic profiles of zolpidem buffered sublingual tablet and zolpidem oral immediate-release tablet: results from a single-center, single-dose, randomized, open-label crossover study in healthy adults. Clin Ther. 2013;35(5):604-611. doi:10.1016/j.clinthera.2013.03.007 [PubMed 23541711]Grzegorzewska AM, Landowski JJ, Cubala WJ. Clinical considerations of sleep related amnestic behaviours associated with zolpidem. Farmakoterapia w Psychiatrii i Neurologii. 2020;36(1):23–31. doi:10.33450/fpn.2020.04.001Gunja N. In the Zzz zone: the effects of Z-drugs on human performance and driving. J Med Toxicol. 2013;9(2):163-171. doi:10.1007/s13181-013-0294-y [PubMed 23456542]Haji Seyed Javadi SA, Hajiali F, Nassiri-Asl M. Zolpidem dependency and withdrawal seizure: a case report study. Iran Red Crescent Med J. 2014;16(11):e19926. doi:10.5812/ircmj.19926 [PubMed 25763219]Hanna AH, Ramsingh D, Sullivan-Lewis W, et al. A comparison of midazolam and zolpidem as oral premedication in children, a prospective randomized double-blinded clinical trial [published online October 17, 2018]. Paediatr Anaesth. 2018. [PubMed 30328648]Harbourt K, Nevo ON, Zhang R, Chan V, Croteau D. Association of eszopiclone, zaleplon, or zolpidem with complex sleep behaviors resulting in serious injuries, including death. Pharmacoepidemiol Drug Saf. 2020;29(6):684-691. doi:10.1002/pds.5004 [PubMed 32323442]Ho T, Jimenez A, Sanchez I, Seeger C, Joseph M. Sleep-related eating disorder associated with zolpidem: cases compiled from a literature review. Sleep Medicine: X. 2020;2:100019. doi:10.1016/j.sleepx.2020.100019Holm KJ and Goa KL, “Zolpidem: An Update of Its Pharmacology, Therapeutic Efficacy and Tolerability in the Treatment of Insomnia,” Drugs, 2000, 59(4):865-89. [PubMed 10804040]Hwang TJ, Ni HC, Chen HC, Lin YT, Liao SC. Risk predictors for hypnosedative-related complex sleep behaviors: a retrospective, cross-sectional pilot study. J Clin Psychiatry. 2010;71(10):1331-1335. doi:10.4088/JCP.09m05083bro [PubMed 20441722]Inagaki T, Miyaoka T, Tsuji S, Inami Y, Nishida A, Horiguchi J. Adverse reactions to zolpidem: case reports and a review of the literature. Prim Care Companion J Clin Psychiatry. 2010;12(6):PCC.09r00849. doi:10.4088/PCC.09r00849bro [PubMed 21494350]Intermezzo (zolpidem tartrate tablet) [prescribing information]. Stamford, CT: Purdue Pharma LP; August 2019.Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):312-313. [PubMed 12534540]Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. doi:10.1056/NEJM200007133430208 [PubMed 10891521]Jones AW, Holmgren A. Concentrations of zolpidem and zopiclone in venous blood samples from impaired drivers compared with femoral blood from forensic autopsies. Forensic Sci Int. 2012;222(1-3):118-123. doi:10.1016/j.forsciint.2012.05.008 [PubMed 22673707]Juric S, Newport DJ, Ritchie JC, Galanti M, Stowe ZN. Zolpidem (Ambien) in pregnancy: placental passage and outcome. Arch Womens Ment Health. 2009;12(6):441-446. [PubMed 19657707]Kolla BP, Lovely JK, Mansukhani MP, Morgenthaler TI. Zolpidem is independently associated with increased risk of inpatient falls. J Hosp Med. 2013;8(1):1-6. doi:10.1002/jhm.1985 [PubMed 23165956]Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]McCall WV. Sleep in the elderly: burden, diagnosis, and treatment. Prim Care Companion J Clin Psychiatry. 2004;6(1):9-20. doi:10.4088/pcc.v06n0104 [PubMed 15486596]McCall WV, Benca RM, Rosenquist PB, et al. Hypnotic medications and suicide: risk, mechanisms, mitigation, and the FDA. Am J Psychiatry. 2017;174(1):18-25. doi:10.1176/appi.ajp.2016.16030336 [PubMed 27609243]Olubodun JO, Ochs HR, von Moltke LL, et al. Pharmaco*kinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men. Br J Clin Pharmacol. 2003;56(3):297-304. doi:10.1046/j.0306-5251.2003.01852.x [PubMed 12919178]Pharmacy Quality Alliance. Use of high-risk medications in the elderly (2017 update) (HRM-2017). https://www.pqaalliance.org/medication-safety. Published 2017. Accessed March 21, 2019.Pons G, Francoual C, Guillet P, et al. Zolpidem excretion in breast milk. Eur J Clin Pharmacol. 1989;37(3):245-248. [PubMed 2612539]Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. 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CloseOxidized regnerated cellulose: Drug informationOxidized regnerated cellulose: Drug informationFor abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USInterceed;Surgicel;Surgicel Fibrillar;Surgicel Nu-Knit;Surgicel SNoW 1"x2";Surgicel SNoW 2"x4";Surgicel SNoW 4"x4"Pharmacologic CategoryHemostatic AgentDosing: AdultHemostasisHemostasis: Topical:Surgicel: Minimal amounts in appropriate size of cellulose are laid or applied to the bleeding site or held firmly against the tissues until hemostasis occurs; remove excess material.Pelvic adhesion reductionPelvic adhesion reduction: Topical:Interceed: Following hemostasis, apply in single layer on and between raw (denuded) surfaces.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued productPad, External:Interceed: (10 ea)Surgicel Fibrillar: (10s, 24s)Surgicel Nu-Knit: (10s, 24s)Surgicel SNoW 1"x2": (10 ea)Surgicel SNoW 2"x4": (10 ea)Surgicel SNoW 4"x4": (10 ea)Powder, Absorbable:Surgicel: 3 g (5 ea)Generic Equivalent Available: USNoAdministration: AdultTopical: Note: Also refer to manufacturer's labeling for detailed administration instructions.Adhesion barrier (Interceed): Place into surgical area as directed.Pad (Surgicel): May be sutured or cut without fraying.Powder (Surgicel): Powder is dry; precise delivery under certain circ*mstances may be difficult. Do not trim applicator tip (applicator tip not intended for laparoscopic or other endoscopic use).Use: Labeled IndicationsHemostasis (Surgicel): Adjunctive use in surgical procedures to control capillary, venous, or small arterial hemorrhage when ligation or other conventional methods of control are impractical or ineffective.Pelvic adhesion reduction (Interceed): Adjuvant in open (laparotomy) gynecologic pelvic surgery for reducing the incidence of postoperative pelvic adhesions after meticulous hemostasis is achieved consistent with microsurgical principles.Adverse ReactionsThe following adverse drug reactions are derived from product labeling unless otherwise specified.Postmarketing:Cardiovascular: Vascular insufficiency (stenosis when applied as a wrap)Gastrointestinal: Intestinal obstruction (after small bowel biopsy) (Bakhit 2019)Genitourinary: Difficulty in micturition (after prostatectomy), ureteral obstruction (after kidney resection)Hypersensitivity: Anaphylaxis (Corti 2021), angioedema (Corti 2021)Local: Application-site burning, application-site edema (encapsulation)Nervous system: Foreign body reaction (Lin 2014), headache, neurotoxicity, paralysis, paraplegia (after thoracotomy) (Brodbelt 2002), stinging sensationOphthalmic: Blindness (when placed in anterior cranial fossa), optic neuropathy (compressive: after orbital surgery) (Arat 2006)Respiratory: Sneezing (epistaxis and rhinological procedures)ContraindicationsInterceed: Infection.Surgicel: Implantation into bone defects (eg, fractures); hemorrhage from large arteries or veins; nonhemorrhagic oozing; use as an adhesion prevention product; intraluminal procedures or use in open blood vessels. Note: Multiple products are available and contraindications may vary by product; also refer to manufacturer's labeling.Warnings/PrecautionsConcerns related to adverse effects:• Foreign body reactions: Have occurred. Remove excess product before surgical closure to facilitate absorption and reduce risk.• Pain/numbness/nerve damage/paralysis: Pain, numbness, nerve damage, and paralysis have been reported if used near a bony or neural space and/or the optic nerve and chiasm; use minimum amount necessary to achieve hemostasis.Dosage forms specific issues:• Powder: Unintentional placement may result in powder scattering and device migration that may increase the risk of adhesion formation. Do not use in conjunction with autologous blood salvage circuits (fragments may pass through the transfusion filters of blood-scavenging system).Other warnings/precautions:• Appropriate use (Interceed): Not indicated as a hemostatic agent. Appropriate means of achieving hemostasis must be employed. Safety and effectiveness in laparoscopic surgery or any procedures other than open (laparotomy) gynecologic microsurgical procedures have not been established. Also refer to manufacturer's labeling for additional warnings/precautions.• Appropriate use (Surgicel): The material should not be moistened before insertion since the hemostatic effect is greater when applied dry. The material should not be impregnated with anti-infective agents or with other materials such as buffering or hemostatic substances. Remove as much of agent as possible with sterile water or saline solution after hemostasis is achieved. Do not leave in a contaminated or infected space without drainage. Always remove completely following hemostasis if applied in proximity to foramina in bone, areas of bony confine, the spinal cord, and/or the optic nerve and chasm; product may swell and exert unwanted pressure. Although packing or wadding sometimes is medically necessary, cellulose should not be used in this manner, unless it is to be removed after hemostasis is achieved. In urological procedures, care must be exercised to prevent plugging of the urethra, ureter, or a catheter. In otorhinolaryngologic surgery, ensure that the material is not aspirated by the patient (eg, controlling hemorrhage after tonsillectomy and controlling epistaxis). In cauterized areas, absorption could be prevented in chemically cauterized areas; cellulose use should not be preceded by application of silver nitrate or any other escharotic chemicals. Also refer to manufacturer's labeling for additional warnings/precautions.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Silver Nitrate: May diminish the therapeutic effect of Cellulose (Oxidized Regenerated). Risk X: Avoid combinationReproductive ConsiderationsInformation related to the use of topical hemostatic agents in gynecologic surgery is limited and use should be restricted to situations where preferred interventions are not ideal or are unsafe (ACOG 2020).Interceed is approved for use as an adjuvant in open (laparotomy) gynecologic pelvic surgery to reduce the incidence of postoperative adhesions. Pelvic adhesions may be associated with pain and infertility; however, it is not clear if use of cellulose (oxidized regenerated) improves fertility or decreases pain (Ahmad 2020; ASRM/SRS 2019).Surgicel is approved to control hemostasis associated with surgery and may be useful in gynecologic surgeries such as conization of the cervix, hysterectomy, and oophorectomy.Pregnancy ConsiderationsInformation related to the use of topical hemostatic agents in gynecologic surgery is limited and use should be restricted to situations where preferred interventions are not ideal or are unsafe (ACOG 2020). Interceed has been evaluated for the prevention of intraperitoneal adhesions associated with cesarean delivery (Chapa 2011; Rottenstreich 2020). Use of Surgicel as adjunctive treatment of hemorrhage at the cesarean incision site has been described (Sharma 2006).Mechanism of ActionCellulose, oxidized regenerated is saturated with blood at the bleeding site and swells into a brownish or black gelatinous mass which aids in the formation of a clot. When used in small amounts, it is absorbed from the sites of implantation with little or no tissue reaction. In addition to providing hemostasis, oxidized regenerated cellulose also has been shown in vitro to have bactericidal properties. Its hemostatic effect is not enhanced by the addition of thrombin.Ahmad G, Kim K, Thompson M, et al. Barrier agents for adhesion prevention after gynaecological surgery. Cochrane Database Syst Rev. 2020;3(3):CD000475. doi:10.1002/14651858.CD000475.pub4 [PubMed 32199406]American College of Obstetricians and Gynecologists (ACOG). Topical hemostatic agents at time of obstetric and gynecologic surgery: ACOG committee opinion, number 812. Obstet Gynecol. 2020;136(4):e81-e89. doi:10.1097/AOG.0000000000004104 [PubMed 32976379]Arat YO, Dorotheo EU, Tang RA, Boniuk M, Schiffman JS. Compressive optic neuropathy after use of oxidized regenerated cellulose in orbital surgery: review of complications, prophylaxis, and treatment. Ophthalmology. 2006;113(2):333-337. doi:10.1016/j.ophtha.2005.11.003 [PubMed 16406540]Bakhit J, Rafique M, Pham TD. Proceed or palliate: Surgicel® mimicking tumor recurrence and causing a small bowel obstruction. J Surg Case Rep. 2019;2019(1):rjz012. doi:10.1093/jscr/rjz012 [PubMed 30740208]Brodbelt AR, Miles JB, Foy PM, Broome JC. Intraspinal oxidised cellulose (Surgicel) causing delayed paraplegia after thoracotomy--a report of three cases. Ann R Coll Surg Engl. 2002;84(2):97-99. [PubMed 11995773]Chapa HO, Venegas G, Vanduyne CP, Antonetti AG, Sandate JP, Silver L. Peritoneal adhesion prevention at cesarean section: an analysis of the effectiveness of an absorbable adhesion barrier. J Reprod Med. 2011;56(3-4):103-109. [PubMed 21542525]Corti MC, Thomas AD, Sayegh MN, Vernon K, Sherman C, Trainor R. Surgicel-induced anaphylaxis post permacath placement. Cureus. 2021;13(8):e16938. doi:10.7759/cureus.16938 [PubMed 34513507]Interceed (oxidized regenerated cellulose) [prescribing information]. Somerville, NJ: Ethicon Inc; March 2017.Larsson B. Efficacy of Interceed in adhesion prevention in gynecologic surgery: a review of 13 clinical studies. J Reprod Med. 1996;41(1):27-34. [PubMed 8855073]Lin B, Yang H, Cui M, Li Y, Yu J. Surgicel application in intracranial hemorrhage surgery contributed to giant-cell granuloma in a patient with hypertension: case report and review of the literature. World J Surg Oncol. 2014;12:101. doi:10.1186/1477-7819-12-101 [PubMed 24745805]Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society of Reproductive Surgeons. Electronic address: asrm@asrm.org; Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society of Reproductive Surgeons. Postoperative adhesions in gynecologic surgery: a committee opinion. Fertil Steril. 2019;112(3):458-463. doi:10.1016/j.fertnstert.2019.06.027 [PubMed 31446904]Rottenstreich M, Rotem R, Hirsch A, et al. The use of absorbable adhesion barriers to reduce the incidence of intraperitoneal adhesions at repeat cesarean delivery. Arch Gynecol Obstet. 2020;302(1):101-108. doi:10.1007/s00404-020-05591-6 [PubMed 32415470]Sharma JB and Malhotra M, "Successful Management of Uterine Incision Hemorrhage in Caesarean Section With Topical Oxidized Regenerated Cellulose (Surgicel Nu Knit): A Case Report," Arch Gynecol Obstet, 2006, 274(2):115-6. [PubMed 16408181]Surgicel Original, Nu-Knit, and Fibrillar (oxidized regenerated cellulose) [prescribing information]. Somerville, NJ: Ethicon US LLC; October 2018.Surgicel Powder (oxidized regenerated cellulose) [prescribing information]. Somerville, NJ: Ethicon Inc; March 2019.Surgicel SNoW (oxidized regenerated cellulose) [prescribing information]. Somerville, NJ: Ethicon Inc; November 2019.Topic 10083 Version 70.0

CloseBismuth subsalicylate: Pediatric drug informationBismuth subsalicylate: Pediatric drug information(For additional information see "Bismuth subsalicylate: Drug information" and see "Bismuth subsalicylate: Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USBismatrol Maximum Strength [OTC] [DSC];Bismatrol [OTC];Diotame InstyDose [OTC];Geri-Pectate [OTC] [DSC];GoodSense Stomach Relief [OTC];Kao-Tin [OTC] [DSC];Peptic Relief [OTC] [DSC];Pepto-Bismol To-Go [OTC];Pepto-Bismol [OTC];Pink Bismuth [OTC];Stomach Relief Extra Strength [OTC];Stomach Relief Plus [OTC];Stomach Relief [OTC]Therapeutic CategoryGastrointestinal Agent, MiscellaneousDosing: PediatricNote: Multiple concentrations of oral liquid formulations exist; close attention must be paid to the concentration when ordering or administering. Children and adolescents who have or are recovering from chicken pox or flu-like symptoms should not use bismuth subsalicylate due to the association with Reye syndrome. Refer to product-specific labeling for approved pediatric ages. Dosing presented as mg of bismuth subsalicylate.Diarrhea, chronicDiarrhea, chronic (Gryboski 1985; Gryboski 1990): Limited data available: Oral liquid:Infants ≥2 months: Oral: 44 mg every 4 to 6 hours.Children <2 years: Oral: 44 mg every 4 hours or 87 mg every 6 hours.Children 2 to <3 years: Oral: 87 mg every 4 to 6 hours.Children 3 to <4 years: Oral: 87 mg every 4 hours.Children 4 to 6 years: Oral: 175 mg every 4 hours.Dosing based on 2 studies; the first was a prospective, double-blind, placebo-controlled clinical trial of 29 infants and children with chronic diarrhea (>6 weeks); after 7 days of bismuth therapy, patients in the treatment group (n=15, age 2 to 30 months) gained significantly more weight and had significantly improved stool characteristics (consistency/frequency) compared to placebo; to prevent recurrence of symptoms, the authors also suggested tapering the medication at the end of therapy (Gryboski 1985). A second study compared bismuth subsalicylate with cholestyramine; patients were treated with bismuth (n=19) for 7 days; bismuth was found to be as effective as cholestyramine in binding of bile acids and at decreasing stool frequency (Gryboski 1990).Diarrhea, dyspepsia, acuteDiarrhea, dyspepsia, acute (gas, upset stomach, indigestion, heartburn, nausea): OTC labeling:Children ≥12 years and Adolescents: Oral: 524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed for up to 2 days. Maximum daily dose: 4,200 mg/day.Helicobacter pylori eradicationHelicobacter pylori eradication: Limited data available: Note: Use as part of an appropriate combination regimen; usual duration of therapy is 14 days (NASPGHAN/ESPGHAN [Jones 2017]).Children and Adolescents (NASPGHAN/ESPGHAN [Jones 2017]):<10 years: Oral: 262 mg 4 times daily.≥10 years: Oral: 524 mg 4 times daily.Traveler's diarrheaTraveler's diarrhea (Gal 2007; Leung 2019; manufacturer's labeling): Limited data available in children <12 years:Children 3 to <6 years: Oral: 87 mg every 30 to 60 minutes as needed; do not exceed 8 doses per 24 hours.Children 6 to <9 years: Oral: 175 mg every 30 to 60 minutes as needed; do not exceed 8 doses per 24 hours.Children 9 to <12 years: Oral: 262 mg every 30 to 60 minutes as needed; do not exceed 8 doses per 24 hours.Children ≥12 years and Adolescents: Oral: 524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed; maximum dose: 4,200 mg per 24 hours.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling; use with caution.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Bismuth subsalicylate: Drug information")Diarrhea/dyspepsiaDiarrhea/dyspepsia: Oral: ~524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed for up to 2 days (maximum: ~4,200 mg/24 hours).Helicobacter pylori eradicationHelicobacter pylori eradication (off-label use):American College of Gastroenterology guidelines (Chey 2007; Chey 2017): Bismuth quadruple therapy: Oral: 300 mg 4 times daily in combination with tetracycline 500 mg 4 times daily, either metronidazole 500 mg 3 or 4 times daily or 250 mg 4 times daily, and standard-dose proton pump inhibitor twice daily; continue regimen for 10 to 14 days.Travelers' diarrhea, prophylaxisTravelers' diarrhea, prophylaxis (off-label use): Oral: ~524 mg 4 times daily with meals and at bedtime during period of risk (ACG [Riddle 2016]; CDC 2020). Note: Safety has not been established for periods >3 weeks (CDC 2020); some experts do not recommend use for trips exceeding 2 weeks in duration (ACG [Riddle 2016]).Travelers' diarrhea, treatmentTravelers' diarrhea, treatment: Oral: ~524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed (maximum: ~4,200 mg/24 hours) (ACG [Riddle 2016]; manufacturer's labeling).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling; use with caution.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSuspension, Oral: Bismatrol Maximum Strength: 525 mg/15 mL (236 mL [DSC]) [contains benzoic acid, d&c red #22 (eosine), saccharin sodium; wintergreen flavor]Diotame InstyDose: 262 mg/15 mL (30 mL) [contains benzoic acid, d&c red #22 (eosine), saccharin sodium, salicylic acid]Geri-Pectate: 262 mg/15 mL (355 mL [DSC]) [contains fd&c red #40 (allura red ac dye)]GoodSense Stomach Relief: 525 mg/30 mL (236 mL) [contains benzoic acid, d&c red #22 (eosine), saccharin sodium, salicylic acid]GoodSense Stomach Relief: 1050 mg/30 mL (236 mL) [contains benzoic acid, d&c red #22 (eosine), saccharin sodium]Pepto-Bismol: 262 mg/15 mL (118 mL) [contains benzoic acid, d&c red #22 (eosine), saccharin sodium; original flavor]Pink Bismuth: 262 mg/15 mL (473 mL [DSC]) [contains benzoic acid, d&c red #22 (eosine), saccharin sodium]Stomach Relief: 525 mg/15 mL (237 mL) [contains d&c red #22 (eosine), saccharin sodium]Stomach Relief: 525 mg/30 mL (237 mL) [alcohol free, sugar free; contains benzoic acid, d&c red #22 (eosine)]Stomach Relief Extra Strength: 525 mg/15 mL (237 mL) [alcohol free, sugar free; contains benzoic acid, d&c red #22 (eosine)]Stomach Relief Plus: 525 mg/15 mL (240 mL, 480 mL)Generic: 525 mg/30 mL (30 mL [DSC])Suspension, Oral, as subsalicylate: Bismatrol: 262 mg/15 mL (236 mL [DSC]) [contains benzoic acid, d&c red #22 (eosine), saccharin sodium; wintergreen flavor]Geri-Pectate: 262 mg/15 mL (355 mL [DSC])Kao-Tin: 262 mg/15 mL (236 mL [DSC], 473 mL [DSC]) [contains fd&c red #40 (allura red ac dye), saccharin sodium, sodium benzoate]Pepto-Bismol: 262 mg/15 mL (473 mL) [contains benzoic acid, d&c red #22 (eosine), saccharin sodium]Pink Bismuth: 262 mg/15 mL (236 mL)Pink Bismuth: 262 mg/15 mL (237 mL [DSC]) [contains benzoic acid, d&c red #22 (eosine), saccharin sodium]Stomach Relief: 527 mg/30 mL (240 mL, 480 mL)Tablet Chewable, Oral: Stomach Relief: 262 mg [contains aspartame]Generic: 262 mgTablet Chewable, Oral, as subsalicylate: Bismatrol: 262 mg [contains saccharin sodium]Peptic Relief: 262 mg [DSC] [contains saccharin sodium]Pepto-Bismol To-Go: 262 mg [sugar free; contains fd&c red #40(allura red ac)aluminum lake, saccharin sodium; cherry flavor]Generic: 262 mgGeneric Equivalent Available: USYesAdministration: PediatricOral:Liquid: Shake well before using.Tablets, chewable: Chew or allow to dissolve in mouth before swallowing.Tablets, nonchewable caplets: Swallow whole with a full glass of water.Administration: AdultOral: Shake liquids well prior to use. Chew tablets thoroughly or allow to dissolve in the mouth before swallowing. Nonchewable tablets should be swallowed whole with a full glass of water.Storage/StabilityStore at room temperature. Avoid excessive heat. Protect from freezing.UseRelief of diarrhea and dyspepsia (gas, upset stomach, indigestion, heartburn, nausea) (OTC products: FDA approved in ages ≥12 years and adults); has also been used for eradication of Helicobacter pylori.Note: Approved ages and uses for generic products may vary; consult product labeling for specific information.Medication Safety IssuesSound-alike/look-alike issues:Kaopectate may be confused with KayexalatePediatric patients: High-risk medication:KIDs List: Salicylates, when used in pediatric patients <18 years of age with suspicion of viral illness (influenza, chickenpox), are identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list and should be used with caution due to risk of Reye syndrome (weak recommendation; very low quality of evidence) (PPA [Meyers 2020]).Other safety concerns:Canadian formulation of Kaopectate does not contain bismuth; the active ingredient in the Canadian formulation is attapulgite.Adverse ReactionsThere are no adverse reactions listed in the manufacturer's labeling.Postmarketing:Gastrointestinal: Esophagitis (acute esophageal necrosis) (Abed 2014), melena (Bierer 1990), melanoglossia (Bierer 1990), staining of tooth (Borbinha 2019)Hypersensitivity: Anaphylaxis (More 2002)Nervous system: Encephalopathy (Borbinha 2019)Otic: Tinnitus (Castelli 2006)ContraindicationsOTC labeling: When used for self-medication, do not use if you are allergic to salicylates (including aspirin) or are taking other salicylates; have an ulcer, bleeding problem or bloody/black stool.Warnings/PrecautionsConcerns related to adverse effects:• Neurotoxicity: Bismuth products may be neurotoxic with very large doses.Dosage forms• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.Other warnings/precautions:• Diagnostic GI procedures: Bismuth absorbs x-rays and may interfere with diagnostic procedures of GI tract.• Self-medication (OTC use): Pediatric patients who have or are recovering from chickenpox or flu-like symptoms should not use subsalicylate. Changes in behavior (along with nausea and vomiting) may be an early sign of Reye syndrome; patients should be instructed to contact their health care provider if these occur. A temporary harmless darkening of the stool and/or tongue may occur with use. Contact a health care provider before use if fever or mucus in the stool occurs. Discontinue use and contact health care provider if any of the following occur: diarrhea lasts >2 days, diarrhea with a fever, symptoms get worse, hearing loss, or ringing in the ears.Warnings: Additional Pediatric ConsiderationsDo not use aspirin-containing products in children and adolescents who have or who are recovering from chickenpox or flu symptoms (due to the association with Reye syndrome); when using aspirin, changes in behavior (along with nausea and vomiting) may be an early sign of Reye syndrome; instruct patients and caregivers to contact their health care provider if these symptoms occur.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAgents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapyAgents with Blood Glucose Lowering Effects: Salicylates may enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects.Risk C: Monitor therapyAjmaline: Salicylates may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased.Risk C: Monitor therapyAmmonium Chloride: May increase the serum concentration of Salicylates. Risk C: Monitor therapyAngiotensin-Converting Enzyme Inhibitors: Salicylates may enhance the nephrotoxic effect of Angiotensin-Converting Enzyme Inhibitors. Salicylates may diminish the therapeutic effect of Angiotensin-Converting Enzyme Inhibitors.Risk C: Monitor therapyAnticoagulants: Salicylates may enhance the anticoagulant effect of Anticoagulants.Risk C: Monitor therapyBenzbromarone: Salicylates may diminish the therapeutic effect of Benzbromarone.Risk C: Monitor therapyBismuth Subcitrate: Bismuth-Containing Compounds may enhance the neurotoxic effect of Bismuth Subcitrate.Risk X: Avoid combinationCarbonic Anhydrase Inhibitors: Salicylates may enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination.Management: Avoid these combinations when possible.Dichlorphenamide use with high-dose aspirin as contraindicated. If another combination is used, monitor patients closely for adverse effects. Tachypnea, anorexia, lethargy, and coma have been reported. Risk D: Consider therapy modificationCorticosteroids (Systemic): Salicylates may enhance the adverse/toxic effect of Corticosteroids (Systemic). These specifically include gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease the serum concentration of Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity.Risk C: Monitor therapyDexketoprofen: Salicylates may enhance the adverse/toxic effect of Dexketoprofen. Dexketoprofen may diminish the therapeutic effect of Salicylates. Salicylates may decrease the serum concentration of Dexketoprofen.Management: The use of high-dose salicylates (3 g/day or more in adults) together with dexketoprofen is inadvisable. Consider administering dexketoprofen 30-120 min after or at least 8 hrs before cardioprotective doses of aspirin to minimize any possible interaction. Risk X: Avoid combinationGinkgo Biloba: May enhance the anticoagulant effect of Salicylates. Management: Consider alternatives to this combination of agents. Monitor for signs and symptoms of bleeding (especially intracranial bleeding) if salicylates are used in combination with ginkgo biloba. Risk D: Consider therapy modificationHerbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Salicylates. Bleeding may occur. Risk C: Monitor therapyHyaluronidase: Salicylates may diminish the therapeutic effect of Hyaluronidase.Risk C: Monitor therapyInfluenza Virus Vaccine (Live/Attenuated): May enhance the adverse/toxic effect of Salicylates. Specifically, Reye's syndrome may develop. Risk X: Avoid combinationLoop Diuretics: Salicylates may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Salicylates.Risk C: Monitor therapyMethotrexate: Salicylates may increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern.Management: Consider avoiding coadministration of methotrexate and salicylates. If coadministration cannot be avoided, monitor for increased toxic effects of methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: Consider therapy modificationNonsteroidal Anti-Inflammatory Agents (Nonselective): May enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Management: Nonselective NSAIDs may reduce aspirin's cardioprotective effects. Administer ibuprofen 30-120 minutes after immediate-release aspirin, 2 to 4 hours after extended-release aspirin, or 8 hours before aspirin. Risk D: Consider therapy modificationNonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of Salicylates. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of salicylates and topical NSAIDs is not recommended. If salicylates and topical NSAIDs are coadministered, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider therapy modificationPotassium Phosphate: May increase the serum concentration of Salicylates. Risk C: Monitor therapyPRALAtrexate: Salicylates may increase the serum concentration of PRALAtrexate. Salicylate doses used for prophylaxis of cardiovascular events are unlikely to be of concern.Management: Consider avoiding concomitant use of salicylates and pralatrexate. If coadministered, monitor for increased pralatrexate adverse effects. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: Consider therapy modificationProbenecid: Salicylates may diminish the therapeutic effect of Probenecid.Risk X: Avoid combinationSalicylates: May enhance the anticoagulant effect of other Salicylates. Risk C: Monitor therapySulfinpyrazone: Salicylates may decrease the serum concentration of Sulfinpyrazone.Risk X: Avoid combinationTetracyclines: Bismuth Subsalicylate may decrease the serum concentration of Tetracyclines.Management: Consider dosing tetracyclines 2 hours before or 6 hours after bismuth. The need to separate doses during Helicobacter pylori eradication regimens is questionable. Risk D: Consider therapy modificationThrombolytic Agents: Salicylates may enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur.Risk C: Monitor therapyValproate Products: Salicylates may increase the serum concentration of Valproate Products.Risk C: Monitor therapyVaricella Virus-Containing Vaccines: Salicylates may enhance the adverse/toxic effect of Varicella Virus-Containing Vaccines. Specifically, the risk for Reye's syndrome may increase.Risk X: Avoid combinationVitamin K Antagonists (eg, warfarin): Salicylates may enhance the anticoagulant effect of Vitamin K Antagonists.Management: Avoid as needed use of salicylates in patients taking vitamin K antagonists. Aspirin (80 to 325 mg/day) may be used with warfarin for prevention of cardiovascular events. If coadministering salicylates and vitamin K antagonists, monitor for bledding. Risk D: Consider therapy modificationDietary ConsiderationsDrink plenty of fluids to help prevent dehydration caused by diarrhea. Some products may contain phenylalanine, potassium, and/or sodium.Pregnancy ConsiderationsBismuth subsalicylate is converted to bismuth and salicylic acid in the GI tract. Following oral administration, salicylates cross the placenta. Very little bismuth is systemically absorbed from this preparation (Bierer 1990; Lione 1988).Following ingestion of bismuth subsalicylate, plasma salicylate concentrations may be comparable to those following ingestion of aspirin (Bierer 1990; Lione 1988). Refer to the aspirin monograph for additional information related to salicylates and pregnancy.Bismuth subsalicylate should not be used in pregnant patients for the treatment of dyspepsia or acute diarrhea (Body 2016) and current guidelines do not recommend use for the treatment or prevention of travelers' diarrhea in pregnancy (CDC 2020).Mechanism of ActionBismuth subsalicylate exhibits both antisecretory and antimicrobial action. This agent may provide some anti-inflammatory action as well. The salicylate moiety provides antisecretory effect and the bismuth exhibits antimicrobial directly against bacterial and viral gastrointestinal pathogens.Pharmaco*kinetics (Adult data unless noted)Absorption: Bismuth: <1%; Subsalicylate: >80%Distribution: Salicylate: Vd: 170 mL/kgProtein binding, plasma: Bismuth and salicylate: >90%Metabolism: Bismuth subsalicylate is converted to bismuth and salicylic acid in the GI tract.Half-life elimination: Terminal: Bismuth: 21 to 72 days; Salicylate: 2 to 5 hoursExcretion: Bismuth: Urine and biliary; Salicylate: Urine (10% excreted unchanged)Pricing: USChewable (Bismuth Subsalicylate Oral)262 mg (per each): $0.06 - $0.08Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalBisbacter (CO);Bismucar (PE);Bismutol (EC);Bitni X Forte Suspension (IL);Facidmol (CR, DO, GT, HN, NI, PA, SV);Gastro-Bismol (TH);Gastro-Bismol L (TH);Kalbeten (IL);Peptolite (IL);Pink Bismuth (IL);Stobiol (ID)For country code abbreviations (show table)Abed J, Mankal P, Judeh H, Kim S. Acute esophageal necrosis: a case of black esophagus associated with bismuth subsalicylate ingestion. ACG Case Rep J. 2014;1(3):131-133. doi:10.14309/crj.2014.27 [PubMed 26157851]Ahlfors CE. Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr. 2001;139(2):317-319. [PubMed 11487763]Bar-Oz B, Bulkowstein M, Benyamini L, et al. Use of antibiotic and analgesic drugs during lactation. Drug Saf. 2003;26(13):925-935. [PubMed 14583068]Bierer DW. Bismuth subsalicylate: history, chemistry, and safety. Rev Infect Dis. 1990;12(Suppl 1):S3-8. [PubMed 2406853]Bismuth Subsalicylate Maximum Strength Stomach Relief Liquid [prescribing information]. Lawrenceville, NJ: Aurohealth LC; November 2020.Body C, Christie JA. Gastrointestinal diseases in pregnancy: nausea, vomiting, hyperemesis gravidarum, gastroesophageal reflux disease, constipation, and diarrhea. Gastroenterol Clin North Am. 2016;45(2):267‐283. doi:10.1016/j.gtc.2016.02.005 [PubMed 27261898]Borbinha C, Serrazina F, Salavisa M, Viana-Baptista M. Bismuth encephalopathy- a rare complication of long-standing use of bismuth subsalicylate. BMC Neurol. 2019;19(1):212. doi:10.1186/s12883-019-1437-9 [PubMed 31464594v]Castelli F, Saleri N, Tomasoni LR, Carosi G. Prevention and treatment of traveler's diarrhea. Focus on antimicrobial agents. Digestion. 2006;73 (Suppl 1):109-118. doi:10.1159/000089786 [PubMed 16498259]Centers for Disease Control and Prevention (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982;31(22):290-291. http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm. [PubMed 6810084]Centers for Disease Control and Prevention (CDC). The pre-travel consultation: travelers' diarrhea. The Yellow Book: CDC health information for international travel, 2020. https://wwwnc.cdc.gov/travel/yellowbook/2020/preparing-international-travelers/travelers-diarrhea. Updated November 22, 2019. Accessed March 2, 2021.Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG clinical guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol. 2017;112(2):212-239. doi:10.1038/ajg.2016.563 [PubMed 28071659]Chey WD and Wong B, “American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection,” Am J Gastroenterol, 2007; 102(8):1808-1825. [PubMed 17608775]Drumm B, Sherman P, Karmali M, et al, “Treatment of Campylobacter pylori-Associated Antral Gastritis in Children With Bismuth Subsalicylate and Ampicillin,” J Pediatr, 1988, 113(5):908-12. [PubMed 3183851]Gal P, Reed M. Medications. In: Kliegman RM, Behrman RE, Jenson HB, et al, eds. Nelson Textbook of Pediatrics. 18th ed. 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Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial. 2007;20(3):217-219. [PubMed 17555487]Topic 101045 Version 285.0

CloseVoriconazole: Drug informationVoriconazole: Drug information(For additional information see "Voriconazole: Patient drug information" and see "Voriconazole: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USVfend;Vfend IVBrand Names: CanadaAPO-Voriconazole;JAMP-Voriconazole;SANDOZ Voriconazole;TEVA-Voriconazole;VfendPharmacologic CategoryAntifungal Agent, Azole Derivative;Antifungal Agent, Oral;Antifungal Agent, ParenteralDosing: AdultNote: Therapeutic drug monitoring: Adjust dose based on serum trough concentration to ensure efficacy and avoid toxicity. Timing and frequency of concentration monitoring is individualized (Ref).AspergillosisAspergillosis:Allergic bronchopulmonary (alternative agent): Oral: 200 mg twice daily for ≥16 weeks in combination with systemic corticosteroids (Ref); may give a loading dose of 400 mg twice daily for the first 2 doses. Note: Some experts reserve for patients who are unable to taper corticosteroids or have an exacerbation of allergic bronchopulmonary aspergillosis (Ref).Chronic cavitary pulmonary: IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref). Note: Some experts reserve IV therapy for severely ill patients (Ref).Oral: 200 mg twice daily; may increase to 300 mg twice daily based on therapeutic drug monitoring (Ref).Duration: ≥6 months; some patients require prolonged, potentially lifelong therapy (Ref).Invasive (including disseminated and extrapulmonary): Note: For severe or progressive infection, some experts use as part of a combination antifungal regimen (Ref).IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref). Note: Once a patient is able to tolerate oral administration, consider transition to oral formulation (Ref).Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref).Duration: Minimum of 6 to 12 weeks, depending on degree/duration of immunosuppression, disease site, and response to therapy (Ref); immunosuppressed patients may require more prolonged treatment (Ref).Ocular (off-label use):Endophthalmitis:Note: Administer a combination of both intraocular (intravitreal and/or intracameral depending on sites of involvement) and systemic (IV or oral) antifungal therapy (Ref).Intraocular: Note: For intraocular injections, extemporaneously prepare dose in 0.1 mL of sterile water or NS.Intravitreal injection: For involvement of the vitreous: 100 mcg per 0.1 mL (sterile water or NS) administered intravitreally once. Intravitreal dose may be repeated in several days if no improvement (Ref).Intracameral injection: For involvement of the anterior segment: 50 mcg per 0.1 mL to 100 mcg per 0.1 mL (sterile water or NS) administered intracamerally (into the aqueous) once (Ref). Note: May also consider intravitreal injection even if vitritis is not apparent, as occult vitreal involvement is possible (Ref).Systemic:IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref). Note: Once a patient is able to tolerate oral administration, consider transition to oral formulation (Ref).Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref). If the oral formulation is used as initial therapy for mild cases, give a loading dose of 400 mg twice daily for the first 2 doses (Ref).Duration: Usually ≥1 month to several months, depending on cause and extent of infection and response to therapy; some patients require prolonged therapy (Ref).Keratitis: Note: Optimal dose not defined.Ophthalmic: Instill 1 drop of an extemporaneously prepared 1% ophthalmic solution topically to the cornea of the affected eye(s) every 1 hour while awake for 1 week, then every 2 hours while awake for 2 weeks, with further continuation at physician discretion (Ref).Candidiasis, treatmentCandidiasis, treatment:Candidemia (neutropenic and non-neutropenic patients), including disseminated candidiasis (alternative agent): Initial therapy: IV: 400 mg twice daily for 2 doses, then 200 to 300 mg IV or orally twice daily or weight-based dosing (6 mg/kg IV twice daily for 2 doses, then 3 to 4 mg/kg IV or orally twice daily) (Ref).Step-down therapy (for clinically stable patients who have responded to initial therapy with negative repeat cultures): Note: For susceptible Candidakrusei isolates, voriconazole is the preferred step-down agent (Ref).Oral: 200 mg twice daily; for susceptible isolates of Candida glabrata, use 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref).Duration: Treat for ≥14 days after first negative blood culture and resolution of signs/symptoms; continue until resolution of neutropenia, if present; metastatic complications warrant a longer duration (Ref).Cardiac infection, native or prosthetic valve endocarditis or device infection (eg, implantable cardiac defibrillator, pacemaker) (alternative agent) (off-label use): Note: Reserve for patients with fluconazole-resistant/voriconazole-susceptible isolates (Ref).Step-down therapy (for clinically stable, blood culture–negative patients following initial therapy with non-azole parenteral therapy): Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref).Duration: For device infection without endocarditis, 4 weeks after device removal for generator pocket infections and ≥6 weeks after device removal for wire infections. For endocarditis, ≥6 weeks after valve replacement surgery, with longer duration for perivalvular abscesses or other complications; long-term suppressive therapy is recommended for prosthetic valve endocarditis or if valve cannot be replaced (Ref).Endophthalmitis (with or without vitritis) (off-label use): Note: Administer a combination of both intraocular (intravitreal and/or intracameral depending on sites of involvement) and systemic (IV or oral) antifungal therapy. For patients with endogenous endophthalmitis without vitritis or macular involvement, intraocular antifungals may not be necessary (Ref).Intraocular: Note: For intraocular injections, extemporaneously prepare dose in 0.1 mL of sterile water or NS.Intravitreal injection: 100 mcg per 0.1 mL (sterile water or NS) administered intravitreally once (Ref). Intravitreal dose may be repeated in several days if no improvement (Ref).Intracameral injection: For exogenous cases involving primarily the aqueous: 50 mcg per 0.1 mL (sterile water or NS) administered intracamerally (into the aqueous) once. Note: May also consider intravitreal injection even if vitritis is not apparent, as occult vitreal involvement is possible (Ref).Ophthalmic: For exogenous cases with concurrent keratitis: Instill 1 drop of an extemporaneously prepared 1% ophthalmic solution topically to the cornea of the affected eye(s) every 1 hour (Ref). Duration depends on response to therapy.Systemic: IV, Oral: 400 mg twice daily for 2 doses, then 200 to 300 mg twice daily or weight-based dosing (6 mg/kg twice daily for 2 doses, then 3 to 4 mg/kg twice daily) for ≥4 to 6 weeks until resolution (Ref).Esophageal: IV, Oral: 200 mg twice daily or weight-based dosing (3 mg/kg twice daily) for 14 to 28 days. Note: Reserve for fluconazole-refractory disease or as an alternative initial agent for patients with HIV (Ref).Oropharyngeal, fluconazole-refractory (alternative agent) (off-label use): Oral: 200 mg twice daily for up to 28 days (Ref).Coccidioidomycosis, refractory to conventional therapyCoccidioidomycosis, refractory to conventional therapy (alternative agent) (off-label use): Note: Initial parenteral antifungal therapy may be warranted.Nonmeningeal infection (eg, bone and/or joint infection, pulmonary infection in select patients): Oral: 400 mg twice daily for 2 doses, then 200 mg twice daily (Ref).Duration: Varies based on site and severity of infection, as well as host immune status; in some cases, lifelong therapy is needed (Ref).Meningitis: Oral: 400 mg twice daily for 2 doses, followed by 200 to 400 mg twice daily (Ref). Duration is lifelong because of the high relapse rate (Ref).FusariosisFusariosis (alternative agent): Invasive:IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref). Note: Some experts suggest initial combination antifungal therapy for patients with severe immunosuppression, severe disease, or persistently positive blood cultures with monotherapy (Ref).Oral, following improvement with initial IV therapy: 200 mg twice daily (Ref).Duration: Often prolonged and depends on site of infection, severity, immune status, and response to therapy (Ref).Keratitis: Ophthalmic: Instill 1 drop of an extemporaneously prepared 1% ophthalmic solution topically to the affected eye(s) every 1 hour; may extend dosing interval based on response. May be used alone or in combination with systemic therapy depending on the severity of illness (Ref). Duration depends on response to therapy; several months are often warranted (Ref).Neutropenic feverNeutropenic fever (empiric antifungal therapy) (alternative agent) (off-label use):IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref).Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily) (Ref).Prophylaxis against invasive fungal infectionsProphylaxis against invasive fungal infections (alternative agent) (off-label use):Hematologic malignancy or post-hematopoietic cell transplant: IV: 4 mg/kg twice daily (Ref).Oral: 200 mg twice daily (Ref).Duration: Varies based on degree and duration of immunosuppression (Ref).Solid organ transplant:IV: 4 mg/kg twice daily; may give a loading dose of 6 mg/kg twice daily for the first 2 doses (Ref).Oral: 200 mg twice daily (Ref); may give a loading dose of 400 mg twice daily for the first 2 doses (Ref). Duration: Varies based on patient risk factors and transplant center protocol (Ref). ScedosporiosisScedosporiosis: IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily (Ref).Oral: 400 mg twice daily for 2 doses, then 200 to 300 mg twice daily (Ref).Duration: Often prolonged and varies based on clinical response and patient immune status (Ref).TalaromycosisTalaromycosis (formerly Penicilliosis) (alternative agent) (off-label use):Treatment, mild disease (skin lesions without bloodstream infection): Oral: 400 mg twice daily for 2 doses, then 200 mg twice daily for 12 weeks, then continue with long-term suppression therapy (Ref).Treatment, moderate to severe disease:Induction therapy: IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily for at least 3 days (Ref).Following IV induction therapy: Oral: 200 mg twice daily for a total of 12 weeks (Ref). If oral therapy is used for induction therapy (eg, when IV formulation is unavailable), give 600 mg twice daily for 2 doses, then 400 mg twice daily for 2 weeks, then 200 mg twice daily for 10 weeks (Ref). Continue with long-term suppression therapy after either regimen.Long-term suppression therapy (secondary prophylaxis): Oral: 200 mg twice daily until cellular immunity is restored (for patients with HIV, when CD4 count >100 cells/mm3 and virologic suppression with antiretroviral therapy is sustained for ≥6 months) (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Altered kidney function:CrCl ≥50 mL/minute: Oral, Ophthalmic, IV: No dosage adjustment necessary (Ref).CrCl <50 mL/minute:Oral, Ophthalmic: No dosage adjustment necessary (Ref).IV: No dosage adjustment necessary for voriconazole component of the IV formulation (Ref); however, use of oral voriconazole or alternative antifungals is preferred if clinically appropriate. IV formulations contain the vehicle sulfobutylether-beta-cyclodextrin (SBECD), which may accumulate. Cyclodextrins have been associated with kidney injury in animal models; however, small studies suggest similar rates of nephrotoxicity to noncyclodextrin-containing antifungals in patients receiving short durations (eg, <10 days) of therapy (Ref). If IV therapy is used, monitor serum creatinine frequently and change to oral voriconazole when possible (Ref).Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2):Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).Oral, IV: Initiate therapy with the maximum recommended indication-specific dose; subsequent dosage adjustments should be made based on therapeutic drug monitoring to ensure pharmaco*kinetic/pharmacodynamic targets are met (Ref).Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (voriconazole component) (Ref):Oral, Ophthalmic: No dosage adjustment or supplemental doses necessary.IV: No dosage adjustment necessary for voriconazole component of the IV formulation (Ref); however, use of oral voriconazole or alternative antifungals is preferred if clinically appropriate. Exposure to SBECD, the carrier excipient in the IV formulation, is increased compared to patients with normal kidney function despite removal by hemodialysis (Ref). If IV therapy is used, use with caution and change to oral voriconazole when possible (Ref).Peritoneal dialysis:Oral, Ophthalmic: No dosage adjustment necessary (Ref).IV: No dosage adjustment necessary for voriconazole component of the IV formulation (Ref); however, use of oral voriconazole or alternative antifungals is preferred if clinically appropriate. Exposure to SBECD, the carrier excipient in the IV formulation, is expected to be increased compared to patients with normal renal function. If IV therapy is used, use with caution and change to oral voriconazole when possible (Ref).CRRT:Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.Oral, Ophthalmic: No dosage adjustment necessary (Ref).IV: Use of oral voriconazole therapy or alternative antifungals is preferred when clinically appropriate; however, due to removal of SBECD, the carrier excipient in the IV formulation, via CRRT, limited data suggest that usual indication-specific doses of IV voriconazole can be considered (Ref).PIRRT (eg, sustained, low-efficiency diafiltration):Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.Oral, Ophthalmic: No dosage adjustment necessary (Ref).IV: Use of oral voriconazole therapy or alternative antifungals is preferred when clinically appropriate. If necessary, usual indication-specific doses of IV voriconazole can be considered; however, use with caution with frequent monitoring of kidney function and conversion to oral voriconazole when possible; a small study in patients receiving extended daily dialysis showed significant accumulation of SBECD, the carrier excipient in the IV formulation (Ref).Dosing: Hepatic Impairment: AdultMild to moderate impairment (Child-Pugh class A or B): Following standard loading dose, reduce maintenance dosage by 50% Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Should only be used if benefit outweighs risk; monitor closely for toxicityDosing: Pediatric(For additional information see "Voriconazole: Pediatric drug information")Note: In pediatric patients <12 years, bioequivalence between the oral tablet and suspension has not been determined; due to possible shortened gastric transit time in infants and children, absorption of tablets may be different than adults; dosing recommendations for infants and children are based on studies with the oral suspension. Data suggests higher doses (mg/kg) than adults are required in patients <15 years and weighing <50 kg.General dosing, susceptible infection: Note: Dosage adjustment may be required if patient does not have adequate response, cannot tolerate dose, or adequate trough concentrations are not achieved; monitor trough concentrations closely (Ref).Infants and Children <2 years: Limited data available: IV, Oral (Oral suspension): Initial: 9 mg/kg/dose every 12 hours followed by monitoring of serum trough concentrations typically initiated after 3 to 5 days; adjust dose to achieve target trough; median final dosage: 31.5 mg/kg/day (range: 12 to 71 mg/kg/day) divided every 12 hours; Note: Doses >40 mg/kg/day were administered in 3 divided doses; dosing based on a retrospective pharmaco*kinetic analysis of patients receiving voriconazole after hematopoietic stem cell transplants (n=11; age range: 0.3 to 2 years) (Ref).Children 2 to <12 years: Note: Monitor serum concentrations to maintain trough concentrations of 2 to 6 mcg/mL (Ref).Loading dose: IV: 9 mg/kg/dose every 12 hours for 2 doses on day 1.Maintenance:IV: 8 mg/kg/dose every 12 hours.Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose; Note: In most patients, oral therapy is not recommended as initial therapy for treatment; it is recommended to convert from parenteral to oral therapy only after significant clinical improvement has been observed.Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).IV:<50 kg: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 4 to 8 mg/kg/dose every 12 hours.≥50 kg: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 3 to 4 mg/kg/dose every 12 hours.Oral:<50 kg: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.≥50 kg: 200 mg every 12 hours.Adolescents ≥15 years:IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses; followed by a maintenance dose of 3 to 4 mg/kg/dose every 12 hours.Oral:<40 kg: 100 mg every 12 hours.≥40 kg: 200 mg every 12 hours.Aspergillosis, invasive, including disseminated and extrapulmonary infection; treatmentAspergillosis, invasive, including disseminated and extrapulmonary infection; treatment (Ref): Note: Duration of therapy should be a minimum of 6 to 12 weeks, although duration is highly dependent on degree/duration of immunosuppression, disease site, and evidence of disease improvement (Ref).Dosage adjustment may be required if patient does not have adequate response, cannot tolerate dose, or adequate trough concentrations are not achieved; monitor trough concentrations closely; therapeutic drug monitoring is critical to ensure efficacy and minimize toxicity; may consider switching to oral therapy once patient is stable and able to tolerate (Ref).Children 2 to <12 years:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses on day 1, followed by a maintenance dose of 8 mg/kg/dose every 12 hours.Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).<50 kg:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours.Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.≥50 kg:IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 4 mg/kg/dose every 12 hours.Oral: 200 to 300 mg every 12 hours.Adolescents ≥15 years:IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 4 mg/kg/dose every 12 hours.Oral: 200 to 300 mg every 12 hours.Candidiasis, prophylaxis for patients at high risk of invasive candidiasisCandidiasis, prophylaxis for patients at high risk of invasive candidiasis (eg, AML, recurrent ALL, allogeneic HSCT): Limited data available:Children 2 to <12 years (Ref):IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses on day 1, followed by a maintenance dose of 8 mg/kg/dose every 12 hours.Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).<50 kg:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).≥50 kg:IV: 4 mg/kg/dose every 12 hours (Ref).Oral: 200 mg every 12 hours (Ref).Adolescents ≥15 years:IV: 4 mg/kg/dose every 12 hours (Ref).Oral: 200 mg every 12 hours (Ref).Candidiasis, invasive; treatmentCandidiasis, invasive; treatment: Note: Voriconazole is considered an alternative therapy and offers little advantage over fluconazole as first-line therapy of candidemia. Step-down therapy to oral voriconazole is recommended only in select clinically stable patients with certain voriconazole-susceptible isolates (eg, Candida krusei) and negative repeat cultures (Ref).Children 2 to <12 years:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses on day 1, followed by a maintenance dose of 8 mg/kg/dose every 12 hours.Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).<50 kg:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours.Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.≥50 kg:IV: Loading dose: 400 mg (6 mg/kg/dose) every 12 hours for 2 doses, followed by 3 to 4 mg/kg/dose every 12 hours.Oral: 200 to 300 mg every 12 hours.Adolescents ≥15 years:IV: Loading dose: 400 mg (6 mg/kg/dose) every 12 hours for 2 doses, followed by 3 to 4 mg/kg/dose every 12 hours.Oral: 200 to 300 mg every 12 hours.Candidiasis, endocarditis/implantable cardiac devices; treatmentCandidiasis, endocarditis/implantable cardiac devices (eg, pacemaker, ICD, VAD); treatment: Limited data available: Note: Voriconazole should only be used as step-down therapy in clinically stable, culture-negative patients following initial therapy.Children 2 to <12 years: Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).<50 kg: Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).≥50 kg: Oral: 200 to 300 mg (3 to 4 mg/kg/dose) twice daily (Ref).Adolescents ≥15 years: Oral: 200 to 300 mg (3 to 4 mg/kg/dose) twice daily (Ref).Candidiasis, esophageal, treatmentCandidiasis, esophageal, treatment: Note: Voriconazole is not considered a first-line therapy for esophageal candidiasis (Ref).Children 2 to <12 years:IV: 4 mg/kg/dose every 12 hours.Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).<50 kg:IV: 4 mg/kg/dose every 12 hours.Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.≥50 kg: Oral: 200 mg twice daily.Adolescents ≥15 years: Oral: 200 mg twice daily (Ref).Fluconazole-refractory infection: Limited data available: Treatment should continue for 14 to 21 days (Ref).Children 2 to <12 years:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).<50 kg:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).≥50 kg: IV, Oral: 200 mg (3 mg/kg/dose) twice daily (Ref).Adolescents ≥15 years: IV, Oral: 200 mg (3 mg/kg/dose) twice daily (Ref).Candidiasis, oropharyngeal, fluconazole-refractory; treatmentCandidiasis, oropharyngeal, fluconazole-refractory; treatment: Limited data available: Treatment should continue for up to 28 days (Ref).Children 2 to <12 years: Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).<50 kg: Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).≥50 kg: Oral: 200 mg twice daily (Ref).Adolescents ≥15 years: Oral: 200 mg twice daily (Ref).Candidiasis, endophthalmitis, voriconazole-susceptible isolatesCandidiasis, endophthalmitis (with or without vitritis), voriconazole-susceptible isolates: Limited data available:Systemic therapy: Note: For patients with vitritis or with macular involvement (with or without vitritis), an intravitreal injection of voriconazole or amphotericin B deoxycholate is also recommended (Ref).Children 2 to <12 years:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).Children ≥12 years and Adolescents ≤14 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).<50 kg:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses; followed by maintenance dose of 8 mg/kg/dose every 12 hours (Ref).Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose (Ref).≥50 kg:IV: Loading dose: 400 mg (6 mg/kg/dose) every 12 hours for 2 doses, followed by 300 mg (4 mg/kg/dose) twice daily (Ref).Oral: 300 mg (4 mg/kg/dose) twice daily (Ref).Adolescents ≥15 years:IV: Loading dose: 400 mg (6 mg/kg/dose) every 12 hours for 2 doses, followed by 300 mg (4 mg/kg/dose) twice daily (Ref).Oral: 300 mg (4 mg/kg/dose) twice daily (Ref).Intravitreal therapy: Patients with vitritis or with macular involvement (with or without vitritis): Children ≥2 years and Adolescents: Intravitreal: 100 mcg of an extemporaneously prepared solution in 0.1 mL sterile water or NS; concomitant systemic antifungal therapy is also recommended.Scedosporiosis, fusariosis, treatmentScedosporiosis, fusariosis, treatment:Children 2 to <12 years:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses on day 1, followed by a maintenance dose of 8 mg/kg/dose every 12 hours.Oral: Oral suspension: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.Children ≥12 years and Adolescents ≤15 years: Note: In this age group, body weight is more important than age in predicting pharmaco*kinetics (Ref).<50 kg:IV: Loading dose: 9 mg/kg/dose every 12 hours for 2 doses, followed by maintenance dose of 8 mg/kg/dose every 12 hours.Oral: 9 mg/kg/dose every 12 hours; maximum dose: 350 mg/dose.≥50 kg:IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses, followed by 4 mg/kg/dose every 12 hours.Oral: 200 mg every 12 hours.Adolescents ≥15 years:IV: Loading dose: 6 mg/kg/dose every 12 hours for 2 doses, followed by 4 mg/kg/dose every 12 hours.Oral: 200 mg every 12 hours.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosage adjustment for inadequate response: Children ≥2 years and Adolescents <15 years weighing <50 kg:IV: Increase by 1 mg/kg/dose increments.Oral: Increase by 1 mg/kg/dose or 50 mg increments; maximum dose: 350 mg/dose.Children ≥12 years and Adolescents <15 years weighing ≥50 kg and Adolescents ≥15 years (regardless of weight):IV: Increase by 1 mg/kg/dose increments.Oral:<40 kg: Titrate in 50 mg/dose increments; minimum recommended dose: 100 mg every 12 hours; maximum recommended dose in manufacturer's labeling: 300 mg/dose.≥40 kg: Increase to 300 mg every 12 hours.Dosage adjustment for patients unable to tolerate treatment:Children ≥2 years and Adolescents <15 years weighing <50 kg:IV: Reduce dose by 1 mg/kg/dose increments.Oral: Reduce dose by 1 mg/kg/dose increments or 50 mg increments.Children ≥12 years and Adolescents <15 years weighing ≥50 kg and Adolescents ≥15 years:IV: Reduce dose by 1 mg/kg/dose increments.Oral: Reduce dose by 50 mg increments. Minimum dose in patients <40 kg: 100 mg/dose; Minimum dose in patients ≥40 kg: 200 mg/dose.Dosing: Kidney Impairment: PediatricOral: Children ≥2 years and Adolescents:Mild to severe impairment: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling; has not been studied. Based on experience in adult patients, it is unlikely that dosage adjustment is necessary.Dialysis: Poorly dialyzed; no supplemental dose or dosage adjustment necessary, including patients on intermittent hemodialysis (IHD) with thrice weekly sessions or peritoneal dialysis.Continuous renal replacement therapy (CRRT) (Ref): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate).Parenteral: IV: Children ≥2 years and Adolescents:CrCl ≥50 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.CrCl <50 mL/minute: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling; has not been studied. Due to accumulation of the intravenous vehicle (cyclodextrin), in adult patients, the manufacturer recommends the use of oral voriconazole in these patients unless an assessment of risk:benefit justifies the use of IV voriconazole; if IV therapy is used, closely monitor serum creatinine and change to oral voriconazole when possible.Dosing: Hepatic Impairment: PediatricBaseline hepatic impairment:Children ≥2 years and Adolescents:Mild to moderate impairment: There are no pediatric-specific dosage adjustments provided in the manufacturer's labeling (has not been studied); based on adult data, dosage reduction may be necessary.Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Should only be used if benefit outweighs risk; monitor closely for toxicity.Dosing: Older AdultRefer to adult dosing.Dosing: Obesity: AdultThe recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.Class 1, 2, or 3 obesity (BMI ≥30 kg/m2):Weight-based dosing: IV, Oral: Initial: Use adjusted body weight for weight-based dose calculations; adjust dose based on serum trough concentration to ensure efficacy and avoid toxicity. Refer to adult dosing for indication-specific doses (Ref).Fixed (non-weight based) dosing: Oral, IV: Initial: No dosage adjustment necessary; use standard doses based on indication (expert opinion). Adjust dose based on serum trough drug concentration to ensure efficacy and avoid toxicity (Ref). Refer to adult dosing for indication-specific doses.Rationale for recommendations:Voriconazole exhibits nonlinear clearance and does not distribute widely into adipose tissue. Use of either weight-based or fixed (non-weight based) dosing is acceptable; in patients with obesity, there are no data directly comparing weight-based vs fixed (non-weight based) dosing (Ref).Weight-based dosing: Pharmaco*kinetic studies in patients with obesity have demonstrated that supratherapeutic trough drug concentration may result when actual body weight is used to calculate weight-based doses. To avoid supratherapeutic trough concentrations and associated toxicity, use adjusted body weight to calculate the weight-based dose (Ref).Fixed (non-weight based) dosing: Fixed dosing has been evaluated in a small number of patients with obesity and is considered an acceptable dosing approach; however, more data evaluating clinical outcomes with this method are needed (Ref).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution Reconstituted, Intravenous: Generic: 200 mg (1 ea)Solution Reconstituted, Intravenous [preservative free]: Vfend IV: 200 mg (1 ea) [latex free]Vfend IV: 200 mg (1 ea)Generic: 200 mg (1 ea)Suspension Reconstituted, Oral: Vfend: 40 mg/mL (75 mL) [contains sodium benzoate; orange flavor]Generic: 40 mg/mL (75 mL)Tablet, Oral: Vfend: 50 mg, 200 mgGeneric: 50 mg, 200 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution Reconstituted, Intravenous: Vfend: 200 mg (1 ea)Generic: 200 mg (1 ea)Suspension Reconstituted, Oral: Vfend: 40 mg/mL (70 mL) [contains sodium benzoate]Tablet, Oral: Vfend: 50 mg, 200 mgGeneric: 50 mg, 200 mgAdministration: AdultOral: Administer 1 hour before or 1 hour after a meal. Shake oral suspension for approximately 10 seconds before each use. Enteral tube feedings may decrease oral absorption; may hold tube feedings for 1 hour before and 1 hour after a voriconazole dose (Ref).IV: Infuse over 1 to 3 hours (rate not to exceed 3 mg/kg/hour). Do not administer as an IV bolus injection. Do not infuse concomitantly into same line or cannula with other drug infusions. Do not infuse concomitantly even in separate lines or cannulas with concentrated electrolyte solutions or blood products. May be infused simultaneously with nonconcentrated electrolytes or TPN through a separate IV line. If TPN is infused through a multiple lumen catheter, use a different port than used for voriconazole.Intravitreal (off-label): Administer an extemporaneously prepared solution of 100 mcg/0.1 mL of voriconazole in sterile water or NS intravitreally (Ref).Ophthalmic (off-label): Administer an extemporaneously prepared voriconazole 10 mg/mL (1%) ophthalmic solution to the affected eye.Administration: PediatricOral: Administer at least one hour before or one hour after a meal; maintain adequate hydration unless instructed to restrict fluid intake.Oral suspension: Shake suspension for approximately 10 seconds before use; do not mix suspension with other medications, flavoring agents, or other fluids.Parenteral: IV infusion: Do not administer IV push; voriconazole must be administered by IV infusion over 1 to 3 hours at a rate not to exceed 3 mg/kg/hour. Do not infuse concomitantly into same line or cannula with other drug infusions, including TPN.Intravitreal: Administer an extemporaneously prepared solution of 100 mcg/0.1 mL of voriconazole in sterile water or NS intravitreally (Ref).Hazardous Drugs Handling ConsiderationsHazardous agent (NIOSH 2016 [group 3]).Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.NIOSH recommends single gloving for administration of intact tablets or capsules. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration. For IV preparation, double gloves, a protective gown, ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator), and closed system transfer devices (CSTDs) are recommended. Double gloving, a gown, and (if dosage form allows) CSTDs are required during IV administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).Use: Labeled IndicationsTreatment of fungal infections in patients ≥2 years of age: Treatment of invasive aspergillosis; treatment of esophageal candidiasis; treatment of candidemia (in non-neutropenic patients); treatment of disseminated Candida infections of the skin and abdomen, kidney, bladder wall, and wounds; treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. (including Fusarium solani) in patients intolerant of, or refractory to, other therapyUse: Off-Label: AdultCandidiasis, cardiac infection (native or prosthetic valve endocarditis or device infection); Candidiasis, endophthalmitis; Candidiasis, oropharyngeal (fluconazole-refractory); Coccidioidomycosis, refractory to conventional therapy; Neutropenic fever, empiric antifungal therapy; Prophylaxis against invasive fungal infections, hematologic malignancy patients or hematopoietic cell transplant recipients; Prophylaxis against invasive fungal infections, solid organ transplant recipients; Talaromycosis (formerly Penicilliosis)Medication Safety IssuesSound-alike/look-alike issues:Vfend may be confused with Venofer, Vimpat.Voriconazole may be confused with fluconazole, itraconazole, posaconazole.Adverse Reactions (Significant): ConsiderationsAcute kidney injuryThere have been isolated case reports of worsening kidney function with IV voriconazole, leading to acute kidney injury (Ref). Historically, it has been recommended to avoid IV voriconazole in patients with CrCl <50 mL/minute because of the potential for the carrier excipient, sulfobutylether-beta-cyclodextrin (SBECD), to accumulate and potentially lead to kidney injury. Data from small retrospective studies suggest that select patients with baseline kidney impairment may safely receive short durations (eg, <10 days) of IV voriconazole (Ref).Mechanism: The excipient SBECD manufactured with IV voriconazole is a second-generation cyclodextrin, and it is the polysubstitution of the hydroxyl hydrogens in the naturally occurring beta-cyclodextrin that might confer less nephrotoxicity (Ref). It has been postulated that the SBECD formulation has properties that do not reabsorb at the renal tubules and do not concentrate in the intracellular tissues (Ref).Onset: Varied (Ref).Risk factors:• Cumulative IV voriconazole dose (≥400 mg/kg) (Ref)• First-generation cyclodextrin excipient (Ref)• Baseline kidney impairment (Ref)• Concurrent use of potentially nephrotoxic medications (eg, foscarnet) (Ref)Cardiovascular effectsAzole antifungals, including voriconazole, have been associated with prolonged QT interval on ECG, which may lead to torsades de pointes (TdP) or polymorphic ventricular arrhythmias, in both adult and pediatric patients. Numerous cases have been reported with voriconazole (Ref), some of which have occurred independently of drug concentrations (Ref). Drug-drug interactions commonly play a significant role in risk related to cardiovascular effects with voriconazole either by an additive pharmacodynamic effect, reducing the clearance of voriconazole, or by lowering potassium and/or magnesium concentrations (Ref).Mechanism: One proposed mechanism is that azole antifungals may block the IKr channel (Ref). Another possible mechanism is depression of rapidly activating delayed rectifier potassium channels (Ref).Onset: Varied; QT prolongation occurred within the first 24 hours up to 23 days after initiation (Ref).Risk factors:Drug-induced QTc prolongation/TdP (in general):• Females (Ref)• Age >65 years (Ref)• Structural heart disease (eg, history of myocardial infarction or heart failure with reduced ejection fraction) (Ref)• Genetic defects of cardiac ion channels (Ref)• History of drug-induced TdP (Ref)• Congenital long QT syndrome (Ref)• Longer baseline QTc interval (eg, >450 msec) or lengthening of the QTc by ≥60 msec (Ref)• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, hypomagnesemia) (Ref)• Bradycardia (Ref)• Hepatic impairment (Ref)• Kidney impairment (Ref)• Diuretic use (Ref)• Sepsis (Ref)• Concurrent administration of multiple medications (≥2) that prolong the QT interval or medications with drug interactions that increase serum concentrations of QT-prolonging medications (Ref)• Some data suggest HIV may be a risk factor, even in antiretroviral therapy-naive patients, especially in patients with CD4 count <200 cells/mm3 (Ref)Dermatologic reactionsSkin photosensitivity has been reported, including erythematous rashes in sun-exposed areas (Ref), bullous phototoxicity (Ref), and pseudoporphyria (Ref) in all ages; a higher frequency of phototoxic reactions has been reported in pediatric patients. Photosensitivity may persist for several months after discontinuation of voriconazole (Ref). Rare cases of skin malignancy (malignant melanoma, squamous cell carcinoma [SCC]), cutaneous SCC in situ have also been reported in adult and pediatric patients (Ref). Severe cutaneous adverse reactions (SCARs), including toxic epidermal necrolysis (Ref) and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported (Ref). Alopecia has also been reported (Ref).Mechanism:• Phototoxicity/skin malignancies: Dose and/or time-related. Unknown; inhibition of CYP3A4 and CYP2C9 by voriconazole may lead to increased levels of the phototoxic compound tretinoin (Ref). Another hypothesis suggests that voriconazole and/or its N-oxide primary metabolite are chromophores, generating phototoxic reactions (Ref).• SCARs: Non–dose-related; immunologic (ie, T-cell-mediated) (Ref).Onset:• Photosensitivity: Varied; 1 week to 3 years (Ref).• Non-melanoma skin cancer: Delayed; mean treatment delay of 36 months. In some patients, voriconazole had been discontinued for 6 months before diagnosis (Ref).• SCARs: Varied; usually occurs 1 to 8 weeks after initiation (Ref); reexposure may lead to more rapid onset (usually within 1 to 4 days) (Ref).Risk factors:Phototoxicity:• Higher dose (Ref)); causal relationship of phototoxic reactions to dose and/or serum concentration have been mixed in pediatric patients with a dose- and/or concentration-dependent relationship reported in some cases and phototoxicities without any relation to dose and/or concentration reported in other cases (Ref)• Pediatric patients (Ref)• Concurrent methotrexate (Ref)Skin malignancy:• Prior history of severe phototoxic reaction (Ref)• Higher dose (SCC) (Ref)• Longer duration of therapy (SCC, especially in patients with lung transplantation) (Ref).• Immunosuppression (SCC, especially in patients with lung or hematopoietic cell transplantation) (Ref)• Ultra-rapid metabolizers (SCC) (Ref)General:• Cross-sensitivity: Cross-reactivity among oral azole antifungals has not been consistently reported in patients with histories of immunologic reactions. No cross-reactivity was noted between fluconazole and voriconazole (Ref), or posaconazole and voriconazole (Ref). Following a graded oral challenge, isavuconazole has been tolerated in a patient with a history of angioedema following voriconazole (Ref)HepatotoxicityAzole antifungals, including voriconazole, may cause hepatotoxicity (ranging from mild, asymptomatic liver abnormalities to hepatic failure) in adult and pediatric patients (Ref). Hepatotoxic reactions occurred more frequently in pediatric patients versus adults in pooled clinical trials. Acute hepatic failure and death have been reported in a child (Ref). Upon discontinuation of therapy, recovery usually takes ~6 to 10 weeks (Ref).Mechanism: Unknown; likely dose and concentration-dependent. Theories range from ability of voriconazole to alter human sterol synthesis to significant drug-drug interactions leading to increased voriconazole plasma levels (Ref). Note: Mitochondrial dysfunction may contribute to hepatotoxicity associated with ketoconazole and posaconazole, but not voriconazole (Ref).Onset: Varied; most cases occur during 10 to 28 days of therapy (Ref).Risk Factors:• Preexisting liver disease (Ref)• Patients with lung transplantation: Age <40 years, cystic fibrosis, early initiation (within 30 days) (Ref)• Concurrent hepatotoxic agents and drug interactions (Ref)• Voriconazole dose and concentration (eg, >4 mg/L) in adult patients (Ref); a correlation between liver function test abnormalities and higher plasma drug concentrations and/or doses has not been clearly established in pediatric patients (Ref)• Voriconazole has a higher risk of liver injury compared to fluconazole and echinocandins (Ref). Voriconazole also appears to have higher risk of hepatotoxicity compared to isavuconazole (Ref).• Cross-reactivity among oral azole antifungals has not been consistently reported in patients with histories of hepatotoxicity (Ref)Ocular and neurological effectsVoriconazole may cause visual disturbance, including blurred vision, optic neuritis, vision color changes, episcleritis, and scleritis (Ref). Visual disturbances may resolve within 24 hours to 2 weeks after discontinuation (Ref). Voriconazole may also cause audio or visual hallucination which may last up to 5 days and are reversible with discontinuation (Ref). Peripheral neuropathy (PN) has also been reported with numbness or tingling in the extremities, which may be rapidly debilitating and irreversible (Ref). Encephalopathy has also been reported (Ref).Mechanism:• Visual disturbances: May be due to effects on rod and cone pathways, hypothesized to be a disinhibition that puts the retina in a more light-adapted state (with increased light sensitivity) (Ref).• Hallucinations: May be caused by active CNS penetration, attributed to higher trough concentrations, which commonly occurs with IV administration.• PN: Unknown; may be caused by a sensory-predominant axonal neuropathy. Mitochondrial diseases may be the root cause of axonal neuropathies (Ref).Onset:• Visual disturbances: Rapid; within a couple of days of initiation (Ref)• Hallucinations: Rapid; within 24 hours of initiation (Ref)• PN: Delayed; >1 month after initiation (Ref)Risk factors:• Visual disturbances: High trough concentrations (>5 mg/L) (Ref)• Hallucinations: High trough concentrations (>5 mg/L) (Ref)• PN: Long-term use and accumulation of voriconazole (Ref)Skeletal effectsPeriosteal disease may occur with voriconazole and is manifested as increased serum alkaline phosphatase, skeletal fluorosis, and conventional radiographs and nuclear scans showing periostitis (Ref). Periostitis is painful and reversible with discontinuation (Ref). Pain usually improves 2 weeks to 4 months after discontinuation, with lab values (alkaline phosphatase) and radiographic findings following this time course (Ref).Mechanism: Dose and duration-dependent; voriconazole is a trifluorinated compound, with 65 mg of fluoride in a 400 mg dose, much greater than the 3 to 4 mg of fluoride required for daily intake (Ref). Fluoride can integrate into the extracellular matrix as fluorapatite, making bone density increase and become more resistant to resorption. This increase in bone density can cause osteosclerosis (bone brittleness), decrease the structural integrity, and make patients more prone to fractures. Fluorapatite can stimulate osteoblastic activity which can lead to periostitis and exostosis (Ref).Onset: Delayed; ~6 months to 3 years after chronic use; however, shorter exposures such as 6 weeks have also been documented (Ref).Risk factors:• Dose (400 mg daily) and duration of use (Ref)• Elevated fluoride levels (Ref)• Post-transplantation (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults unless otherwise specified.>10%:Cardiovascular: Hypertension (children, adolescents: 11%; adults: <2%)Dermatologic: Skin rash (children, adolescents: 13%; adults: 2% to 4%) (table 1)Voriconazole: Adverse Reaction: Skin RashVoriconazole: Adverse Reaction: Skin RashDrug (Voriconazole)ComparatorPopulationNumber of Patients (Voriconazole)Number of Patients (Comparator)Comments13%N/AChildren and adolescents105N/AN/A4%4%Adults468185Comparator: amphotericin B4%0.8%Adults468131Comparator: amphotericin B followed by fluconazole2%0.5%Adults200191Comparator: fluconazoleEndocrine & metabolic: Hyperkalemia (≤17%), hypokalemia (children, adolescents: 11%; adults: <1%)Gastrointestinal: Abdominal pain (children, adolescents: 12%; adults: <2%), diarrhea (children, adolescents: 11%; adults: <2%), nausea (children, adolescents: 13%; adults: 1% to 4%), vomiting (children, adolescents: 20%; adults: 1% to 3%)Hepatic: Increased serum alanine aminotransferase (children, adolescents, adults: 2% to 23%), increased serum alkaline phosphatase (children, adolescents, adults: 4% to 23% (table 2)Voriconazole: Adverse Reaction: Increased Serum Alkaline Phosphatase), increased serum aspartate aminotransferase (children, adolescents, adults: 2% to 20%)Voriconazole: Adverse Reaction: Increased Serum Alkaline PhosphataseDrug (Voriconazole)ComparatorPopulationIndicationNumber of Patients (Voriconazole)Number of Patients (Comparator)Comments8%N/AChildren and adolescentsN/A97N/AN/A23%23%AdultsCandidemia261115Comparator: amphotericin B followed by fluconazole10%8%AdultsEsophageal candidiasis187186Comparator: fluconazole16%22%AdultsInvasive aspergillosis181173Comparator: amphotericin B5%2%AdultsN/A200191Comparator: fluconazole4%2%AdultsN/A468185Comparator: amphotericin B4%2%AdultsN/A468131Comparator: amphotericin B followed by fluconazoleOphthalmic: Visual disturbance (children, adolescents: 26%, adults: 14% to 16%; likely serum concentration dependent [Imhof 2006; Pascual 2008; Tan 2006]) (table 3)Voriconazole: Adverse Reaction: Visual DisturbanceVoriconazole: Adverse Reaction: Visual DisturbanceDrug (Voriconazole)ComparatorPopulationNumber of Patients (Voriconazole)Number of Patients (Comparator)Comments26%N/AChildren and adolescents105N/AN/A16%4%Adults200191Comparator: fluconazole14%0.5%Adults468185Comparator: amphotericin B14%0%Adults468131Comparator: amphotericin B followed by fluconazoleRenal: Renal insufficiency (children, adolescents: 5%; adults: ≤1%; increased serum creatinine: children, adolescents: <5%; adults: ≤21%; acute kidney injury: <1%) (table 4)Voriconazole: Adverse Reaction: Acute Kidney InjuryVoriconazole: Adverse Reaction: Acute Kidney InjuryDrug (Voriconazole)ComparatorPopulationNumber of Patients (Voriconazole)Number of Patients (Comparator)Comments0.4%6%Adults468185Comparator: Amphotericin B0.4%5%Adults468131Comparator: Amphotericin B followed by fluconazole0%0%Adults200191Comparator: FluconazoleRespiratory: Epistaxis (children, adolescents: 16%; adults: <2%)Miscellaneous: Fever (children, adolescents: 25%; adults: 2%)1% to 10%:Cardiovascular: Acute myocardial infarction (<2%), atrial fibrillation (<2%), atrioventricular nodal arrhythmia (<2%), bigeminy (<2%), bradycardia (children, adolescents, adults: <5%), bundle branch block (<2%), cardiomegaly (<2%), cardiomyopathy (<2%), chest pain (<2%), complete atrioventricular block (<2%), deep vein thrombophlebitis (<2%), edema (<2%), endocarditis (<2%), extrasystoles (<2%), flushing (children, adolescents: <5%), heart failure (<2%), hypotension (children, adolescents: 9%; adults: <2%), orthostatic hypotension (<2%), peripheral edema (children, adolescents: 9%; adults: <2%), phlebitis (children, adolescents, adults: <5%), prolonged QT interval on ECG (<2%), pulmonary embolism (<2%), substernal pain (<2%), supraventricular extrasystole (<2%), supraventricular tachycardia (children, adolescents, adults: <5%), syncope (children, adolescents, adults: <5%), tachycardia (children, adolescents: 7%; adults: 1%), thrombophlebitis (<2%), torsades de pointes (<2%), vasodilation (<2%), ventricular fibrillation (<2%), ventricular tachycardia (<2%)Dermatologic: Allergic dermatitis (children, adolescents: <5%), alopecia (children, adolescents, adults: <5%), cellulitis (<2%), cheilitis (<2%), contact dermatitis (children, adolescents, adults: <5%), diaphoresis (<2%), ecchymoses (<2%), eczema (<2%), erythema multiforme (<2%), exfoliative dermatitis (children, adolescents, adults: <5%), fixed drug eruption (<2%), furunculosis (<2%), maculopapular rash (<2%), malignant melanoma (<2%), pruritus (children, adolescents, adults: <5%), psoriasis (<2%), skin discoloration (<2%), skin photosensitivity (<2%), Stevens-Johnson syndrome (<2%), toxic epidermal necrolysis (<2%) (Gomulka 2014), urticaria (children, adolescents, adults: <5%), xeroderma (<2%)Endocrine & metabolic: Adrenocortical insufficiency (<2%), albuminuria (<2%), decreased glucose tolerance (<2%), decreased libido (<2%), diabetes insipidus (<2%), hypercalcemia (children, adolescents, adults: <5%), hypercholesterolemia (<2%), hyperglycemia (children, adolescents: 7%; adults: <2%), hypermagnesemia (children, adolescents, adults: <5%), hypernatremia (<2%), hyperphosphatemia (children, adolescents: <5%), hyperthyroidism (<2%), hyperuricemia (<2%), hypervolemia (<2%), hypoalbuminemia (children, adolescents: 5%), hypocalcemia (children, adolescents: 6%; adults: <2%), hypoglycemia (children, adolescents, adults: <5%), hypomagnesemia (children, adolescents, adults: ≤5%), hyponatremia (<2%), hypophosphatemia (children, adolescents: 6%; adults: <2%), hypothyroidism (<2%), increased lactate dehydrogenase (<2%), pseudoporphyria (<2%)Gastrointestinal: Abdominal distention (children, adolescents, adults: ≤5%), ageusia (<2%), anorexia (<2%), cholecystitis (<2%), cholelithiasis (<2%), cholestasis (children and adolescents: <5%), Clostridioides difficile colitis (<2%), constipation (children, adolescents, adults: ≤5%), duodenitis (<2%), dysgeusia (<2%), dyspepsia (children, adolescents, adults: <5%), dysphagia (<2%), esophageal ulcer (<2%), esophagitis (<2%), flatulence (<2%), gastric ulcer (<2%), gastroenteritis (<2%), gastrointestinal hemorrhage (<2%), gingival hemorrhage (<2%), gingival hyperplasia (<2%), gingivitis (<2%), glossitis (<2%), hematemesis (<2%), intestinal perforation (<2%), melanosis (<2%), melena ( <2%), oral inflammation (children, adolescents: 6%), oral mucosa ulcer (<2%), pancreatitis (<2%), parotid gland enlargement (<2%), perforated duodenal ulcer (<2%), periodontitis (<2%), peritonitis (<2%), proctitis (<2%), rectal hemorrhage (<2%), stomatitis (<2%), xerostomia (<2%)Genitourinary: Anuria (<2%), blighted ovum (<2%), dysmenorrhea (<2%), dysuria (<2%), epididymitis (<2%), glycosuria (<2%), hematuria (<2%), hemorrhagic cystitis (<2%), impotence (<2%), oliguria (<2%), pelvic pain (<2%), scrotal edema (<2%), uremia (<2%), urinary incontinence (<2%), urinary retention (<2%), urinary tract infection (<2%), uterine hemorrhage (<2%), vagin*l hemorrhage (<2%)Hematologic & oncologic: Agranulocytosis (<2%), anemia (children, adolescents, adults: <5%), aplastic anemia (<2%), disseminated intravascular coagulation (<2%), eosinophilia (<2%), hemolytic anemia (<2%), leukopenia (children, adolescents, adults: <5%), lymphadenopathy (<2%), lymphangitis (<2%), macrocytic anemia (<2%), megaloblastic anemia (<2%), microcytic anemia (<2%), pancytopenia (children, adolescents, adults: <5%), petechia (<2%), prolonged bleeding time (<2%), purpuric disease (<2%), splenomegaly (<2%), squamous cell carcinoma (<2%; including cutaneous squamous cell carcinoma in situ), thrombocytopenia (children, adolescents: 10%; adults: <2%), thrombotic thrombocytopenic purpura (<2%)Hepatic: Ascites (<2%), cholestatic jaundice (2%), hepatic coma (<2%), hepatic failure (<2%), hepatitis (<2%), hepatomegaly (<2%), hyperbilirubinemia (children, adolescents: <5%; adults: ≤1%), increased gamma-glutamyl transferase (children, adolescents, adults: <5%), jaundice (children, adolescents, adults: <5%)Hypersensitivity: Angioedema (<2%), facial edema (<2%), hypersensitivity reaction (children, adolescents, adults: <5%), nonimmune anaphylaxis (<2%), tongue edema (<2%)Immunologic: Graft-versus-host disease (<2%)Infection: Herpes simplex infection (<2%), infection (<2%; including bacterial infection, fungal infection), sepsis (<2%)Local: Inflammation at injection site (<2%), injection-site infection (<2%), pain at injection site (<2%)Nervous system: Abnormal dreams (<2%), agitation (children, adolescents, adults: <5%), akathisia (<2%), amnesia (<2%), anxiety (children, adolescents, adults: <5%), asthenia (children, adolescents, adults: <5%), ataxia (children, adolescents, adults: <5%), brain edema (<2%), cerebral hemorrhage (<2%), cerebral ischemia (<2%), cerebrovascular accident (<2%), chills (children, adolescents, adults: <5%), coma (<2%), confusion (<2%), delirium (<2%), dementia (<2%), depersonalization (<2%), depression (children, adolescents, adults: <5%), dizziness (children, adolescents, adults: ≤5%), drowsiness (<2%), emotional lability (children, adolescents: <5%), encephalitis (<2%), encephalopathy (<2%), euphoria (<2%), extrapyramidal reaction (<2%), Guillain-Barre syndrome (<2%), hallucination (children, adolescents, adults: ≤5%; literature suggests up to ~17% incidence; likely serum concentration dependent [Bayhan 2016; Imhof 2006; Pascual 2008; Tan 2006]) (table 5)Voriconazole: Adverse Reaction: Hallucination, headache (children, adolescents: 10%; adults: 2%), hypertonia (<2%), hypoesthesia (<2%), hypothermia (children, adolescents: <5%), insomnia (children, adolescents, adults: <5%), intracranial hypertension (<2%), lethargy (children, adolescents: <5%), myasthenia (<2%), neuralgia (<2%), neuropathy (<2%), pain (<2%), paresthesia (children, adolescents, adults: <5%), psychosis (<2%), seizure (children, adolescents, adults: <5%; including tonic clonic), suicidal ideation (<2%), tremor (<2%), vertigo (children, adolescents, adults: <5%), voice disorder (<2%)Voriconazole: Adverse Reaction: HallucinationDrug (Voriconazole)ComparatorPopulationNumber of Patients (Voriconazole)Number of Patients (Comparator)Comments5%N/AChildren and adolescents105N/AN/A3%0.5%Adults468185Comparator: amphotericin B3%0%Adults468131Comparator: amphotericin B followed by fluconazole0%0%Adults200191Comparator: fluconazoleNeuromuscular & skeletal: Arthralgia (children, adolescents, adults: <5%), arthritis (<2%), back pain (<2%), discoid lupus erythematosus (<2%), increased creatine phosphokinase in blood specimen (<2%), lower limb cramp (<2%), myalgia (children, adolescents, adults: <5%), myopathy (<2%), ostealgia (<2%), osteomalacia (<2%), osteonecrosis (<2%), osteoporosis (<2%)Ophthalmic: Accommodation disturbance (<2%), blepharitis (<2%), chromatopsia (≤1%), color blindness (<2%), conjunctivitis (children, adolescents, adults: <5%), corneal opacity (<2%), diplopia (<2%), dry eye syndrome (children, adolescents, adults: <5%), eye pain (<2%), keratitis (children, adolescents, adults: <5%), keratoconjunctivitis (<2%), mydriasis (<2%), night blindness (<2%), nystagmus disorder (children, adolescents, adults: <5%), oculogyric crisis (<2%), optic atrophy (<2%), optic neuritis (<2%), papilledema (<2%), photophobia (children, adolescents, adults: ≤6%), retinal hemorrhage (<2%), retinitis (<2%), scleritis (<2%), subconjunctival hemorrhage (<2%), uveitis (<2%), visual field defect (<2%)Otic: Deafness (<2%), hypoacusis (<2%), otalgia (<2%), otitis externa (<2%), tinnitus (children, adolescents, adults: <5%)Renal: Decreased creatinine clearance (<2%), flank pain (<2%), hydronephrosis (<2%), increased blood urea nitrogen (<2%), nephritis (<2%), nephrosis (<2%), renal pain (<2%), renal tubular necrosis (<2%)Respiratory: Acute respiratory distress syndrome (<2%), bronchospasm (children, adolescents: <5%), cough (children, adolescents: 10%; adults: <2%), cyanosis (<2%), dyspnea (children, adolescents: 6%; adults: <2%), flu-like symptoms (<2%), hemoptysis (children, adolescents, adults: ≤5%), hypoxia (<2%), nasal congestion (children, adolescents: <5%), pharyngitis (<2%), pleural effusion (<2%), pneumonia (<2%), pulmonary edema (<2%), respiratory failure (children, adolescents: <5%), respiratory tract infection (<2%), rhinitis (<2%), sinusitis (<2%), tachypnea (children and adolescents: <5%), upper respiratory tract infection (children and adolescents: 5%)Miscellaneous: Granuloma (<2%), multiorgan failure (<2%)Postmarketing:Dermatologic: Changes in nails (Malani 2014), cutaneous lupus erythematosus (Ezra 2016), phototoxicity (Barbosa 2014; Kim 2018)Hepatic: Hepatotoxicity (Ferrajulo 2010; Lo Re 2016; Mohammed 2022)Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms (Kaneko 2018)Nervous system: Peripheral neuropathy (Baxter 2011)Neuromuscular & skeletal: Myositis (Happaerts 2022), periosteal disease (Cormican 2018; Hussain 2018, Murray 2022), skeletal fluorosis (Cormican 2018; Hussain 2018)Ophthalmic: Episcleritis (Bayhan 2016), ocular epitheliopathy (ocular surface dysplasia) (Agarwal 2022), vision color changes (Bayhan 2016)ContraindicationsHypersensitivity to voriconazole or any component of the formulation; coadministration with barbiturates (long acting), carbamazepine, efavirenz (≥400 mg daily), ergot derivatives (ergotamine and dihydroergotamine), ivabradine, lurasidone, naloxegol, pimozide, quinidine, rifampin, rifabutin, ritonavir (≥800 mg daily; also avoid low-dose [eg, 200 mg daily] dosing if possible), sirolimus, St. John's wort, tolvaptan, venetoclax (during initiation and ramp-up phase in chronic lymphocytic leukemia or small lymphocytic lymphoma patients).Canadian labeling: Additional contraindications (not in the US labeling): Coadministration with eszopiclone (when used in patients ≥65 years of age), lovastatin, midazolam (oral), simvastatin, and triazolam.Documentation of allergenic cross-reactivity for imidazole antifungals is limited; however, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Adrenal insufficiency: Reversible adrenal insufficiency in patients receiving an azole with or without concurrent corticosteroid use has been reported. Cushing syndrome in patients taking voriconazole concurrently with corticosteroids has also been reported. Monitor adrenal function as clinically necessary during and after treatment, particularly in patients receiving corticosteroids concomitantly. Educate patients to get medical care if signs and symptoms of adrenal insufficiency or Cushing syndrome occur.• Dermatologic reactions: Patients, including children, should avoid exposure to direct sunlight and should use protective clothing and high SPF sunscreen.• Toxicity symptoms: Voriconazole demonstrates nonlinear pharmaco*kinetics. Dose modifications may result in unpredictable changes in serum concentrations and contribute to toxicity. It is important to note that cutoff trough threshold values ranged widely among studies; however, an upper limit of <5.0 mg/L would be reasonable for most disease states (see Reference Range section).Disease-related concerns:• Electrolyte abnormalities: Correct electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia) prior to initiating and during therapy.• Hepatic impairment: Use with caution; adjustments to maintenance dosing is required in mild to moderate hepatic cirrhosis (Child-Pugh class A and B). In patients with severe hepatic insufficiency use only if the benefit outweighs the potential risk.• Renal impairment: The manufacturer recommends avoiding the use of IV voriconazole in patients with renal impairment due to potential accumulation of the excipient sulfobutylether-beta-cyclodextrin, which may lead to kidney injury. However, limited data suggest that patients with baseline kidney impairment may safely receive short durations of IV voriconazole (Kim 2016; Lilly 2013; Neofytos 2012; Oude Lashof 2012).Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.• Oral:- Lactose: Tablets contain lactose; avoid administration in hereditary galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption.- Sucrose: Suspension contains sucrose; use caution with fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption.Warnings: Additional Pediatric ConsiderationsThe bioequivalence of the oral suspension and tablets has not been evaluated in pediatric patients. Studies have shown children <12 years of age have a lower bioavailability than adults (Friberg 2012; Karlsson 2009); it is recommended to initiate therapy in children with intravenous regimen and only switch to oral therapy once significant clinical improvement has been observed. The oral dosing recommended for children is based on studies that utilized the oral suspension formulation. Oral bioavailability may be limited in children 2 to 12 years with malabsorption and very low weight for age; in these cases, intravenous voriconazole is recommended.Metabolism/Transport EffectsSubstrate of CYP2C19 (major), CYP2C9 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C19 (moderate), CYP2C9 (weak), CYP3A4 (strong)Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Abemaciclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Abemaciclib.Management: In patients taking abemaciclib at a dose of 200 mg or 150 mg twice daily, reduce the dose to 100 mg twice daily when combined with strong CYP3A4 inhibitors. In patients taking abemaciclib 100 mg twice daily, decrease the dose to 50 mg twice daily. Risk D: Consider therapy modificationAbrocitinib: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Abrocitinib.Risk C: Monitor therapyAcalabrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Acalabrutinib.Risk X: Avoid combinationAdagrasib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Adagrasib may increase the serum concentration of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Adagrasib. Management: Consider alternatives to this combination. Avoid use of adagrasib and strong CYP3A4 inhibitors until adagrasib concentrations have reached stead state (ie, after 8 days of therapy). If combined monitor closely for QTc interval prolongation and arrhythmias Risk D: Consider therapy modificationAdo-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component.Management: Avoid concomitant use of ado-trastuzumab emtansine and strong CYP3A4 inhibitors when possible. Consider alternatives that do not inhibit CYP3A4 or consider administering after CYP3A4 inhibitor discontinuation. Monitor for toxicities if combined. Risk D: Consider therapy modificationAlfentanil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfentanil.Management: If use of alfentanil and strong CYP3A4 inhibitors is necessary, consider dosage reduction of alfentanil until stable drug effects are achieved. Frequently monitor patients for respiratory depression and sedation when these agents are combined. Risk D: Consider therapy modificationAlfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin.Risk X: Avoid combinationAlitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic).Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor. Risk D: Consider therapy modificationAlmotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan.Management: Limit initial almotriptan dose to 6.25 mg and maximum dose to 12.5 mg in any 24-period when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Risk D: Consider therapy modificationAlosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron.Risk C: Monitor therapyALPRAZolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ALPRAZolam.Risk X: Avoid combinationAminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).Risk X: Avoid combinationAminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).Risk C: Monitor therapyAmiodarone: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of Amiodarone. Risk X: Avoid combinationAmisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapyAmLODIPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of AmLODIPine.Risk C: Monitor therapyAmphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B.Risk C: Monitor therapyAntihepaciviral Combination Products: May decrease the serum concentration of Voriconazole. Management: Concurrent use of voriconazole with antihepaciviral combination products should be avoided unless the patient-specific benefit/risk ratio justifies the use of voriconazole. Decreased efficacy of voriconazole is possible. Risk D: Consider therapy modificationApixaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Apixaban.Risk C: Monitor therapyAprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant.Risk X: Avoid combinationARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole.Management: Aripiprazole dose reductions are required for indications other than major depressive disorder. Dose reductions vary based on formulation, CYP2D6 genotype, and use of CYP2D6 inhibitors. See full interaction monograph for details. Risk D: Consider therapy modificationARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil.Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP3A4 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg). Max dose is 441 mg in CYP2D6 PMs or if also taking strong CYP2D6 inhibitors. Risk D: Consider therapy modificationArtemether and Lumefantrine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Artemether and Lumefantrine. Specifically, concentrations of dihydroartemisinin (DHA), the active metabolite of artemether may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Artemether and Lumefantrine.Risk C: Monitor therapyAsciminib: May increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Asciminib. Risk C: Monitor therapyAstemizole: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Astemizole. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Astemizole.Risk X: Avoid combinationAsunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir.Risk X: Avoid combinationAtazanavir: May decrease the serum concentration of Voriconazole. Atazanavir may increase the serum concentration of Voriconazole. Voriconazole may decrease the serum concentration of Atazanavir. Management: Voriconazole should not be used in a patient who is being treated with ritonavir-boosted atazanavir unless the benefits of the combination outweigh the potential risks.Extra monitoring for both loss of effectiveness and toxicity is warranted. Risk D: Consider therapy modificationAtogepant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Atogepant.Management: The recommended dose of atogepant is 10 mg once daily when coadministered with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationAtorvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Atorvastatin.Risk C: Monitor therapyAvacopan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avacopan.Management: Decrease the avacopan dose to 30 mg once daily during coadministration with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationAvanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.Risk X: Avoid combinationAvapritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avapritinib.Risk X: Avoid combinationAxitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib.Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Risk D: Consider therapy modificationBarnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine.Risk X: Avoid combinationBedaquiline: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Bedaquiline. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Bedaquiline.Management: Consider alternatives to this drug combination and avoid use for more than 14 days. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationBelzutifan: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Belzutifan.Risk C: Monitor therapyBenidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benidipine.Risk C: Monitor therapyBenperidol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benperidol.Risk C: Monitor therapyBenzhydrocodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased.Risk C: Monitor therapyBetamethasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Nasal).Risk C: Monitor therapyBetamethasone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Ophthalmic).Risk C: Monitor therapyBetamethasone (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Systemic).Risk C: Monitor therapyBetamethasone (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Topical).Risk C: Monitor therapyBlonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin.Risk X: Avoid combinationBortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib.Risk C: Monitor therapyBosentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosentan.Risk C: Monitor therapyBosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib.Risk X: Avoid combinationBrentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.Risk C: Monitor therapyBrexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole.Management: Reduce brexpiprazole dose 50% with strong CYP3A4 inhibitors; reduce to 25% of usual if used with both a strong CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer. Risk D: Consider therapy modificationBrigatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brigatinib.Management: Avoid concurrent use of brigatinib with strong CYP3A4 inhibitors when possible. If combination cannot be avoided, reduce the brigatinib dose by approximately 50%, rounding to the nearest tablet strength (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg). Risk D: Consider therapy modificationBrivaracetam: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Brivaracetam.Risk C: Monitor therapyBromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine.Management: Consider alternatives to the use of bromocriptine with strong CYP3A4 inhibitors. If combined, monitor closely for increased bromocriptine toxicities and consider bromocriptine dose reductions. Risk D: Consider therapy modificationBromperidol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromperidol.Risk C: Monitor therapyBrotizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brotizolam.Risk C: Monitor therapyBudesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal).Risk C: Monitor therapyBudesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation).Management: Consider alternatives to this combination when possible. If combined, monitor for increased corticosteroid adverse effects during coadministration of inhaled budesonide and strong CYP3A4 inhibitors. Risk D: Consider therapy modificationBudesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic).Management: Avoid the concomitant use of CYP3A4 inhibitors and oral budesonide. If patients receive both budesonide and a strong CYP3A4 inhibitor, they should be closely monitored for signs and symptoms of corticosteroid excess. Risk D: Consider therapy modificationBudesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical).Risk X: Avoid combinationBuprenorphine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Buprenorphine.Risk C: Monitor therapyBusPIRone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of BusPIRone.Management: Limit the buspirone dose to 2.5 mg daily and monitor patients for increased buspirone effects/toxicities if combined with strong CYP3A4 inhibitors. Dose adjustments of buspirone or a strong CYP3A4 inhibitor should be based on clinical assessment. Risk D: Consider therapy modificationButorphanol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Butorphanol.Risk C: Monitor therapyCabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel.Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Risk D: Consider therapy modificationCabozantinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib.Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, decrease cabozantinib capsules (Cometriq) by 40 mg from previous dose or decrease cabozantinib tablets (Cabometyx) by 20 mg from previous dose. Risk D: Consider therapy modificationCalcifediol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol.Risk C: Monitor therapyCalcitriol (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcitriol (Systemic).Risk C: Monitor therapyCannabidiol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabidiol.Risk C: Monitor therapyCannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased.Risk C: Monitor therapyCapmatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Capmatinib.Risk C: Monitor therapyCarBAMazepine: May decrease the serum concentration of Voriconazole. Risk X: Avoid combinationCariprazine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Cariprazine. Specifically, concentrations of didesmethylcariprazine (DDCAR), the primary active metabolite of cariprazine, may increase. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine.Management: Decrease cariprazine dose 50% (4.5 mg to 1.5 mg or 3 mg; 1.5 mg to 1.5 mg every other day) if starting a strong CYP3A4 inhibitor. If on a strong CYP3A4 inhibitor, start cariprazine at 1.5 mg day 1, 0 mg day 2, then 1.5 mg daily. May increase to 3 mg daily Risk D: Consider therapy modificationCarisoprodol: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Carisoprodol. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Carisoprodol.Risk C: Monitor therapyCeritinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ceritinib. Management: Avoid use of ceritinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease ceritinib dose by one-third (to the nearest 150 mg) and monitor patients for ceritinib toxicities including QTc prolongation. Risk D: Consider therapy modificationChlordiazePOXIDE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ChlordiazePOXIDE.Risk C: Monitor therapyCiclesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ciclesonide (Oral Inhalation).Risk C: Monitor therapyCilnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilnidipine.Risk C: Monitor therapyCilostazol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol.Management: Decrease the dose of cilostazol to 50 mg twice daily when combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationCinacalcet: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cinacalcet.Risk C: Monitor therapyCisapride: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Cisapride. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Cisapride.Risk X: Avoid combinationCisapride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cisapride.Risk X: Avoid combinationCitalopram: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with voriconazole, which is a moderate CYP2C19 inhibitor. Monitor for citalopram toxicity (eg, serotonin syndrome), QTc prolongation, and arrhythmias (including torsades de pointes). Risk D: Consider therapy modificationClarithromycin: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of Clarithromycin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyClindamycin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Clindamycin (Systemic).Risk C: Monitor therapyCloBAZam: CYP2C19 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of CloBAZam.Risk C: Monitor therapyClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyClonazePAM: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ClonazePAM.Risk C: Monitor therapyClopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel.Risk C: Monitor therapyCobicistat: Voriconazole may increase the serum concentration of Cobicistat. Cobicistat may increase the serum concentration of Voriconazole.Management: Careful consideration of the risk/benefit ratio for voriconazole use is recommended prior to its use in patients who are being treated with cobicistat-containing products. Risk D: Consider therapy modificationCobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib.Risk X: Avoid combinationCodeine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Codeine.Risk C: Monitor therapyColchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine.Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details. Risk D: Consider therapy modificationConivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan.Risk X: Avoid combinationCopanlisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Copanlisib.Management: If concomitant use of copanlisib and strong CYP3A4 inhibitors cannot be avoided, reduce the copanlisib dose to 45 mg. Monitor patients for increased copanlisib effects/toxicities. Risk D: Consider therapy modificationCortisone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cortisone.Risk C: Monitor therapyCrizotinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, crizotinib dose adjustments are required, which vary according to indication. See full interaction monograph for details. Risk D: Consider therapy modificationCycloSPORINE (Systemic): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CycloSPORINE (Systemic). Fluconazole and isavuconazonium considerations are addressed in separate monographs.Management: Consider reducing cyclosporine doses by 50% to 80% during coadministration with ketoconazole, 50% with voriconazole or itraconazole, and 25% with posaconazole. Cyclosporine dose reductions may be required with other azoles. Risk D: Consider therapy modificationCYP2C19 Inducers (Moderate): May decrease the serum concentration of Voriconazole. Risk C: Monitor therapyCYP2C19 Inhibitors (Moderate): May increase the serum concentration of Voriconazole. Risk C: Monitor therapyCYP2C9 Inhibitors (Moderate): May increase the serum concentration of Voriconazole. Risk C: Monitor therapyCYP3A4 Inducers (Moderate): May decrease the serum concentration of Voriconazole. Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of Voriconazole. Management: Consider alternatives to this combination when possible. If combined, monitor for decreased voriconazole concentrations and effects. Risk D: Consider therapy modificationCYP3A4 Inhibitors (Strong): May increase the serum concentration of Voriconazole. Risk C: Monitor therapyCyproterone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cyproterone.Risk C: Monitor therapyDabrafenib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Dabrafenib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dabrafenib.Management: Consider alternatives to these QT-prolonging strong CYP3A4 inhibitors for patients being treated with dabrafenib. If such a combination cannot be avoided, monitor closely for dabrafenib-related adverse effects, including QTc interval prolongation. Risk D: Consider therapy modificationDaclatasvir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir.Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. Risk D: Consider therapy modificationDapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine.Risk X: Avoid combinationDaridorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daridorexant.Risk X: Avoid combinationDarifenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Darifenacin.Management: Limit the darifenacin dose to no more than 7.5 mg daily if combined with strong CYP3A4 inhibitors. Monitor patients for increased darifenacin toxicities (eg, dry mouth, constipation, headache, CNS effects) when these agents are combined. Risk D: Consider therapy modificationDarunavir: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Darunavir. Management: This combination should be avoided unless the risks of potentially altered drug concentrations are outweighed by potential benefits of therapy. Risk D: Consider therapy modificationDasatinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dasatinib. Management: Avoid this combination if possible. If combined, decrease dasatinib dose from 140 mg to 40 mg, 100 mg to 20 mg, or 70 mg to 20 mg. If taking 60 mg or 40 mg daily, stop dasatinib until the CYP3A4 inhibitor is discontinued. Monitor for prolonged QT interval Risk D: Consider therapy modificationDeflazacort: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deflazacort.Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Risk D: Consider therapy modificationDelamanid: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Delamanid. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Delamanid.Management: If coadministration of delamanid with any strong CYP3A4 inhibitor is considered necessary, very frequent monitoring of ECGs is recommended throughout the full delamanid treatment period. Risk D: Consider therapy modificationDexAMETHasone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DexAMETHasone (Ophthalmic).Risk C: Monitor therapyDexAMETHasone (Systemic): May decrease the serum concentration of Voriconazole. Risk C: Monitor therapyDiazePAM: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of DiazePAM.Risk C: Monitor therapyDichlorphenamide: Antifungal Agents (Azole Derivatives, Systemic) may enhance the hypokalemic effect of Dichlorphenamide.Risk C: Monitor therapyDiclofenac (Systemic): Voriconazole may increase the serum concentration of Diclofenac (Systemic).Risk C: Monitor therapyDiclofenac (Topical): Voriconazole may increase the serum concentration of Diclofenac (Topical).Risk C: Monitor therapyDilTIAZem: CYP3A4 Inhibitors (Strong) may increase the serum concentration of DilTIAZem.Risk C: Monitor therapyDOCEtaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOCEtaxel.Management: Avoid the concomitant use of docetaxel and strong CYP3A4 inhibitors when possible. If combined use is unavoidable, consider a 50% docetaxel dose reduction and monitor for increased docetaxel toxicities. Risk D: Consider therapy modificationDomperidone: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Domperidone.Risk X: Avoid combinationDoxazosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Doxazosin.Risk C: Monitor therapyDoxercalciferol: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol.Risk C: Monitor therapyDOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional).Risk X: Avoid combinationDOXOrubicin (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Liposomal).Risk C: Monitor therapyDronabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol.Risk C: Monitor therapyDronedarone: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Dronedarone. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dronedarone.Risk X: Avoid combinationDutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride.Risk C: Monitor therapyDuvelisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Duvelisib.Management: Reduce the dose of duvelisib to 15 mg twice a day when used together with a strong CYP3A4 inhibitor. Monitor closely for evidence of altered response to treatment. Risk D: Consider therapy modificationDydrogesterone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dydrogesterone.Risk C: Monitor therapyEbastine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ebastine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ebastine.Risk C: Monitor therapyEfavirenz: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Efavirenz. Management: Use of standard doses of these drugs is contraindicated. The voriconazole oral maintenance dose should be increased to 400 mg every 12 hours, and the efavirenz dose should be reduced to 300 mg daily. Risk D: Consider therapy modificationEfonidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Efonidipine.Risk C: Monitor therapyElagolix: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elagolix.Management: Use of the elagolix 200 mg twice daily dose with a strong CYP3A4 inhibitor for longer than 1 month is not recommended. Limit combined use of the elagolix 150 mg once daily dose with a strong CYP3A4 inhibitor to a maximum of 6 months. Risk D: Consider therapy modificationElagolix, Estradiol, and Norethindrone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Elagolix, Estradiol, and Norethindrone may decrease the serum concentration of CYP3A4 Inhibitors (Strong). Specifically, concentrations of strong CYP3A4 inhibitors that are also CYP3A4 substrates may be decreased.Risk X: Avoid combinationElbasvir and Grazoprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elbasvir and Grazoprevir.Management: Consider alternatives to this combination when possible. If combined, monitor for increased elbasvir/grazoprevir toxicities, including ALT elevations. Risk D: Consider therapy modificationEletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan.Risk X: Avoid combinationElexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor.Management: When combined with strong CYP3A4 inhibitors, administer two elexacaftor/tezacaftor/ivacaftor tablets (100 mg/50 mg/75 mg) in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor (150 mg) alone should be administered. Risk D: Consider therapy modificationEliglustat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat.Management: Reduce eliglustat dose to 84 mg daily in CYP2D6 EMs when used with strong CYP3A4 inhibitors. Use of strong CYP3A4 inhibitors is contraindicated in CYP2D6 IMs, PMs, or in CYP2D6 EMs who are also taking strong or moderate CYP2D6 inhibitors. Risk D: Consider therapy modificationEncorafenib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Encorafenib. Management: Avoid use of encorafenib and strong CYP3A4 inhibitors when possible. If combined, decrease encorafenib dose from 450 mg to 150 mg; or from 300 mg, 225 mg, or 150 mg to 75 mg. Monitor closely for QT interval prolongation. Risk D: Consider therapy modificationEntrectinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Entrectinib. Risk X: Avoid combinationEplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone.Risk X: Avoid combinationErdafitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erdafitinib.Management: Avoid concomitant use of erdafitinib and strong CYP3A4 inhibitors when possible. If combined, monitor closely for erdafitinib adverse reactions and consider dose modifications accordingly. Risk D: Consider therapy modificationErgot Derivatives (Vasoconstrictive CYP3A4 Substrates): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ergot Derivatives (Vasoconstrictive CYP3A4 Substrates).Risk X: Avoid combinationErlotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib.Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of erlotinib-associated adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Risk D: Consider therapy modificationErythromycin (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Erythromycin (Systemic). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationEscitalopram: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of Escitalopram. Risk C: Monitor therapyEstrogen Derivatives: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estrogen Derivatives.Risk C: Monitor therapyEszopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone.Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression). Risk D: Consider therapy modificationEtizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam.Risk C: Monitor therapyEtravirine: May increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Etravirine. Risk C: Monitor therapyEverolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus.Management: Consider avoiding use of strong CYP3A4 inhibitors with everolimus. If combined, closely monitor for increased everolimus serum concentrations and toxicities. Everolimus dose reductions will likely be required. Risk D: Consider therapy modificationEvogliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Evogliptin.Risk C: Monitor therapyFedratinib: Voriconazole may increase the serum concentration of Fedratinib.Risk X: Avoid combinationFelodipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Felodipine.Management: Consider using lower felodipine doses when combined with strong CYP3A4 inhibitors. Monitor patients for increased felodipine effects and toxicities (eg, hypotension, edema) when combined. Risk D: Consider therapy modificationFentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL.Management: Consider fentanyl dose reductions when combined with a strong CYP3A4 inhibitor. Monitor for respiratory depression and sedation. Upon discontinuation of a CYP3A4 inhibitor, consider a fentanyl dose increase; monitor for signs and symptoms of withdrawal. Risk D: Consider therapy modificationFesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine.Management: Limit fesoterodine doses to 4 mg daily in patients who are also receiving strong CYP3A4 inhibitors. This combination is not recommended in pediatric patients weighing 25 kg up to 35 kg. Risk D: Consider therapy modificationFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFinerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Finerenone.Risk X: Avoid combinationFlibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin.Management: Use of flibanserin with strong CYP3A4 inhibitors is contraindicated. If starting flibanserin, start 2 weeks after the last dose of the CYP3A4 inhibitor. If starting a CYP3A4 inhibitor, start 2 days after the last dose of flibanserin. Risk X: Avoid combinationFlucloxacillin: May decrease the serum concentration of Voriconazole. Management: Consider alternatives to this combination when possible. If combined, monitor for reduced voriconazole serum concentrations and efficacy. Increased voriconazole doses may be needed. Risk D: Consider therapy modificationFluconazole: May enhance the QTc-prolonging effect of Voriconazole. Fluconazole may increase the serum concentration of Voriconazole. Risk X: Avoid combinationFluorouracil Products: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Fluorouracil Products.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyFluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal).Risk X: Avoid combinationFluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation).Management: Consider alternatives to this combination if possible. Coadministration of fluticasone propionate and strong CYP3A4 inhibitors is not recommended. If combined, monitor patients for systemic corticosteroid adverse effects (eg, adrenal suppression). Risk D: Consider therapy modificationFluticasone (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Topical).Risk C: Monitor therapyFosamprenavir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fosamprenavir.Risk C: Monitor therapyFosaprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fosaprepitant.Risk X: Avoid combinationFosphenytoin-Phenytoin: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Fosphenytoin-Phenytoin. Management: Increase maintenance dose of voriconazole from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours in patients who weigh 40 kg or more or from 100 mg to 200 mg orally every 12 hours for patients who weigh less than 40 kg. Risk D: Consider therapy modificationFostamatinib: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fostamatinib.Risk C: Monitor therapyFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationGalantamine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Galantamine.Risk C: Monitor therapyGefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib.Risk C: Monitor therapyGilteritinib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Gilteritinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Gilteritinib.Management: Consider alternatives to the use of gilteritinib with strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. Risk D: Consider therapy modificationGlasdegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Glasdegib.Management: Consider alternatives to this combination when possible. If the combination must be used, monitor closely for evidence of QT interval prolongation and other adverse reactions to glasdegib. Risk D: Consider therapy modificationGuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE.Management: Reduce the extended-release guanfacine dose 50% when combined with a strong CYP3A4 inhibitor. Monitor for increased guanfacine toxicities when these agents are combined. Risk D: Consider therapy modificationHalofantrine: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Halofantrine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Halofantrine.Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationHaloperidol: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyHormonal Contraceptives: May increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Hormonal Contraceptives. Risk C: Monitor therapyHYDROcodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of HYDROcodone.Risk C: Monitor therapyHydrocortisone (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Hydrocortisone (Systemic).Risk C: Monitor therapyIbrexafungerp: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrexafungerp.Management: Decrease the ibrexafungerp dose to 150 mg every 12 hours for 2 doses in patients receiving strong CYP3A4 inhibitors. Risk D: Consider therapy modificationIbrutinib: Voriconazole may increase the serum concentration of Ibrutinib.Management: Ibrutinib dose reductions are required when combined with voriconazole. Dose recommendations depend on the indication for ibrutinib, age of the patient, and the voriconazole dose. See full Lexi Interact monograph for details. Risk D: Consider therapy modificationIbuprofen: Voriconazole may increase the serum concentration of Ibuprofen. Specifically, concentrations of the S-(+)-ibuprofen enantiomer may be increased.Risk C: Monitor therapyIdelalisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Idelalisib.Management: Use alternative therapies that are not strong CYP3A4 inhibitors whenever possible. If unable to use alternative drugs, monitor patients more frequently for idelalisib toxicities. Risk D: Consider therapy modificationIfosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide.Risk C: Monitor therapyIloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone.Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Risk D: Consider therapy modificationImatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib.Risk C: Monitor therapyImidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin.Risk C: Monitor therapyIndinavir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Indinavir.Risk C: Monitor therapyInfigratinib: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Infigratinib. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Infigratinib.Risk X: Avoid combinationInhibitors of the Proton Pump (PPIs and PCABs): Voriconazole may increase the serum concentration of Inhibitors of the Proton Pump (PPIs and PCABs). Inhibitors of the Proton Pump (PPIs and PCABs) may increase the serum concentration of Voriconazole.Risk C: Monitor therapyIrinotecan Products: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased.Management: Avoid administration of strong CYP3A4 inhibitors during and within 1 week prior to irinotecan administration, unless no therapeutic alternatives to these agents exist. If combined, monitor closely for increased irinotecan toxicities. Risk D: Consider therapy modificationIsavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations.Risk X: Avoid combinationIsradipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Isradipine.Risk C: Monitor therapyIstradefylline: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Istradefylline.Management: Limit the maximum istradefylline dose to 20 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased istradefylline effects/toxicities. Risk D: Consider therapy modificationItraconazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Itraconazole.Risk C: Monitor therapyIvabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine.Risk X: Avoid combinationIvacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor.Management: Ivacaftor dose reductions are required; consult full drug interaction monograph content for age- and weight-specific recommendations. Risk D: Consider therapy modificationIvosidenib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ivosidenib. Management: Avoid using strong CYP3A4 inhibitors together with ivosidenib if possible. If the combination must be used, reduce the ivosidenib dose to 250 mg once daily and monitor for increased ivosidenib toxicities, including QTc interval prolongation. Risk D: Consider therapy modificationIxabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone.Management: Avoid use of ixabepilone and strong CYP3A4 inhibitors when possible. If combined, reduce the ixabepilone dose to 20 mg/m2. The previous ixabepilone dose can be resumed 1 week after discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider therapy modificationKetamine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ketamine.Risk C: Monitor therapyKetoconazole (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ketoconazole (Systemic).Risk C: Monitor therapyLacidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacidipine.Risk C: Monitor therapyLapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib.Management: Avoid use of lapatinib and strong CYP3A4 inhibitors when possible. If combined, a reduced lapatinib dose of 500 mg daily should be considered. The previous lapatinib dose can be resumed 1 week after discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider therapy modificationLarotrectinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Larotrectinib.Management: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Increase to previous dose after stopping the inhibitor after a period of 3 to 5 times the inhibitor's half-life. Risk D: Consider therapy modificationLemborexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lemborexant.Risk X: Avoid combinationLercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine.Risk X: Avoid combinationLetermovir: May decrease the serum concentration of Voriconazole. Management: If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced voriconazole serum concentrations and efficacy. Risk D: Consider therapy modificationLeuprolide and Norethindrone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Leuprolide and Norethindrone. Specifically, concentrations of norethindrone may increase.Risk C: Monitor therapyLevamlodipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levamlodipine.Risk C: Monitor therapyLevobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.Risk C: Monitor therapyLevoketoconazole: QT-prolonging CYP3A4 Substrates may enhance the QTc-prolonging effect of Levoketoconazole. Levoketoconazole may increase the serum concentration of QT-prolonging CYP3A4 Substrates.Risk X: Avoid combinationLevomethadone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomethadone.Risk C: Monitor therapyLevomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran.Management: The dose of levomilnacipran should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationLidocaine (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lidocaine (Systemic).Risk C: Monitor therapyLomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide.Risk X: Avoid combinationLonafarnib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lonafarnib.Risk X: Avoid combinationLopinavir: May decrease the serum concentration of Voriconazole. Management: This combination should be avoided unless the risks of potentially subtherapeutic voriconazole concentrations are outweighed by potential benefits of therapy. Risk D: Consider therapy modificationLorlatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lorlatinib.Management: Avoid use of lorlatinib with strong CYP3A4 inhibitors. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily, or from 75 mg once daily to 50 mg once daily. Risk D: Consider therapy modificationLovastatin: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Lovastatin. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin.Risk X: Avoid combinationLumacaftor and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumacaftor and Ivacaftor.Management: When initiating or resuming lumacaftor/ivacaftor after a therapy interruption of 7 days or more, reduce the lumacaftor/ivacaftor dose to 1 tablet daily or 1 packet of oral granules every other day for the first week, and then resume the standard dose. Risk D: Consider therapy modificationLumateperone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumateperone.Management: Limit the lumateperone dose to 10.5 mg once daily when used with a strong CYP3A4 inhibitor. Risk D: Consider therapy modificationLurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone.Risk X: Avoid combinationLurbinectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurbinectedin.Risk X: Avoid combinationMacitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan.Risk X: Avoid combinationManidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Manidipine.Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inhibitors. If combined, monitor closely for increased manidipine effects and toxicities. Manidipine dose reductions may be required. Risk D: Consider therapy modificationMaraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc.Management: Reduce maraviroc to 150mg twice/day in adult and pediatrics weighing 40kg or more. See full interaction monograph for dose adjustments in pediatrics weighing 10 to less than 40kg. Do not use if CrCl less than 30mL/min or in those weighing less than 10 kg. Risk D: Consider therapy modificationMavacamten: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mavacamten.Risk X: Avoid combinationMavacamten: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Mavacamten.Risk X: Avoid combinationMefloquine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mefloquine.Risk C: Monitor therapyMeperidine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Meperidine.Risk C: Monitor therapyMethadone: Voriconazole may enhance the QTc-prolonging effect of Methadone. Voriconazole may increase the serum concentration of Methadone.Management: Consider alternatives to this combination. Methadone dose reduction may be necessary when used with voriconazole. With any concurrent use, monitor closely for evidence of methadone toxicities such as QT-prolongation or respiratory depression. Risk D: Consider therapy modificationMethotrexate: May enhance the photosensitizing effect of Voriconazole. Risk C: Monitor therapyMethoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic).Risk C: Monitor therapyMethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone.Risk C: Monitor therapyMidazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Midazolam.Management: Avoid use of nasal midazolam and strong CYP3A4 inhibitors whenever possible, and consider alternatives to use with other routes of midazolam (oral, IV, IM). If combined, consider lower midazolam doses and monitor for increased midazolam toxicities. Risk D: Consider therapy modificationMidostaurin: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Midostaurin. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Midostaurin.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationMiFEPRIStone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone.Management: For treatment of hyperglycemia in Cushing's syndrome, start mifepristone at 300 mg/day, may titrate to a maximum of 900 mg/day. If starting a strong CYP3A4 inhibitor and taking > 300 mg/day mifepristone, decrease the mifepristone dose by 300 mg/day. Risk D: Consider therapy modificationMirodenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil.Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination. Risk D: Consider therapy modificationMirtazapine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirtazapine.Risk C: Monitor therapyMirvetuximab Soravtansine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirvetuximab Soravtansine.Risk C: Monitor therapyMitapivat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mitapivat.Risk X: Avoid combinationMizolastine: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Mizolastine.Risk X: Avoid combinationMobocertinib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Mobocertinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase serum concentrations of the active metabolite(s) of Mobocertinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Mobocertinib.Risk X: Avoid combinationMoclobemide: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Moclobemide.Risk C: Monitor therapyMometasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mometasone (Nasal).Risk C: Monitor therapyMometasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mometasone (Oral Inhalation).Risk C: Monitor therapyMometasone (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mometasone (Topical).Risk C: Monitor therapyNaldemedine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naldemedine.Risk C: Monitor therapyNalfurafine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nalfurafine.Risk C: Monitor therapyNaloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol.Risk X: Avoid combinationNelfinavir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nelfinavir.Risk C: Monitor therapyNeratinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Neratinib.Risk X: Avoid combinationNevirapine: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Nevirapine. Risk C: Monitor therapyNiCARdipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiCARdipine.Risk C: Monitor therapyNIFEdipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NIFEdipine.Management: Consider alternatives to this combination when possible. If combined, initiate nifedipine at the lowest dose available and monitor patients closely for increased nifedipine effects and toxicities (eg, hypotension, edema). Risk D: Consider therapy modificationNilotinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Nilotinib. Management: Avoid concomitant use of nilotinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, nilotinib dose reductions are required. Monitor patients for nilotinib toxicities including QTc prolongation and arrhythmias. Risk D: Consider therapy modificationNilvadipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilvadipine.Risk C: Monitor therapyNiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine.Risk X: Avoid combinationNirmatrelvir and Ritonavir: May decrease the serum concentration of Voriconazole. Nirmatrelvir and Ritonavir may increase the serum concentration of Voriconazole. Management: Consider avoiding this combination if possible. NIH COVID-19 treatment guidelines state voriconazole may be continued in patients treated with nirmatrelvir and ritonavir, but patients should be monitored for adverse effects. Risk D: Consider therapy modificationNisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine.Risk X: Avoid combinationNitrendipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nitrendipine.Risk C: Monitor therapyOlaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib.Management: Avoid use of strong CYP3A4 inhibitors with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib tablets should be reduced to 100 mg twice daily and the dose of olaparib capsules should be reduced to 150 mg twice daily. Risk D: Consider therapy modificationOliceridine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oliceridine.Risk C: Monitor therapyOlmutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olmutinib.Risk C: Monitor therapyOmeprazole: May increase the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Omeprazole. Risk C: Monitor therapyOndansetron: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Ondansetron.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyOrelabrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Orelabrutinib.Risk X: Avoid combinationOsilodrostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Osilodrostat.Management: Reduce osilodrostat dose by 50% during coadministration with a strong CYP3A4 inhibitor. Risk D: Consider therapy modificationOsimertinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationOspemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene.Risk C: Monitor therapyOxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin.Risk C: Monitor therapyOxyCODONE: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased.Risk C: Monitor therapyPAcl*taxel (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PAcl*taxel (Conventional).Risk C: Monitor therapyPAcl*taxel (Protein Bound): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PAcl*taxel (Protein Bound).Risk C: Monitor therapyPacritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pacritinib.Risk X: Avoid combinationPalbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib.Management: Avoid concurrent use of strong CYP3A4 inhibitors with palbociclib when possible. If the use of a strong CYP3A4 inhibitor cannot be avoided, decrease the palbociclib dose to 75 mg/day. Risk D: Consider therapy modificationPalovarotene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palovarotene.Risk X: Avoid combinationPanobinostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat.Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Monitor patient response to therapy closely for evidence of more severe adverse effects related to panobinostat therapy. Risk D: Consider therapy modificationParecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Specifically, serum concentrations of the active moiety valdecoxib may be increased.Risk C: Monitor therapyParicalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol.Risk C: Monitor therapyPAZOPanib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of PAZOPanib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of PAZOPanib.Risk X: Avoid combinationPemigatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pemigatinib.Management: If combined use cannot be avoided, reduce the pemigatinib dose from 13.5 mg daily to 9 mg daily, or from 9 mg daily to 4.5 mg daily. Resume prior pemigatinib dose after stopping the strong inhibitor once 3 half-lives of the inhibitor has passed. Risk D: Consider therapy modificationPentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPexidartinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pexidartinib.Management: Avoid use of pexidartinib with strong CYP3A4 inhibitors if possible. If combined use cannot be avoided, pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg per day to 200 mg once daily Risk D: Consider therapy modificationPHENobarbital: May decrease the serum concentration of Voriconazole. Risk X: Avoid combinationPimavanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin.Management: Decrease the pimavanserin dose to 10 mg daily when combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationPimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus.Risk C: Monitor therapyPimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combinationPiperaquine: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Piperaquine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Piperaquine.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationPolatuzumab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be increased.Risk C: Monitor therapyPONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib.Management: Avoid concomitant use if possible. If combined, reduce ponatinib dose as follows: If taking 45 mg, reduce to 30 mg; if taking 30 mg, reduce to 15 mg; if taking 15 mg, reduce to 10 mg. If taking 10 mg, avoid concomitant use with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationPorfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.Risk C: Monitor therapyPosaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Risk X: Avoid combinationPralsetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pralsetinib.Risk X: Avoid combinationPrazepam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Prazepam.Risk C: Monitor therapyPraziquantel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel.Risk C: Monitor therapyPrednisoLONE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PrednisoLONE (Systemic).Risk C: Monitor therapyPredniSONE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PredniSONE.Risk C: Monitor therapyPrimidone: May decrease the serum concentration of Voriconazole. Risk X: Avoid combinationProguanil: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Proguanil. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Proguanil.Risk C: Monitor therapyPropofol: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Propofol.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Antidepressants (Moderate Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk).Risk C: Monitor therapyQT-prolonging Antipsychotics (Moderate Risk): Voriconazole may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Voriconazole. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-Prolonging Inhalational Anesthetics (Moderate Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-Prolonging Inhalational Anesthetics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Miscellaneous Agents (Highest Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk).Risk X: Avoid combinationQT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQUEtiapine: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QUEtiapine. Management: Reduce the quetiapine dose to one-sixth of the regular dose when initiating these strong CYP3A4 inhibitors. In patients already receiving these strong CYP3A4 inhibitors, initiate quetiapine at the lowest dose and titrate cautiously as needed. Risk D: Consider therapy modificationQuiNIDine: May enhance the QTc-prolonging effect of Voriconazole. Voriconazole may increase the serum concentration of QuiNIDine. Risk X: Avoid combinationQuinidine (Non-Therapeutic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Quinidine (Non-Therapeutic).Risk C: Monitor therapyRadotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Radotinib.Risk X: Avoid combinationRamelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon.Risk C: Monitor therapyRanolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine.Risk X: Avoid combinationReboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine.Risk C: Monitor therapyRed Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased.Risk X: Avoid combinationRegorafenib: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Regorafenib. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib.Risk X: Avoid combinationRepaglinide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide.Risk C: Monitor therapyRetapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin.Management: The use of retapamulin with strong CYP3A4 inhibitors is not recommended in patients less than 2 years old. No action is required in other populations. Risk C: Monitor therapyRibociclib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ribociclib. Management: Avoid concomitant use of ribociclib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease the ribociclib dose to 400 mg daily. Monitor for ribociclib toxicities including QTc prolongation and arrhythmias. Risk D: Consider therapy modificationRifabutin: May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Rifabutin. Risk X: Avoid combinationRifAMPin: May decrease the serum concentration of Voriconazole. Risk X: Avoid combinationRifamycin: May decrease the serum concentration of Voriconazole. Risk C: Monitor therapyRilpivirine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rilpivirine.Risk C: Monitor therapyRimegepant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rimegepant.Risk X: Avoid combinationRiociguat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Riociguat.Risk C: Monitor therapyRipretinib: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ripretinib. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ripretinib.Risk C: Monitor therapyRitonavir: May increase the serum concentration of Voriconazole. Ritonavir may decrease the serum concentration of Voriconazole. Management: Concurrent voriconazole and high-dose ritonavir (adult doses of 400 mg every 12 hrs or greater) is contraindicated. Voriconazole with lower-dose ritonavir should be avoided unless benefits outweigh risk of inadequate voriconazole concentrations. Risk D: Consider therapy modificationRivaroxaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rivaroxaban.For clarithromycin, refer to more specific clarithromycin-rivaroxaban monograph recommendations.Risk C: Monitor therapyRoflumilast-Containing Products: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Roflumilast-Containing Products.Risk C: Monitor therapyRomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin.Risk C: Monitor therapyRupatadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rupatadine.Risk X: Avoid combinationRuxolitinib (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib (Systemic).Management: This combination should be avoided under some circ*mstances; dose adjustments may be required in some circ*mstances and depend on the indication for ruxolitinib. See monograph for details. Risk D: Consider therapy modificationRuxolitinib (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib (Topical).Risk X: Avoid combinationSaccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii.Risk X: Avoid combinationSalmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol.Risk X: Avoid combinationSaquinavir: May enhance the QTc-prolonging effect of Voriconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapySAXagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin.Management: Limit the saxagliptin dose to 2.5 mg daily when combined with strong CYP3A4 inhibitors. When using the saxagliptin combination products saxagliptin/dapagliflozin or saxagliptin/dapagliflozin/metformin, avoid use with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationSelpercatinib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Selpercatinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Selpercatinib.Management: Avoid combination if possible. If use is necessary, reduce selpercatinib dose as follows: from 120mg twice/day to 40mg twice/day, or from 160mg twice/day to 80mg twice/day. Monitor QT interval more closely for QTc interval prolongation and arrhythmias. Risk D: Consider therapy modificationSelumetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Selumetinib.Management: Avoid concomitant use when possible. If combined, selumetinib dose reductions are recommended and vary based on body surface area and selumetinib dose.For details, see the full drug interaction monograph or selumetinib prescribing information. Risk D: Consider therapy modificationSertindole: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Sertindole. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Sertindole.Risk X: Avoid combinationSibutramine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Sibutramine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sibutramine.Risk C: Monitor therapySildenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sildenafil.Management: Use of sildenafil for pulmonary arterial hypertension (PAH) should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, consider using a lower starting dose of 25 mg and monitor patients for sildenafil toxicities. Risk D: Consider therapy modificationSilodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin.Risk X: Avoid combinationSimeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir.Risk X: Avoid combinationSimvastatin: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Simvastatin. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin.Risk X: Avoid combinationSirolimus (Conventional): Voriconazole may increase the serum concentration of Sirolimus (Conventional).Risk X: Avoid combinationSirolimus (Protein Bound): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sirolimus (Protein Bound).Risk X: Avoid combinationSirolimus (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sirolimus (Topical).Risk C: Monitor therapySolifenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Solifenacin.Management: Limit adult solifenacin doses to 5 mg daily and limit doses in pediatric patients to the recommended weight-based starting dose (and do not increase the dose) when combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationSonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib.Risk X: Avoid combinationSt John's Wort: May decrease the serum concentration of Voriconazole. Risk X: Avoid combinationSUFentanil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUFentanil.Management: If a strong CYP3A4 inhibitor is initiated in a patient on sufentanil, consider a sufentanil dose reduction and monitor for increased sufentanil effects and toxicities (eg, respiratory depression). Risk D: Consider therapy modificationSulfonylureas: Voriconazole may increase the serum concentration of Sulfonylureas.Risk C: Monitor therapySUNItinib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of SUNItinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of SUNItinib.Management: Avoid when possible. If combined, decrease sunitinib dose to a minimum of 37.5 mg daily when treating GIST or RCC. Decrease sunitinib dose to a minimum of 25 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Risk D: Consider therapy modificationSuvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant.Risk X: Avoid combinationTacrolimus (Systemic): Voriconazole may increase the serum concentration of Tacrolimus (Systemic).Management: Reduce tacrolimus dose to approximately one-third of the original dose when starting concurrent voriconazole. Tacrolimus whole blood trough concentrations should be monitored closely beginning within 1 to 3 days of concomitant use. Risk D: Consider therapy modificationTacrolimus (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tacrolimus (Topical).Risk C: Monitor therapyTadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil.Management: Avoid this combination in patients taking tadalafil for pulmonary arterial hypertension. In patients taking tadalafil for ED or BPH, max tadalafil dose is 2.5 mg if taking daily or 10 mg no more frequently than every 72 hours if used as needed. Risk D: Consider therapy modificationTamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin.Risk X: Avoid combinationTasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon.Risk C: Monitor therapyTazemetostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tazemetostat.Risk X: Avoid combinationTelithromycin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Telithromycin.Risk C: Monitor therapyTemsirolimus: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Temsirolimus. Specifically, concentrations of sirolimus may be increased.Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inhibitors. If coadministration is unavoidable, decrease temsirolimus dose to 12.5 mg per week. Resume previous temsirolimus dose 1 week after discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider therapy modificationTerfenadine: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Terfenadine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Terfenadine.Risk X: Avoid combinationTetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol.Risk C: Monitor therapyTetrahydrocannabinol and Cannabidiol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol.Risk C: Monitor therapyTezacaftor and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tezacaftor and Ivacaftor.Management: If combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. Tezacaftor/ivacaftor dose depends on age and weight; see full Lexi-Interact monograph for details. Risk D: Consider therapy modificationThiotepa: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Thiotepa.Management: Avoid coadministration of thiotepa and strong CYP3A4 inhibitors. If concomitant use cannot be avoided, monitor for thiotepa adverse effects and decreased efficacy. Risk D: Consider therapy modificationTicagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor.Risk X: Avoid combinationTisotumab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tisotumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.Risk C: Monitor therapyTofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib.Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full Lexi Interact monograph for details. Risk D: Consider therapy modificationTolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine.Management: The maximum recommended dose of tolterodine is 2 mg per day (1 mg twice daily for immediate-release tablets or 2 mg daily for extended-release capsules) when used together with a strong CYP3A4 inhibitor. Risk D: Consider therapy modificationTolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan.Risk X: Avoid combinationToremifene: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Toremifene. Management: Avoid concomitant use of toremifene and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, monitor patients for toremifene toxicities including QTc prolongation and TdP. Risk D: Consider therapy modificationTrabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin.Risk X: Avoid combinationTraMADol: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol.Risk C: Monitor therapyTraZODone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraZODone.Management: Consider the use of a lower trazodone dose and monitor for increased trazodone effects (eg, sedation, QTc prolongation) if combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationTretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tretinoin (Systemic).Risk C: Monitor therapyTriamcinolone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triamcinolone (Nasal).Risk C: Monitor therapyTriamcinolone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triamcinolone (Ophthalmic).Risk C: Monitor therapyTriamcinolone (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triamcinolone (Systemic).Management: Consider alternatives to this combination when possible. If combined, monitor for increased corticosteroid adverse effects during coadministration of triamcinolone and strong CYP3A4 inhibitors. Risk D: Consider therapy modificationTriamcinolone (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triamcinolone (Topical).Risk C: Monitor therapyTriazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triazolam.Risk X: Avoid combinationUbrogepant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ubrogepant.Risk X: Avoid combinationUdenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil.Risk X: Avoid combinationUlipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal.Risk C: Monitor therapyUpadacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Upadacitinib.Management: For ulcerative colitis use upadacitinib 30 mg/day for 8 weeks for induction, then 15 mg/day for maintenance. For rheumatoid arthritis, psoriatic arthritis, or atopic dermatitis use upadacitinib 15 mg/day. Monitor for upadacitinib toxicities. Risk D: Consider therapy modificationValbenazine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Valbenazine.Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modificationVardenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vardenafil.Management: Limit Levitra (vardenafil) dose to a single 2.5 mg dose within a 24-hour period if combined with strong CYP3A4 inhibitors. Avoid concomitant use of Staxyn (vardenafil) and strong CYP3A4 inhibitors. Combined use is contraindicated outside of the US. Risk D: Consider therapy modificationVemurafenib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Vemurafenib. Management: Avoid concomitant use of vemurafenib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined monitor patients for vemurafenib toxicities including QTc prolongation and TdP, and consider a vemurafenib dose reduction. Risk D: Consider therapy modificationVenetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax.Management: Coadministration is contraindicated during venetoclax initiation and ramp-up in CLL/SLL patients. Reduced venetoclax doses are required during ramp-up for patients with AML, and all maintenance therapy. See full Lexi Interact monograph for details. Risk D: Consider therapy modificationVenlafaxine: Voriconazole may enhance the adverse/toxic effect of Venlafaxine. Voriconazole may increase the serum concentration of Venlafaxine.Risk C: Monitor therapyVerapamil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Verapamil.Risk C: Monitor therapyVerteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.Risk C: Monitor therapyVilanterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilanterol.Risk C: Monitor therapyVilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone.Management: Limit the maximum vilazodone dose to 20 mg daily in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Risk D: Consider therapy modificationVinBLAStine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinBLAStine.Risk C: Monitor therapyVinCRIStine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine.Management: Seek alternatives to this combination when possible. If combined, monitor closely for vincristine toxicities (eg, neurotoxicity, gastrointestinal toxicity, myelosuppression). Risk D: Consider therapy modificationVinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal).Risk X: Avoid combinationVindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine.Risk C: Monitor therapyVinflunine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Vinflunine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine.Risk X: Avoid combinationVinorelbine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine.Risk C: Monitor therapyVitamin K Antagonists (eg, warfarin): CYP2C9 Inhibitors (Weak) may increase the serum concentration of Vitamin K Antagonists.Risk C: Monitor therapyVoclosporin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Voclosporin.Risk X: Avoid combinationVorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar.Risk X: Avoid combinationZanubrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zanubrutinib.Management: Decrease the zanubrutinib dose to 80 mg once daily during coadministration with a strong CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details. Risk D: Consider therapy modificationZolpidem: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zolpidem.Risk C: Monitor therapyZopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone.Management: If coadministered with strong CYP3A4 inhibitors, initiate zopiclone at 3.75 mg in adults, with a maximum dose of 5 mg. Monitor for zopiclone toxicity (eg, drowsiness, confusion, lethargy, ataxia, respiratory depression). Risk D: Consider therapy modificationFood InteractionsFood may decrease voriconazole absorption.Management: Oral voriconazole should be taken 1 hour before or 1 hour after a meal. Maintain adequate hydration unless instructed to restrict fluid intake.Reproductive ConsiderationsWomen of childbearing potential should use effective contraception during treatment.Pregnancy ConsiderationsAdverse events were observed in animal reproduction studies. Voriconazole can cause fetal harm when administered to a pregnant woman.Breastfeeding ConsiderationsIt is not known if voriconazole is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, the manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother.Monitoring ParametersHepatic function at initiation, weekly during the first month and then monthly during course of treatment if no abnormalities noted; renal function (particularly serum creatinine, at baseline and periodically during therapy; especially with IV formulation in patients with CrCl <50 mL/min); serum electrolytes (particularly calcium, magnesium and potassium) prior to initiation and during therapy; visual function (visual acuity, visual field and color perception) if treatment course continues >28 days; phototoxic reactions (especially in pediatric patients); pancreatic function (in patients at risk for acute pancreatitis); total body skin examination yearly (more frequently if lesions noted); signs/symptoms of fluorosis or periostitis (eg, skeletal pain, radiologic findings).Monitoring of serum trough concentrations is recommended for the majority of patients, but especially in the following infections: Invasive aspergillosis treatment (and prolonged prophylaxis) and endophthalmitis (IDSA [Patterson 2016]; MSG-ERC [Johnson 2020]; Riddell 2011).For invasive aspergillosis, the Infectious Diseases Society of America recommends monitoring trough serum concentrations after steady state has been reached (4 to 7 days after therapy initiation); the need for continued or repeat monitoring is a patient specific decision influenced by many factors (eg, infection severity, cost, assay availability) (IDSA [Patterson 2016]).Reference RangeTrough recommendations in adult patients:Invasive aspergillosis (non-CNS infection) (IDSA [Patterson 2016]):Efficacy: >1 to 1.5 mcg/mLMinimize toxicity: <5 to 6 mcg/mLCNS aspergillosis (meningitis, ventriculitis):Goal: Trough levels between 2 and 5 mcg/mL (IDSA [Tunkel 2017])Endophthalmitis:Goal: Trough levels between 2 and 5 mcg/mL (Riddell 2011)Other infections (Dolton 2012; Hamada 2012; Mitsani 2012; Park 2012):Efficacy: >1.0 mcg/mLMinimize toxicity: <4.0 mcg/mLTherapeutic range in adult patients (Dolton 2012; Hamada 2012; Luong 2016; Mitsani 2012; Park 2012; Tomblyn 2009): 1 to 5 mcg/mLMechanism of ActionInterferes with fungal cytochrome P450 activity (selectively inhibits 14-alpha-lanosterol demethylation), decreasing ergosterol synthesis (principal sterol in fungal cell membrane) and inhibiting fungal cell membrane formation.Pharmaco*kineticsNote: Overall, in pediatric patients, voriconazole pharmaco*kinetics are complex. In pediatric patients 12 to 14 years and weighing >50 kg and adolescents ≥15 years (regardless of weight) data suggests that the pharmaco*kinetics are similar to adults (Friberg 2012). In pediatric patients <12 years of age, voriconazole pharmaco*kinetics are poorly understood, exhibiting both inter- and intrapatient variability; individualized dosing is recommended (Friberg 2012; Karlsson 2009; Stockman 2014; Walsh 2010).Distribution: Extensive tissue distribution; CSF concentration ~50% of plasma concentration (Walsh 2008)Vd:Children 2 to <12 years: Biphasic, Vd (central): 0.81 L/kg; Vd (peripheral): 2.2 L/kg (Karlsson 2009)Adults: 4.6 L/kgProtein binding: 58%Metabolism: Hepatic, via CYP2C19 (major pathway) and CYP2C9 and CYP3A4 (less significant); saturable (may demonstrate nonlinearity); the N-oxide major metabolite has minimal antifungal activity; CYP2C19 exhibits genetic polymorphism (15% to 20% Asians may be poor metabolizers of voriconazole; 3% to 5% Caucasians and African Americans may be poor metabolizers). In children 2 to 12 years, metabolic clearance is faster than in adults (Walsh 2010). In children 2 to 12 years, the majority of data has shown that the pharmaco*kinetic parameters of voriconazole are affected by a patient's CYP2C19 genotype (Hicks 2014; Narita 2013; Wang 2014) although, an initial report suggested CYP2C19 genotype had no apparent effect on exposure in children (Driscoll 2011).Bioavailability: Oral:Children 2 to <12 years: Reported range highly variable: ~45% to 64% (Friberg 2012; Karlsson 2009) and values as high as 80% have been reported (Neely 2010)Adults: 96%Half-life elimination: Variable, dose-dependent. Steady-state is achieved by day 3 when an IV loading dose is administered and between days 5 and 8 if no loading dose is used (Purkins 2003).Time to peak: Oral:Children 2 to <12 years: Median: 1.1 hours (range: 0.73 to 8.03 hours) (Driscoll 2011)Adults: 1 to 2 hoursExcretion: Urine (<2% as unchanged drug)Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: Accumulation of the IV vehicle sulfobutyl ether beta-cyclodextrin sodium (SBECD) occurs in patients with renal impairment (CrCl <50 mL/minute).Hepatic function impairment: AUC is 3.2-fold higher in patients with mild to moderate hepatic impairment (Child-Pugh class A and B).Pricing: USSolution (reconstituted) (Vfend IV Intravenous)200 mg (per each): $72.36Solution (reconstituted) (Voriconazole Intravenous)200 mg (per each): $42.00 - $152.58Suspension (reconstituted) (Vfend Oral)40 mg/mL (per mL): $8.20Suspension (reconstituted) (Voriconazole Oral)40 mg/mL (per mL): $14.07 - $22.51Tablets (Vfend Oral)50 mg (per each): $1.79200 mg (per each): $4.47Tablets (Voriconazole Oral)50 mg (per each): $9.72 - $19.88200 mg (per each): $23.70 - $79.52Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAvoazole (TW);Conazoglob (EG);Pinup (CN);Progil (BD);Varcon (BD);Velenaxol (BR);Verria (CZ, NL);Vertimal (IL);VFEND (AE, AR, AT, AU, BE, BG, BH, BM, BR, BZ, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EC, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, ID, IE, IL, IS, IT, JO, JP, KR, KW, LB, LT, LV, MT, MX, MY, NI, NL, NO, NZ, PA, PE, PH, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, SV, TH, TR, TW, UA, ZA);Vfend (BB);Vodask (NL);Vonaz (LK);Vopregin (PL);Voramol (HU);Vorcum (VE);Voricon (BD);Vorifull (TR);Vorigrand (EG);Vorik (VE);Vorisam (TW);Vorix (TR);Vornal (HR);Vttack (AU)For country code abbreviations (show table)<800> Hazardous Drugs—Handling in Healthcare Settings. 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Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60. doi:10.1093/cid/ciw326. [PubMed 27365388]Peng LW, Lien YH. Pharmaco*kinetics of single, oral-dose voriconazole in peritoneal dialysis patients. Am J Kidney Dis. 2005;45(1):162-166. doi:10.1053/j.ajkd.2004.09.017 [PubMed 15696456]Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis. 2003;36(9):1122-1131. doi:10.1086/374557 [PubMed 12715306]Philip A, Sivaprakasam P, Sagar TG, Ganesan P. Voriconazole-induced pancreatitis in a patient of acute myeloid leukemia and invasive aspergillosis. J Pediatr Hematol Oncol. 2012;34(5):406. doi:10.1097/MPH.0b013e318257dc7a [PubMed 22713708]Philips JA, Marty FM, Stone RM, Koplan BA, Katz JT, Baden LR. Torsades de pointes associated with voriconazole use. 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CloseQuadrivalent meningococcal conjugate vaccine (MenACWY-D, MenACWY-CRM, MenACWY-TT): Drug informationQuadrivalent meningococcal conjugate vaccine (MenACWY-D, MenACWY-CRM, MenACWY-TT): Drug information(For additional information see "Quadrivalent meningococcal conjugate vaccine (MenACWY-D, MenACWY-CRM, MenACWY-TT): Patient drug information" and see "Quadrivalent meningococcal conjugate vaccine (MenACWY-D, MenACWY-CRM, MenACWY-TT): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USMenactra;MenQuadfi;MenveoBrand Names: CanadaMenactra;MenQuadfi;Menveo;NimenrixPharmacologic CategoryVaccine;Vaccine, Inactivated (Bacterial)Dosing: AdultMeningococcal disease, preventionMeningococcal disease, prevention:ACIP recommendations (CDC/ACIP [Mbaeyi 2020]): Use of the abbreviation MenACWY refers to any meningococcal quadrivalent conjugate vaccine. MenACWY-CRM refers specifically to Menveo; MenACWY-D refers specifically to Menactra; MenACWY-TT refers specifically to MenQuadfi. Vaccines from different manufacturers are considered interchangeable; however, it is recommended (not required) that the same product be used for all doses.Primary vaccination:Routine for persons NOT at increased risk for meningococcal disease:Adults 19 to 21 years of age: IM: Not routinely recommended; may receive one 0.5 mL dose as a catch-up vaccination if no dose was received after the sixteenth birthday.Adults ≥22 years of age: Not routinely recommended; see dosing for persons at increased risk.Routine for persons at increased risk for meningococcal disease:Note: If using MenACWY-D (Menactra) for individuals with anatomic or functional asplenia or HIV, administer ≥4 weeks after completion of pneumococcal conjugate vaccine.Adults not previously vaccinated who have functional or anatomic asplenia, HIV infection, persistent complement deficiencies (including complement deficiencies or complement inhibitor use [eg, eculizumab, ravulizumab]): IM: Two 0.5 mL doses, given ≥2 months apart.Adults not previously vaccinated who are first-year college students living in residential housing; traveling to or residing in areas where meningococcal disease is endemic/hyperendemic; at risk during a community outbreak; military recruits; or microbiologists routinely exposed to N. meningitidis: IM: One 0.5 mL dose. College students should have documentation of a vaccination not more than 5 years before enrollment (preferably a dose on or after their sixteenth birthday).Adults previously vaccinated with a single dose of MenACWY who later develop an underlying condition for which meningococcal 2-dose vaccination is recommended: IM: Administer second dose as soon as possible (≥8 week interval between doses); restarting the 2-dose series is not necessary.Booster vaccination: Persons NOT at increased risk for meningococcal disease (routine vaccination): Adults ≤21 years of age: IM: One 0.5 mL dose if the first dose was given prior to the sixteenth birthday. A booster dose is not needed if the primary dose was given after the sixteenth birthday unless the person becomes at increased risk for meningococcal disease.Persons at increased risk for meningococcal disease: Repeat dose every 5 years if the person remains at increased risk.Canadian National Advisory Committee on Immunizationrecommendations (NACI 2020): Note: NACI recommendations do not yet reflect the approval of MenQuadfi.Primary vaccination: Routine:Patients 12 to 24 years of age: IM: 0.5 mL as a single dose. Note: Routinely administered at 12 years of age, regardless if previously immunized as an infant or toddler. Administer either monovalent conjugate meningococcal vaccine (Men-C-C) or quadrivalent conjugate meningococcal vaccines (Men-C-ACYW); refer to provincial/local schedules.Persons at increased risk for meningococcal disease who have not been previously vaccinated:Adults at increased risk of disease due to underlying medical conditions (persistent complement deficiencies [including eculizumab use]; properdin, factor D, or primary antibody deficiencies; functional or anatomic asplenia; sickle cell disease, combined T- and B-cell immunodeficiencies; HIV infection): IM: Two 0.5 mL doses, given 8 weeks apart. Note: Doses may be administered ≥4 weeks apart if accelerated vaccination is needed.Adults at increased risk of exposure (travelers to areas with high rates of endemic meningococcal disease or transmission; military recruits; laboratory personnel routinely exposed to N. meningitidis): IM: Two 0.5 mL doses, given 8 weeks apart. Note: Doses may be administered ≥4 weeks apart if accelerated vaccination is needed.Booster vaccination: Persons at increased risk for meningococcal disease: Repeat dose every 5 years if the person remains at increased risk.Postexposure management or outbreak controlPostexposure management (close contacts) or outbreak control (off-label use) (NACI 2020): Recommendations dependent on meningococcal serogroup involved in exposure or outbreak:Serogroup C:Previously unvaccinated: IM: 0.5 mL/dose immediately after exposure (monovalent or quadrivalent vaccine may be used).Previously vaccinated: IM: If vaccinated at <1 year of age or if at high risk for invasive meningococcal disease due to underlying medical condition, revaccinate with 0.5 mL/dose if ≥4 weeks since last dose; otherwise revaccinate if at least 1 year since last dose (monovalent or quadrivalent vaccine may be used).Serogroup A, Y, or W-135:Previously unvaccinated: IM: 0.5 mL/dose immediately after exposure; high-risk individuals with underlying medical conditions routinely require a total of 2 doses (administered at least 8 weeks apart or at least 4 weeks apart when more rapid immunization is needed).Previously vaccinated: IM:If previously vaccinated with only monovalent conjugate meningococcal group C vaccine (Men C-C), administer 0.5 mL/dose (quadrivalent vaccine) immediately after exposure, regardless of when Men C-C was given.If previously vaccinated with quadrivalent vaccine at <1 year of age or if at high risk for invasive meningococcal disease due to underlying medical condition, revaccinate with 0.5 mL/dose (quadrivalent vaccine) if ≥4 weeks since last dose; otherwise re-vaccinate if at least 1 year since last dose.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Pediatric(For additional information see "Quadrivalent meningococcal conjugate vaccine (MenACWY-D, MenACWY-CRM, MenACWY-TT): Pediatric drug information")Meningococcal disease, preventionMeningococcal disease, prevention:ACIP recommendations (CDC/ACIP [Mbaeyi 2020]): Note: Use of the abbreviation, MenACWY, refers to any meningococcal quadrivalent conjugate vaccine. MenACWY-CRM refers specifically to Menveo; MenACWY-D refers specifically to Menactra; MenACWY-TT refers specifically to MenQuadfi. Vaccines from different manufacturers are considered interchangeable; however, it is recommended (not required) that the same product be used for all doses. Consult CDC/ACIP annual immunization schedules for additional information including specific detailed recommendations for catch-up scenarios and/or care of patients with high-risk conditions. According to ACIP, doses administered ≤4 days before minimum interval or age are considered valid; however, local or state mandates may supersede this timeframe (ACIP [Kroger 2022]).Primary vaccination (CDC/ACIP [Mbaeyi 2020]): Note: Although FDA approved in <11 years of age, use in patients <11 years is only recommended in those at increased risk; routine use not recommended by ACIP.Patients NOT at increased risk for meningococcal disease: Children 11 or 12 years: MenACWY-CRM (Menveo [1- or 2-vial formulation]), MenACWY-D (Menactra), or MenACWY-TT (MenQuadfi): IM: 0.5 mL as a single dose. Children not currently at increased risk for meningococcal disease who were previously vaccinated prior to their 10th birthday should receive the routinely recommended dose of MenACWY at 11 to 12 years. Children who received MenACWY at 10 years of age do not need an additional dose at 11 to 12 years.Adolescents: MenACWY-CRM (Menveo [1- or 2-vial formulation]), MenACWY-D (Menactra), or MenACWY-TT (MenQuadfi): IM: 0.5 mL as a single dose if not previously vaccinated.Patients at increased risk for meningococcal disease: Note: MenACWY-D (Menactra) product should be avoided in patients <2 years of age due to interference with PCV-13 immunogenicity; if MenACWY-D must be used, administer it before or concomitantly with DTaP, and administer ≥4 weeks after completion of all PCV doses as age appropriate. Dosing schedules, including number of doses, intervals, and product preference vary based on patient age and reason for increased risk of meningococcal disease.Infants ≥2 months and Children <2 years: Anatomic or functional asplenia (including sickle cell disease); HIV infection; persistent complement component deficiency (including complement inhibitor use [eg, eculizumab, ravulizumab]); an outbreak (due to a vaccine serogroup); or travel to or residence in countries with hyperendemic or epidemic meningococcal disease: Dosing based on age at initial dose.Infants 2 to <3 months: MenACWY-CRM (Menveo [2-vial formulation]): IM: 0.5 mL per dose for a total of 4 doses administered at 2, 4, 6, and 12 months of age.Infants 3 to 6 months: MenACWY-CRM (Menveo [2-vial formulation]): IM: 0.5 mL per dose at 8-week intervals for 1 or 2 doses until patient is ≥7 months of age; once patient ≥7 months of age, administer an additional dose; once patient ≥12 months of age and at least 12 weeks after the last dose, administer a final dose.Infants and Children 7 to 23 months: Note: MenACWY-CRM (Menveo) preferred in patients with HIV infection or asplenia.MenACWY-CRM (Menveo [2-vial formulation]): Infants and Children 7 to 23 months: IM: 0.5 mL per dose for a total of 2 doses; the second dose should be administered at age ≥12 months and at least 12 weeks after the first dose.MenACWY-D (Menactra): Infants and Children 9 to 23 months: IM: 0.5 mL per dose for a total of 2 doses; the second dose should be administered at least 12 weeks after the first dose. May be given as early as 8 weeks apart if needed prior to travel. Note: Administer before or concomitantly with DTaP and ≥4 weeks after completion of all PCV doses.Children 2 to <10 years (not previously vaccinated): Note: Administer MenACWY-D (Menactra) before or concomitantly with DTaP and ≥4 weeks after completion of all PCV doses; may be given at any time in relation to Tdap or Td.Persistent complement deficiencies (including complement inhibitor use [eg, eculizumab, ravulizumab]); functional or anatomic asplenia; HIV infection: MenACWY-CRM (Menveo [2-vial formulation]), MenACWY-D (Menactra), or MenACWY-TT (MenQuadfi): IM: 0.5 mL per dose for a total of 2 doses administered at least 8 weeks apart.At risk during an outbreak (due to vaccine serogroup) or traveling to or residing in areas where meningococcal disease is endemic/hyperendemic: MenACWY-CRM (Menveo [2-vial formulation]), MenACWY-D (Menactra), or MenACWY-TT (MenQuadfi): IM: 0.5 mL as a single dose.Children ≥10 years and Adolescents (not previously vaccinated): Note: Administer MenACWY-D (Menactra) before or concomitantly with DTaP and ≥4 weeks after completion of all PCV doses; may be given at any time in relation to Tdap or Td.Persistent complement deficiencies (including complement inhibitor use [eg, eculizumab, ravulizumab]); functional or anatomic asplenia; HIV infection: MenACWY-CRM (Menveo [1- or 2-vial formulation]), MenACWY-D (Menactra), or MenACWY-TT (MenQuadfi): IM: 0.5 mL per dose for a total of 2 doses administered at least 8 weeks apart.At risk during an outbreak (due to vaccine serogroup); traveling to or residing in areas where meningococcal disease is endemic/hyperendemic; military recruits; first-year college students living in residential halls; or microbiologists routinely exposed to N. meningitidis: MenACWY-CRM (Menveo [1- or 2-vial formulation]), MenACWY-D (Menactra), or MenACWY-TT (MenQuadfi): IM: 0.5 mL as a single dose. Note: College students living in residence halls should have documentation of a vaccination not more than 5 years before entry (preferably a dose on or after their 16th birthday).Booster vaccination (CDC/ACIP [Mbaeyi 2020]):Patients NOT at increased risk for meningococcal disease:Adolescents ≥16 years: MenACWY-CRM (Menveo [1- or 2-vial formulation]), MenACWY-D (Menactra), or MenACWY-TT (MenQuadfi): IM: 0.5 mL as a single dose. If primary vaccination was at 11 to 12 years, the booster dose should be given at age 16. If the primary vaccination was given at 13 to 15 years, the booster dose should be given at age 16 to 18. Minimum interval between MenACWY doses is 8 weeks. A booster dose is not needed if the primary dose was given after the 16th birthday unless the person becomes at increased risk for meningococcal disease.Patients remaining at increased risk for meningococcal disease due to complement component deficiency (including due to complement inhibitor use), anatomic or functional asplenia (including sickle cell disease), HIV infection, travel to or residence in an area where meningococcal disease is hyperendemic or endemic, or during an outbreak: Children 3 to <10 years: MenACWY-CRM (Menveo [2-vial formulation]), MenACWY-D (Menactra), or MenACWY-TT (MenQuadfi): IM: 0.5 mL per dose; Note: Age for booster dose(s), number of dose(s), and dosing interval depends on age at previous dose and duration of increased risk.If first dose received at <7 years of age: IM: 0.5 mL per dose; administer booster dose 3 years after primary vaccination and every 5 years thereafter if the person remains at increased risk.If first dose received at ≥7 years of age: IM: 0.5 mL per dose; administer booster dose 5 years after primary vaccination and every 5 years thereafter if the person remains at increased risk.Children ≥10 years and Adolescents: MenACWY-CRM (Menveo [1- or 2-vial formulation]), MenACWY-D (Menactra), or MenACWY-TT (MenQuadfi): IM: 0.5 mL per dose; Note: Age for booster dose(s), number of dose(s), and dosing interval depends on age at previous dose and duration of increased risk.If first dose received at <7 years of age: IM: 0.5 mL per dose; administer booster dose 3 years after primary vaccination and every 5 years thereafter if the person remains at increased risk.If first dose received at ≥7 years of age: IM: 0.5 mL per dose; administer booster dose 5 years after primary vaccination and every 5 years thereafter if the person remains at increased risk.Canadian labeling: Meningococcal disease, preventionMeningococcal disease, prevention: NACI recommendations (NACI 2020): Note: In patients ≥2 years of age, any of the available MenACWY vaccines may be used. NACI recommendations do not yet reflect the approval of Nimenrix in patients 6 weeks to 23 months of age or MenQuadfi in patients ≥12 months of age. Abbreviations identifying types of vaccine or specific products reflect NACI terminology.Primary vaccination:PatientsNOT at increased risk for meningococcal disease:Children ≥12 years and Adolescents: Men-C-ACWY-CRM (Menveo), Men-C-ACWY-DT (Menactra), or Men-C-ACWY-TT (Nimenrix): IM: 0.5 mL as a single dose. Note: Routinely administered at 12 years of age, regardless if previously immunized as an infant or toddler. Administer either monovalent conjugate meningococcal vaccine (Men-C-C) or quadrivalent conjugate meningococcal vaccine (Men-C-ACWY); refer to provincial/local schedules.Patients at increased risk for meningococcal disease (due to underlying medical conditions or exposure risk) who have not been previously vaccinated:Infants ≥2 months and Children <2 years: Dosing based on age at initial dose: MenACWY-CRM (Menveo):≥2 to <12 months: IM: 0.5 mL per dose for 2 or 3 doses administered ≥8 weeks apart; an additional dose should be administered between 12 and 23 months of age and ≥8 weeks after the previous dose.12 to <24 months: IM: 0.5 mL per dose for a total of 2 doses ≥8 weeks apart; doses may be administered ≥4 weeks apart if accelerated vaccination is needed.Children ≥2 years and Adolescents: Men-C-ACWY-CRM (Menveo), Men-C-ACWY-DT (Menactra), or Men-C-ACWY-TT (Nimenrix): IM: 0.5 mL per dose for a total of 2 doses ≥8 weeks apart; doses may be administered ≥4 weeks apart if accelerated vaccination is needed.Booster vaccination: Patients remaining at increased risk for meningococcal disease due to underlying medical conditions or exposure risk: Men-C-ACWY-CRM (Menveo), Men-C-ACWY-DT (Menactra), or Men-C-ACWY-TT (Nimenrix): Note: Recommendations are based on age at initial vaccination:Initially vaccinated at <7 years of age: IM: 0.5 mL per dose every 3 to 5 years.Initially vaccinated at ≥7 years of age: IM: 0.5 mL per dose every 5 years.Postexposure management (close contacts) or outbreak control: Note: Recommendations dependent on meningococcal serogroup involved in exposure or outbreak; certain patients may also require chemoprophylaxis following contact with a case. Refer to provincial/local health officials for more information.Serogroup C outbreak: Note: Monovalent meningococcal group C vaccine or quadrivalent meningococcal vaccine (MenACWY) may be used.Children ≥11 years and Adolescents: Men-C-ACWY-CRM (Menveo), Men-C-ACWY-DT (Menactra), or Men-C-ACWY-TT (Nimenrix):Previously unvaccinated: IM: 0.5 mL per dose; administer 1 dose immediately after exposure.Previously vaccinated: IM: If vaccinated at <1 year of age or if at high risk for invasive meningococcal disease due to underlying medical condition, revaccinate with single dose of 0.5 mL if ≥4 weeks since last dose; otherwise revaccinate if ≥1 year since last dose.Serogroup A, Y, or W-135 outbreak:Infants 2 to <12 months: Men-C-ACWY-CRM (Menveo):Previously unvaccinated or vaccinated with only meningococcal group C conjugate vaccine: IM: 0.5 mL per dose immediately after exposure then complete routine series.Previously vaccinated with Men-C-ACWY-CRM: IM: If ≥4 weeks since last dose, revaccinate with a single 0.5 mL dose, then complete series.Children 12 to <24 months: Men-C-ACWY-CRM (Menveo):Previously unvaccinated or vaccinated with only meningococcal group C conjugate vaccine: IM: 0.5 mL per dose; administer 2 doses ≥8 weeks apart.Previously vaccinated: IM: If vaccinated at <1 year of age or if at high risk for invasive meningococcal disease due to underlying medical condition, revaccinate with single dose of 0.5 mL if ≥4 weeks since last dose; otherwise revaccinate if ≥1 year since last dose.Children ≥2 years and Adolescents: Men-C-ACWY-CRM (Menveo), Men-C-ACWY-DT (Menactra), or Men-C-ACWY-TT (Nimenrix):Previously unvaccinated or vaccinated with only meningococcal group C conjugate vaccine: IM: 0.5 mL per dose; administer 1 dose immediately after exposure.Previously vaccinated: IM: If vaccinated at <1 year of age or if at high risk for invasive meningococcal disease due to underlying medical condition, revaccinate with single dose of 0.5 mL if ≥4 weeks since last dose; otherwise revaccinate if ≥1 year since last dose.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Injection, solution:Menactra: 4 mcg each of meningococcal polysaccharides A, C, Y, and W-135 [bound to diphtheria toxoid 48 mcg] per 0.5 mL [MCV4 or MenACWY-D] [contains formaldehyde]Injection, solution, reconstituted [preservative free]:Menveo: MenA oligosaccharide 10 mcg, MenC oligosaccharide 5 mcg, MenY oligosaccharide 5 mcg, and MenW-135 oligosaccharide 5 mcg [bound to CRM197 protein 32.7-64.1 mcg] per 0.5 mL [MenACWY-CRM; supplied in two vials, one containing MenA powder and one containing MenCYW-135 liquid]MenQuadfi: 10 mcg each of meningococcal polysaccharides A, C, Y, and W per 0.5 mL [may contain formaldehyde]Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Injection, solution [preservative free]:Menactra: 4 mcg each of meningococcal polysaccharides A, C, Y, and W-135 [bound to diphtheria toxoid ~48 mcg] per 0.5 mLInjection, solution, reconstituted [preservative free]:Menveo: MenA oligosaccharide 10 mcg, MenC oligosaccharide 5 mcg, MenW-135 oligosaccharide 5 mcg, and MenY oligosaccharide 5 mcg [bound to CRM197 protein ~47 mcg] per 0.5 mL [MenACWY-CRM; supplied in two vials, one containing MenA powder and one containing MenCYW-135 liquid]Nimenrix: 5 mcg each of meningococcal polysaccharides A, C, Y, and W-135 [bound to tetanus toxoid 44 mcg] per 0.5 mLProduct AvailabilityMenveo one vial formulation: FDA approved October 2022; availability anticipated in December 2022. Menveo one vial formulation does not require reconstitution prior to use and is indicated for use in patients 10 through 55 years of age.Medication Guide and/or Vaccine Information Statement (VIS)In the United States, the appropriate CDC-approved Vaccine Information Statement (VIS) must be provided to the patient/caregiver before administering each dose of this vaccine; the VIS edition date and date it was provided to the patient/caregiver should be recorded as required by US law; VIS is available at http://www.cdc.gov/vaccines/hcp/vis/vis-statements/mening.html.Administration: AdultIM: Administer by IM route, preferably into the central deltoid region. Use proper injection technique in the deltoid muscle (eg, injecting in the central, thickest part of the muscle) to reduce the risk of shoulder injury related to vaccine administration (Cross 2016; Foster 2013). Do not administer via IV, SUBQ, or intradermal route. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection. To prevent syncope related injuries, patients should be vaccinated while seated or lying down (ACIP [Kroger 2022]). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, Vaccine Information Statement (VIS) edition date and date it was provided, and the administering person's name, title, and address be recorded.For patients at risk of hemorrhage, the vaccine should be administered intramuscularly if, in the opinion of a physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, intramuscular vaccination can be scheduled shortly after such therapy is administered. A fine needle (23 gauge or smaller) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient or family should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (ACIP [Kroger 2022]).For IM administration only. Based on limited data, inadvertent SUBQ administration provides a lower serologic response; however, the response is still considered to be protective. If inadvertently administered by the SUBQ route, revaccination is not necessary.Menveo: Prior to using the 2-vial formulation, the powder (MenA vial) must be reconstituted with the liquid (MenCYW vial). If the liquid MenCYW is advertently administered without the MenA component, then revaccination is not needed unless the patient plans to travel internationally (ie, region where serogroup A meningococcal disease is endemic or where vaccination is required) (CDC/ACIP [Mbaeyi 2020]).Administration: PediatricIM: Administer by IM injection into anterolateral aspect of the thigh in infants and in the deltoid muscle to children and adolescents. Use proper injection technique in the deltoid muscle (eg, injecting in the central, thickest part of the muscle) to reduce the risk of shoulder injury related to vaccine administration (Cross 2016; Foster 2013). Not for intradermal, SUBQ, or IV administration. Menveo (2-vial formulation) and Nimenrix [Canadian product] must be administered within 8 hours after reconstitution. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (ACIP [Kroger 2022]). To prevent syncope-related injuries, adolescents should be vaccinated while seated or lying down (ACIP [Kroger 2022]). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, Vaccine Information Statement (VIS) edition date and date it was provided, and the administering person's name, title, and address be recorded.Menveo (2-vial formulation): Must be reconstituted prior to use to ensure all serotypes of quadrivalent vaccine in dose for administration (see "Preparation for Administration"; 1-vial formulation does not require reconstitution). If the liquid MenCYW is accidentally administered without the MenA component, then revaccination is not needed unless the patient plans to travel internationally to a region where serogroup A meningococcal disease is endemic or where vaccination is required (CDC/ACIP [Mbaeyi 2020]).For patients at risk of hemorrhage, the vaccine should be administered IM if, in the opinion of a physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, IM vaccination can be scheduled shortly after such therapy is administered. A fine needle (23-gauge or smaller) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient or family should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (ACIP [Kroger 2022]).Based on limited data, inadvertent SUBQ administration provides a lower serologic response; however, the response is still considered to be protective. If inadvertently administered by the SUBQ route, revaccination is not necessary.Use: Labeled IndicationsMeningococcal disease prevention: Active immunization against invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y, and W-135 in the following persons:- Menveo: ≥2 months to ≤55 years of age (2-vial formulation); ≥10 years to ≤55 years of age (1-vial formulation)- Menactra: ≥9 months to ≤55 years of age- MenQuadfi: ≥2 years of age (US labeling); ≥12 months of age (Canadian labeling)- Nimenrix (Canadian product): ≥6 weeks to ≤55 years of ageThe Advisory Committee on Immunization Practices (ACIP) (CDC/ACIP [Mbaeyi 2020]): ACIP recommends routine vaccination of the following:- Children and adolescents 11 or 12 years of age with a booster dose at 16 years of age.- Persons ≥2 months of age who are at increased risk of meningococcal disease.- Persons ≥2 months of age at increased risk during an outbreak (eg, in community or organizational settings, and among men who have sex with men).Those at increased risk of meningococcal disease include the following:- Persons with certain medical conditions such as anatomic or functional asplenia (including sickle cell disease), HIV infection, or complement component deficiencies (eg, C3, C5-C9, properdin, factor H, or factor D deficiencies; persons receiving complement inhibitors [eg, eculizumab, ravulizumab]).- Persons who travel to or reside in countries where meningococcal disease is hyperendemic or epidemic.- Unvaccinated or incompletely vaccinated first year college students living in residence halls.- Military recruits.- Microbiologists with routine exposure to Neisseria meningitidis isolates.The Canadian National Advisory Committee on Immunization (NACI): NACI recommends a routine vaccination at ~12 years of age but no booster unless at a continued high risk of exposure. Any quadrivalent vaccine may be used; NACI does not have a preference. NACI recommends use of Menveo (off-label use) for high risk persons 2 months to 2 years of age if vaccination with a quadrivalent vaccine is needed; may also be considered for use in persons ≥56 years of age (NACI 39[1] 2013). Additional recommendations may be found at https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html.Medication Safety IssuesSound-alike/look-alike issues:MenACWY-D (Menactra) may be confused with MenACWY-CRM (Menveo) or MenACWY-TT (MenQuadfi).MCV (meningococcal conjugate vaccine; MCV4 is the correct abbreviation) may be confused with PCV (pneumococcal conjugate vaccine; PCV13 is the correct abbreviation).MCV (meningococcal conjugate vaccine; MCV4 is the correct abbreviation) may be confused with MMR (measles, mumps, and rubella virus vaccine).MCV4 may be confused with MMRV (measles, mumps, rubella, and varicella) vaccine.Meningococcal ACWY (MenACWY) vaccine may be confused with meningococcal B (MenB) vaccine.Administration issue:Menactra (MenACWY-D) and MenQuadfi (MenACWY-TT) should be administered by intramuscular (IM) injection only. Inadvertent subcutaneous (SUBQ) administration of Menactra has been reported; possibly due to confusion of this product with Menomune (MPSV4), a meningococcal polysaccharide vaccine, which is administered by the SUBQ route. MPSV4 is no longer available in the United States.Menveo (MenACWY-CRM) is supplied as a 1-vial formulation and also as a 2-vial formulation, one containing MenCYW-135 liquid and one containing MenA lyophilized powder, which must be mixed together in order to administer the recommended vaccine components. Errors have occurred when both vials were not used or were mixed improperly. Ensure proper preparation before administering.Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Actual percentages may vary by product and age group. Adverse reactions occur with children, adolescents, and adults unless otherwise specified.>10%:Gastrointestinal: Anorexia (8% to 12%; infants: 30%), change in appetite (infants and children: 9% to 23%), diarrhea (infants, children, adolescents, and adults: 7% to 16%; severe diarrhea [infants: ≤2%]), nausea (5% to 12%), vomiting (2% to 3%; infants: 5% to 14%, severe vomiting: <1%)Local: Erythema at injection site (infants, children, adolescents, and adults: 4% to 32%), induration at injection site (infants, children, adolescents, and adults: 7% to 19%), pain at injection site (26% to 59%), swelling at injection site (infants, children, adolescents, and adults: 3% to 22%), tenderness at injection site (infants and children: 10% to 41%)Nervous system: Drowsiness (infants and children: 11% to 50%), excessive crying (infants and children: 12% to 41%), fatigue (adolescents and adults: 17% to 38%), headache (children: 5% to 18%; adolescents and adults: 19% to 41%), irritability (infants and children: 12% to 57%), malaise (10% to 28%), pain (60%)Neuromuscular & skeletal: Arthralgia (3% to 20%), myalgia (10% to 43%)Miscellaneous: Fever (infants, children, adolescents, and adults: ≤12%)1% to 10%:Dermatologic: Skin rash (infants, children, adolescents, and adults: 1% to 6%)Nervous system: Chills (4% to 10%)<1%:Endocrine & metabolic: Dehydration (infants and children)Gastrointestinal: Abdominal pain (children)Hepatic: Viral hepatitisHypersensitivity: AngioedemaInfection: Herpes zoster infection, staphylococcal infection (children)Nervous system: Dizziness, febrile seizure (children), simple focal seizuresNeuromuscular & skeletal: Herniated discRespiratory: Pneumonia (infants and children; lobar pneumonia [children])Frequency not definedNervous system: Acute disseminated encephalomyelitis, seizureRespiratory: Wheezing (infants)Postmarketing:Cardiovascular: Hypotension, syncope, vasodepressor syncopeDermatologic: Erythema of skin, exfoliation of skin, pruritus, urticariaHematologic & oncologic: LymphadenopathyHepatic: Increased serum alanine aminotransferaseHypersensitivity: Anaphylaxis, hypersensitivity reactionLocal: Cellulitis at injection site, inflammation at injection site, injection-site pruritus, swelling of injected limbNervous system: Balance impairment, Bell palsy, facial nerve paralysis, Guillain-Barré syndrome, paresthesia, transverse myelitis, vertigoNeuromuscular & skeletal: OstealgiaOphthalmic: BlepharoptosisOtic: Auditory impairment, otalgia, vestibular disturbanceRespiratory: Apnea (premature infants), dyspnea, oropharyngeal pain, upper airway swellingMiscellaneous: SwellingContraindicationsSevere hypersensitivity (eg, anaphylaxis) to other meningococcal-containing vaccines or any component of the formulation including diphtheria toxoid or CRM197 (a diphtheria toxin carrier protein) (Menactra and Menveo only) or tetanus toxoid (MenQuadfi only).Warnings/PrecautionsConcerns related to adverse effects:• Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (ACIP [Kroger 2022]).• Shoulder injury related to vaccine administration: Vaccine administration that is too high on the upper arm may cause shoulder injury (eg, shoulder bursitis, tendinopathy) resulting in shoulder pain and reduced range of motion following injection. Use proper injection technique for vaccines administered in the deltoid muscle (eg, injecting in the central, thickest part of the muscle) to reduce the risk of shoulder injury related to vaccine administration (Cross 2016; Foster 2013).• Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes after vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (ACIP [Kroger 2022]).Disease-related concerns:• Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Defer administration in patients with moderate or severe acute illness (with or without fever); vaccination should not be delayed for patients with mild acute illness (with or without fever) (ACIP [Kroger 2022]).• Bleeding disorders: Use with caution in patients with a history of bleeding disorders (including thrombocytopenia); bleeding/hematoma may occur from IM administration; if the patient receives antihemophilia or other similar therapy, IM injection can be scheduled shortly after such therapy is administered (ACIP [Kroger 2022]).• Diphtheria or tetanus immunization: Immunization with Menveo or Menactra does not substitute for routine diphtheria immunization; immunization with MenQuadfi or Nimenrix (Canadian product) does not substitute for routine tetanus immunization.• Guillain-Barré syndrome: Has been temporally associated with Menactra; use with caution in patients with a history of Guillain-Barré syndrome.• Meningococcal infections: Not to be used to treat meningococcal infections or to provide immunity against N. meningitidis serogroup B.Concurrent drug therapy issues:• Anticoagulant therapy: Use with caution in patients receiving anticoagulant therapy; bleeding/hematoma may occur from IM administration (ACIP [Kroger 2022]).• Vaccines: In order to maximize vaccination rates, the ACIP recommends simultaneous administration (ie, >1 vaccine on the same day at different anatomic sites) of all age-appropriate vaccines (live or inactivated) for which a person is eligible at a single clinic visit, unless contraindications exist. The ACIP prefers each dose of a specific vaccine in a series come from the same manufacturer when possible; however, vaccination should not be deferred because a specific brand name is unavailable (ACIP [Kroger 2022]).Administration of Menactra (MenACWY-D) 1 month after Daptacel (DTaP) has been shown to have reduced meningococcal antibody responses in children; these vaccines should be administered simultaneously or Menactra should be administered prior to or 6 months after Daptacel. If child is traveling to a hyperendemic or epidemic area or where an outbreak is occurring, administer MenACWY-D regardless of the timing of DTaP receipt. This interaction does not apply to Menveo (MenACWY-CRM) or MenQuadfi (MenACWY-TT) (CDC/ACIP [Mbaeyi 2020]).Simultaneous administration of Menactra (MenACWY-D) and pneumococcal conjugate vaccine (7-valent) (PCV7) produced reduced concentrations of 3 serotypes of pneumococcus. Therefore, ACIP recommends that in persons with anatomic or functional asplenia or HIV, Menactra should be given ≥4 weeks after completion of the PCV13 series (ACIP [Kroger 2022]).Special populations:• Altered immunocompetence: Patients with certain complement deficiencies, HIV infection, or with anatomic or functional asplenia, and patients receiving complement inhibitors (eg, eculizumab, ravulizumab) are at an increased risk for invasive meningococcal infection, including post vaccination (CDC/ACIP [Mbaeyi 2020]). Consider deferring immunization during periods of severe immunosuppression (eg, patients receiving chemo/radiation therapy or other immunosuppressive therapy [including high-dose corticosteroids]); may have a reduced response to vaccination. In general, household and close contacts of persons with altered immunocompetence may receive all age-appropriate vaccines. Inactivated vaccines should be administered ≥2 weeks prior to planned immunosuppression when feasible; inactivated vaccines administered during chemotherapy should be readministered after immune competence is regained (ACIP [Kroger 2022]; IDSA [Rubin 2014]).• Pediatric: Apnea has been reported following IM vaccine administration in premature infants; consider clinical status implications. In general, preterm infants should be vaccinated at the same chronological age as full-term infants (AAP [Saari 2003]; ACIP [Kroger 2022]). Children with functional or anatomic asplenia or HIV infection should delay receiving Menactra (MenACWY-D) until 2 years of age to avoid immune interference with the 13-valent pneumococcal conjugate vaccine (PCV13); Menactra should be given at least 4 weeks after completion of the PCV13 series; if meningococcal immunity is required in pediatric patients 2 to 23 months of age, the alternative is administration of Menveo (MenACWY-CRM) (CDC/ACIP [Mbaeyi 2020]).Dosage form specific issues:• Menveo: Menveo is available as a 1-vial formulation that does not require mixing, as well as a 2-vial formulation that requires mixing prior to administration.Other warnings/precautions:• Antipyretics: Antipyretics have not been shown to prevent febrile seizures; antipyretics may be used to treat fever or discomfort following vaccination (ACIP [Kroger 2022]). One study reported that routine prophylactic administration of acetaminophen to prevent fever prior to vaccination decreased the immune response of some vaccines; the clinical significance of this reduction in immune response has not been established (Prymula 2009).• Appropriate use: Use of this vaccine for specific medical and/or other indications (eg, immunocompromising conditions, hepatic or kidney disease, diabetes) is also addressed in the annual ACIP Recommended Immunization Schedules (refer to CDC schedule for detailed information). Specific recommendations for use of this vaccine in immunocompromised patients with asplenia, cancer, HIV infection, cerebrospinal fluid leaks, cochlear implants, hematopoietic stem cell transplant (prior to or after), sickle cell disease, solid organ transplant (prior to or after), or those receiving immunosuppressive therapy for chronic conditions are available from the IDSA (Rubin 2014).• Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval. Vaccines may not be effective if administered during periods of altered immune competence (ACIP [Kroger 2022]).Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Acetaminophen: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of acetaminophen before or during vaccine administration when possible. Acetaminophen is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modificationCladribine: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of cladribine when possible. Patients vaccinated less than 14 days before initiating or during cladribine should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modificationCorticosteroids (Systemic): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Administer vaccines at least 2 weeks prior to immunosuppressive corticosteroids if possible. If patients are vaccinated less than 14 days prior to or during such therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationDiphtheria and Tetanus Toxoids, and Acellular Pertussis Vaccine: May diminish the therapeutic effect of Meningococcal (Groups A / C / Y and W-135) Conjugate Vaccine. More specifically, prior administration of the diphtheria and tetanus toxoids, and acellular pertussis vaccine may diminish antibody response to the meningococcal (groups A / C / Y / and W-135) diphtheria conjugate vaccine in some patients. Management: Administer the meningococcal (groups A / C / Y and W-135) conjugate vaccine (Menactra brand) before or concurrently with the diphtheria and tetanus toxoids, and acellular pertussis vaccine (Daptacel brand) in children 4 to 6 years of age. Risk D: Consider therapy modificationElivaldogene Autotemcel: May enhance the adverse/toxic effect of Vaccines. Specifically, there may be a greater risk for contracting an infection from any live vaccine. Elivaldogene Autotemcel may diminish the therapeutic effect of Vaccines. Management: Administration of vaccines is not recommended in the 6 weeks before myeloablative conditioning, and until hematologic recovery after elivaldogene autotemcel treatment. Risk X: Avoid combinationFingolimod: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting fingolimod. If vaccinated during fingolimod therapy, revaccinate 2 to 3 months after fingolimod discontinuation. Risk D: Consider therapy modificationImmunosuppressants (Cytotoxic Chemotherapy): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modificationImmunosuppressants (Miscellaneous Oncologic Agents): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modificationImmunosuppressants (Therapeutic Immunosuppressant Agents): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modificationMethotrexate: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Administer vaccines at least 2 weeks prior to methotrexate initiation, if possible. If patients are vaccinated less than 14 days prior to or during methotrexate therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationPneumococcal Conjugate Vaccine (13-Valent): Meningococcal (Groups A / C / Y and W-135) Conjugate Vaccine may diminish the therapeutic effect of Pneumococcal Conjugate Vaccine (13-Valent).Management: Administer MenACYW-D (Menactra brand) vaccine at least 4 weeks after the final dose of the PCV13 vaccine series in patients with anatomic asplenia or functional asplenia. For details and recommendations for children under 2 years, see full monograph. Risk D: Consider therapy modificationPropacetamol: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of propacetamol before or during vaccine administration when possible. Propacetamol is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modificationRiTUXimab: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of rituximab when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 6 months after therapy is complete. Risk D: Consider therapy modificationSiponimod: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Avoid administration of vaccines (inactivated) during treatment with siponimod and for 1 month after discontinuation due to potential decreased vaccine efficacy. Risk D: Consider therapy modificationTeplizumab: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Vaccination with inactivated or non-replicating vaccines is not recommended in the 2 weeks prior to teplizumab therapy, during treatment, or for 6 weeks following completion of therapy. Risk D: Consider therapy modificationTetanus Toxoids Vaccines: May diminish the therapeutic effect of Meningococcal (Groups A / C / Y and W-135) Conjugate Vaccine. Management: When possible, administer the meningococcal polysaccharide (groups A / C / Y and W-135) conjugate vaccine (Nimenrix brand) either together with, or at least one month before, a tetanus toxoids-containing vaccine. Risk D: Consider therapy modificationPregnancy ConsiderationsBased on available data, an increased risk of adverse pregnancy outcomes has not been observed following maternal vaccination with a meningococcal (Groups A / C / Y and W-135) diphtheria conjugate vaccine (Becerra-Culqui 2020; CDC/ACIP [Mbaeyi 2020]; Myers 2017; Zheteyeva 2013).Inactivated bacterial vaccines have not been shown to cause increased risks to the fetus. Use of meningococcal conjugate vaccines may be considered for use in pregnant patients at increased risk of infection (ACIP [Kroger 2022]). Pregnant patients should be vaccinated if otherwise indicated (CDC/ACIP [Mbaeyi 2020]).Data collection to monitor pregnancy and infant outcomes following exposure to Menactra or MenQuadfi is ongoing. Health care providers are encouraged to enroll patients exposed to Menactra or MedQuadfi during pregnancy in the Sanofi Pasteur Inc vaccine registry (1-800-822-2463).Breastfeeding ConsiderationsIt is not known if this vaccine is present in breast milk.According to the manufacturer, the decision to continue or discontinue breastfeeding following immunization should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of vaccination to the mother. Inactivated vaccines do not affect the safety of breastfeeding for the mother or the infant (ACIP [Kroger 2022]). Lactating patients should be vaccinated if otherwise indicated (CDC/ACIP [Mbaeyi 2020]). Breastfeeding infants should be vaccinated according to the recommended schedules (ACIP [Kroger 2022]).Monitoring ParametersMonitor for hypersensitivity and syncope for at least 15 minutes following administration (ACIP [Kroger 2022]). If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion.Mechanism of ActionInduces immunity against meningococcal disease via the formation of bactericidal antibodies directed toward the polysaccharide capsular components of Neisseria meningitidis serogroups A, C, Y and W-135.Pharmaco*kineticsOnset of action: Postvaccination seroconversion is typically achieved by 1 month following dose (or last dose in a series, if multiple doses given). (CDC/ACIP [Mbaeyi 2020]).Duration of action: Antibody waning is observed over 3 to 5 years following primary vaccination; in adolescents, antibodies persist for ≥4 years following a booster dose. Antibody waning may vary with specific product and among serogroups (CDC/ACIP [Mbaeyi 2020]).Brand Names: InternationalMenactra (BB, CL, HK, IL, JP, KR, LB, MY, PH, QA, SA, SG, TH, TR);Menacttra (AR);Menveo (AT, BB, BE, CH, CL, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HK, HR, HU, ID, IE, IL, KR, LB, LT, LU, LV, MT, MY, NL, NO, PH, PL, PT, QA, RO, SA, SE, SK, TR)For country code abbreviations (show table)Becerra-Culqui TA, Sy LS, Ackerson BK, et al. Safety of MenACWY-CRM vaccine exposure during pregnancy. Vaccine. 2020;38(12):2683-2690. doi:10.1016/j.vaccine.2020.02.008 [PubMed 32057568]Bilukha OO, Rosenstein N; National Center for Infectious Diseases; Centers for Disease Control and Prevention. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR-7):1-21. [PubMed 15917737]Bröker M, Dull PM, Rappuoli R, et al. Chemistry of a new investigational quadrivalent meningococcal conjugate vaccine that is immunogenic at all ages. Vaccine. 2009; 27(41):5574-5580. [PubMed 19619500]Canadian National Advisory Committee on Immunization (NACI). Meningococcal vaccine: Canadian Immunization Guide. https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-13-meningococcal-vaccine.html. Updated February 2020. Accessed: June 15, 2020.Canadian National Advisory Committee on Immunization (NACI), Advisory Committee Statement, "Update on the Use of Quadrivalent Conjugate Meningococcal Vaccines," CCDR, 2013, 39(1). Available at http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/13vol39/acs-dcc-1/index-eng.phpCenters for Disease Control and Prevention. CDC Yellow Book: Health Information for International Travel 2020. New York, NY: Oxford University Press; 2019. https://wwwnc.cdc.gov/travel/yellowbook/2020/table-of-contents. Updated 2019. Accessed January 17, 2020.Centers for Disease Control and Prevention (CDC). Vaccination guidance during a pandemic. Updated October 20, 2020. Available at https://www.cdc.gov/vaccines/pandemic-guidance/index.htmlCross GB, Moghaddas J, Buttery J, Ayoub S, Korman TM. Don't aim too high: avoiding shoulder injury related to vaccine administration. Aust Fam Physician. 2016;45(5):303-306. [PubMed 27166466]Foster SL, Davis MV. Vaccine administration: preventing serious shoulder injuries. J Am Pharm Assoc (2003). 2013;53(1):102-103. doi:10.1331/JAPhA.2013.13503 [PubMed 23636163]Kim DK, Riley LE, Harriman KH, et al; Advisory Committee on Immunization Practices (ACIP), ACIP Adult Immunization Work Group. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older—United States, 2017. MMWR Morb Mortal Wkly Rep. 2017; 66(5):136-138. doi: 10.15585/mmwr.mm6605e2. [PubMed 28182599]Kim DK, Riley LE, Hunter P. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older - United States, 2018. MMWR Morb Mortal Wkly Rep. 2018;67(5):158-160. [PubMed 29420462]Kroger A, Bahta L, Hunter P. General best practice guidelines for immunization: best practices guidance of the Advisory Committee on Immunization Practices (ACIP). https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. Accessed February 10, 2022.Mbaeyi SA, Bozio CH, Duffy J, et al. Meningococcal vaccination: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020. MMWR Recomm Rep. 2020;69(9):1-41. [PubMed 33417592]Menactra (meningococcal [groups A, C, Y and W-135] polysaccharide diphtheria toxoid conjugate vaccine) [product monograph]. Toronto, Ontario, Canada: Sanofi Pasteur Limited; November 2017.Menactra (meningococcal [groups A, C, Y and W-135] polysaccharide diphtheria toxoid conjugate vaccine) [prescribing information]. Swiftwater, PA: Sanofi Pasteur Inc; July 2019.MenQuadfi (meningococcal [groups A, C, Y and W-135] conjugate vaccine) [prescribing information]. Swiftwater, PA; Sanofi Pasteur Inc; June 2022.MenQuadfi (meningococcal [groups A, C, Y and W-135] conjugate vaccine) [prescribing information]. Swiftwater, PA; Sanofi Pasteur Inc; October 2021.MenQuadfi (meningococcal [groups A, C, Y and W-135] conjugate vaccine) [product monograph]. Toronto, Ontario, Canada: Sanofi Pasteur Limited; October 2020.Menveo (meningococcal [groups A, C, Y and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine) [prescribing information]. Durham, NC: GlaxoSmithKline; October 2022.Menveo (meningococcal [groups A, C, Y and W-135] oligosaccharide diphtheria CRM197 conjugate vaccine) [product monograph]. Mississauga, Ontario, Canada: GlaxoSmithKline Inc; June 2020.Myers TR, McNeil MM, Ng CS, Li R, Lewis PW, Cano MV. Adverse events following quadrivalent meningococcal CRM-conjugate vaccine (Menveo®) reported to the Vaccine Adverse Event Reporting system (VAERS), 2010-2015. Vaccine. 2017;35(14):1758-1763. doi: 10.1016/j.vaccine.2017.02.030. [PubMed 28262331]National Center for Immunization and Respiratory Diseases (NCIRD). General recommendations on immunization—recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Recomm Rep. 2011;60:993]. MMWR Recomm Rep. 2011;60(2):1-64. [PubMed 21293327]Nimenrix (meningococcal [groups A, C, Y and W-135] conjugate vaccine) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; December 2018.Nimenrix (meningococcal [groups A, C, Y and W-135] conjugate vaccine) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; August 2021.Perrett KP, Snape MD, Ford KJ, et al. Immunogenicity and immune memory of a nonadjuvanted quadrivalent meningococcal glycoconjugate vaccine in infants. Pediatr Infect Dis J. 2009;28(3):186-193. [PubMed 19209097]Prymula R, Siegrist CA, Chlibek R, et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet. 2009;374(9698):1339-1350. [PubMed 19837254]Reisinger KS, Baxter R, Block SL, et al. Quadrivalent meningococcal vaccination of adults: Phase III comparison of an investigational conjugate vaccine, MenACWY-CRM, with the licensed vaccine, Menactra. Clin Vaccine Immunol. 2009;16(12):1810-1815. [PubMed 19812260]Robinson CL, Romero JR, Kempe A, Pellegrini C, Szilagyi P. Advisory Committee on Immunization Practices recommended immunization schedule for children and adolescents aged 18 years or younger - United States, 2018. MMWR Morb Mortal Wkly Rep. 2018;67(5):156-157. [PubMed 29420458]Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44-e100. [PubMed 24311479]Saari TN; American Academy of Pediatrics Committee on Infectious Diseases. Immunization of preterm and low birth weight infants. American Academy of Pediatrics Committee on Infectious Diseases. Pediatrics. 2003;112(1 Pt 1):193-198. [PubMed 12837889]World Health Organization (WHO). Guiding principles for immunization activities during the COVID-19 pandemic: interim guidance, 26 March 2020. Published March 26, 2020. Available at https://apps.who.int/iris/handle/10665/331590Zheteyeva Y, Moro PL, Yue X, Broder K. Safety of meningococcal polysaccharide-protein conjugate vaccine in pregnancy: a review of the Vaccine Adverse Event Reporting System. Am J Obstet Gynecol. 2013;208(6):478.e1-e6. doi: 10.1016/j.ajog.2013.02.027. [PubMed 23453881]Topic 10140 Version 217.0

CloseHuman papillomavirus 9-valent vaccine (9vHPV): Pediatric drug informationHuman papillomavirus 9-valent vaccine (9vHPV): Pediatric drug information(For additional information see "Human papillomavirus 9-valent vaccine (9vHPV): Drug information" and see "Human papillomavirus 9-valent vaccine (9vHPV): Patient drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USGardasil 9Brand Names: CanadaGardasil 9Therapeutic CategoryVaccine;Vaccine, Inactivated (Viral)Dosing: PediatricNote: Consult CDC/ACIP annual immunization schedules for additional information including specific detailed recommendations for catch-up scenarios and/or care of patients with high-risk conditions. According to ACIP, doses administered ≤4 days before minimum interval or age are considered valid; however, local or state mandates may supersede this timeframe (Ref).Primary immunizationPrimary immunization: Children ≥9 years and Adolescents: IM: 0.5 mL per dose for 2 or 3 doses; see the following recommendations for number and timing of doses (Ref).CDC/ACIP recommended immunization schedule: Routine vaccination at 11 to 12 years of age for all persons; may start as early as 9 years of age. AAP and ACS recommend routine vaccination between 9 and 12 years of age (Ref).In a 2-dose schedule, minimum interval between first and second doses is 5 months.In a 3-dose schedule, minimum interval between first and second doses is 4 weeks; the minimum interval between the second and third dose is 12 weeks; the minimum interval between first and third doses is 5 months (Ref).Non-immunocompromised patients and certain specified medical conditions: Asplenia, asthma, chronic granulomatous disease, chronic liver disease, chronic lung disease, chronic renal disease, central nervous system, anatomic barrier defects (eg, cochlear implant), complement deficiency, diabetes, heart disease, or sickle cell disease:Children ≥9 years and Adolescents <15 years: 2-dose series: IM: 0.5 mL at 0, and 6 to 12 months. Administer first dose at age 11 to 12 years. For patients with any history of sexual abuse or assault, vaccination should be started at 9 years.Adolescents ≥15 years: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months.Immunocompromised patients: Including those with conditions that might reduce cell-mediated or humoral immunity, such as B lymphocyte antibody deficiencies, T lymphocyte complete or partial defects, HIV infection, malignant neoplasms, transplantation, autoimmune disease, or immunosuppressive therapy:Children ≥9 years and Adolescents: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months.Manufacturing labeling: May not reflect current practice:Children ≥9 years and Adolescents <15 years:2-dose series: IM: 0.5 mL per dose; administer the second dose at 6 to 12 months after initial dose. If the second dose is inadvertently administered earlier than 5 months after the first dose, then patient should be converted to a 3-dose series.3-dose series: IM: 0.5 mL per dose; administer the second and third doses at 2 and 6 months after initial dose.Adolescents ≥15 years: IM: 0.5 mL per dose for a total of 3 doses; administer the second and third doses at 2 and 6 months after initial dose.Catch-up immunizationCatch-up immunization: CDC/ACIP recommendations (Ref): Note: Do not restart the series. If doses have been given, begin the below schedule at the applicable dose number. Children ≥9 years and Adolescents: IM: 0.5 mL per dose for a total of 2 to 3 doses (See CDC/ACIP recommendations in Primary Immunization for 2-dose vs 3-dose schedule criteria):First dose given on the elected date.Second dose given at least 4 weeks after the first dose (for a 3-dose schedule) or 5 months after the first dose (for a 2-dose schedule).Third dose (for a 3-dose schedule) given at least 12 weeks after the second dose and at least 5 months after the first dose.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Adult(For additional information see "Human papillomavirus 9-valent vaccine (9vHPV): Drug information")ImmunizationImmunization: IM:Manufacturer's labeling: Adults ≤45 years of age: 3-dose series: 0.5 mL at 0, 2, and 6 months.CDC/ACIP recommended immunization schedule: Adults ≤26 years of age: Catch-up vaccination is recommended in all persons ≤26 years of age if not previously vaccinated or have not completed the 3-dose series (typically administer first dose at age 11 to 12 years). Second and third doses may be given after age 26 years to complete a previously initiated series (Ref). Note: Shared clinical decision-making regarding catch-up human papillomavirus vaccination is recommended for some adults 27 to 45 years of age (Ref). The American Cancer Society does not endorse vaccination in adults 27 to 45 years of age (Ref).Have not received any doses: 3-dose series: IM: 0.5 mL at 0, 1 to 2, and 6 months. There should be a 4-week minimum interval between the first and second dose; a 12-week minimum interval between the second and third dose; a 5-month minimum interval between the first and third dose.Partially vaccinated, first dose before 15 years of age:If 2 doses administered at least 5 months apart: No more doses needed.If only a single dose or if doses <5 months apart: IM: Administer one additional 0.5 mL dose.Partially vaccinated, first dose at 15 years of age or later: Complete 3-dose series: IM: There should be a 4-week minimum interval between the first and second dose; a 12-week minimum interval between the second and third dose; a 5-month minimum interval between the first and third dose.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer's labeling.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Suspension, Intramuscular [preservative free]: Gardasil 9:(0.5 mL) [contains polysorbate 80, yeast extract]Suspension Prefilled Syringe, Intramuscular [preservative free]: Gardasil 9:(0.5 mL) [contains polysorbate 80, yeast extract]Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Suspension, Intramuscular [preservative free]:Gardasil 9: (0.5 mL) [contains polysorbate 80, yeast extract; latex-free]Suspension Prefilled Syringe, Intramuscular [preservative free]:Gardasil 9: (0.5 mL) [contains polysorbate 80, yeast extract; latex-free]Medication Guide and/or Vaccine Information Statement (VIS)In the US, the appropriate CDC-approvedVaccine Information Statement (VIS) must be provided to the patient prior to administering each dose of this vaccine; VIS is available at http://www.cdc.gov/vaccines/hcp/vis/vis-statements/hpv-gardasil-9.htmlAdministration: PediatricIM: Shake suspension well before use. Do not use if discolored or if contains particulate matter, or if syringe is cracked. Inject the entire dose IM into the deltoid region of the upper arm or higher anterolateral thigh area. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (Ref). To prevent syncope related injuries, adolescents should be vaccinated while seated or lying down (Ref). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, Vaccine Information Statement (VIS) edition date and date it was provided, and the administering person's name, title, and address be recorded.For patients at risk of hemorrhage following intramuscular injection, the vaccine should be administered intramuscularly if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, intramuscular vaccination can be scheduled shortly after such therapy is administered. A fine needle (23-gauge or smaller) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (Ref).Administration: AdultIM: Shake suspension well before use. Do not use if discolored or if contains particulate matter, or if syringe is cracked. Inject the entire dose IM into the deltoid region of the upper arm or higher anterolateral thigh area. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (Ref). To prevent syncope-related injuries, patients should be vaccinated while seated or lying down (Ref). US law requires that the date of administration, the vaccine manufacturer, lot number of vaccine, Vaccine Information Statement edition date and date it was provided, and the administering person's name, title, and address be recorded.For patients at risk of hemorrhage following IM injection, the vaccine should be administered IM if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, IM vaccination can be scheduled shortly after such therapy is administered. A fine needle (≤23-gauge) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (Ref).Storage/StabilityStore refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect from light.Administer as soon as possible after being removed from refrigeration. HPV 9-valent vaccine can be administered provided total (cumulative multiple excursion) time out of refrigeration (at temperatures between 8°C and 25°C) does not exceed 72 hours. Cumulative multiple excursions between 0°C and 2°C are also permitted as long as the total time between 0°C and 2°C does not exceed 72 hours. These are not, however, recommendations for storage.UsePrevention of the following: Cervical, vulvar, vagin*l, anal, oropharyngeal, and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58; genital warts caused by HPV types 6 and 11; cervical adenocarcinoma in situ; and vulvar, vagin*l, cervical, or anal intraepithelial neoplasia caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 (All indications: FDA approved in females ages 9 to 45 years).Prevention of the following: Genital warts caused by HPV types 6 and 11; anal, oropharyngeal, and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58; and anal intraepithelial neoplasia grades 1, 2, and 3 caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 (All indications: FDA approved in males ages 9 to 45 years).The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination for females and males 11 to 12 years of age; for patients with any history of sexual abuse or assault, vaccination should be started at 9 years of age. Catch-up vaccination is recommended for all persons through 26 years of age. Shared clinical decision-making regarding catch-up HPV vaccination is recommended for some adults 27 to 45 years of age (CDC/ACIP [Meites 2019]). The American Academy of Pediatrics (AAP) and the American Cancer Society (ACS) recommend routine vaccination for individuals 9 to 12 years of age (ACS [Saslow 2020]; Red Book [AAP 2018]). ACS recommends catch-up vaccination only for individuals through 26 years of age (ACS [Saslow 2020]).Medication Safety IssuesSound-alike/look-alike issues:Papillomavirus vaccine 9-valent (Gardasil 9) may be confused with Papillomavirus vaccine types 6, 11, 16, 18 (Gardasil)HPV (human papilloma virus vaccine, 9vHPV is the correct abbreviation) may be confused with IPV (inactivated poliovirus vaccine)HPV (human papilloma virus vaccine, 9vHPV is the correct abbreviation) may be confused with HBV (previously used for hepatitis B vaccine; HepB is correct abbreviation)HPV (human papilloma virus vaccine, 9vHPV is the correct abbreviation) may be confused with Hib (Haemophilus b conjugate vaccine)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Reported incidences are for females 9 to 45 years of age and males 9 to 26 years of age.>10%:Local: Erythema at injection site (7% to 42%; increased with successive doses), pain at injection site (63% to 90%), swelling at injection site (13% to 49%; increased with successive doses)Nervous system: Headache (7% to 20%)1% to 10%:Dermatologic: Injection site pruritus (1% to 8%)Gastrointestinal: Diarrhea (≤1%), nausea (1% to 4%), upper abdominal pain (≤2%)Immunologic: Autoimmune disease (2%)Local: Bleeding at injection site (1%), bruising at injection site (2%), hematoma at injection site ( ≤5%), hypersensitivity reaction at injection site (1%), induration at injection site (≤2%), injection site nodule (1%), injection site reaction (≤1%)Nervous system: Dizziness (≤3%), fatigue (1% to 3%)Neuromuscular & skeletal: Myalgia (≤1%)Respiratory: Oropharyngeal pain (1% to 3%)Miscellaneous: Fever (2% to 10%)<1%:Local: Warm sensation at injection siteRespiratory: Upper respiratory tract infectionFrequency not defined:Hypersensitivity: Hypersensitivity reactionRespiratory: Status asthmaticusPostmarketing:Cardiovascular: SyncopeDermatologic: UrticariaGastrointestinal: VomitingContraindicationsHypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of this vaccine or human papillomavirus (types 6, 11, 16, 18) vaccine (recombinant).Warnings/PrecautionsConcerns related to adverse effects:• Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (ACIP [Kroger 2021]).• Shoulder injury related to vaccine administration: Vaccine administration that is too high on the upper arm may cause shoulder injury (eg, shoulder bursitis or tendinitis) resulting in shoulder pain and reduced range of motion following injection. Use proper injection technique for vaccines administered in the deltoid muscle (eg, injecting in the central, thickest part of the muscle) to reduce the risk of shoulder injury related to vaccine administration (Cross 2016; Foster 2013).• Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes after vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (ACIP [Kroger 2021]).Disease-related concerns:• Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Defer administration in patients with moderate or severe acute illness (with or without fever); vaccination should not be delayed for patients with mild acute illness (with or without fever) (ACIP [Kroger 2021]).• Bleeding disorders: Use with caution in patients with a history of bleeding disorders (including thrombocytopenia); bleeding/hematoma may occur from IM administration; if the patient receives antihemophilia or other similar therapy, IM injection can be scheduled shortly after such therapy is administered (ACIP [Kroger 2021]).• Human papillomavirus infection: There is no evidence that individuals already infected with human papillomavirus (HPV) will be protected; those already infected with 1 or more HPV types were protected from disease caused by the remaining HPV types. Not for the treatment of active disease; will not protect against diseases not caused by HPV vaccine types not included in the vaccine. Does not eliminate the necessity for recommended cervical or anal cancer screenings.Concurrent drug therapy issues:• Anticoagulant therapy: Use with caution in patients receiving anticoagulant therapy; bleeding/hematoma may occur from IM administration (ACIP [Kroger 2021]).• Vaccines: In order to maximize vaccination rates, the ACIP recommends simultaneous administration of all age-appropriate vaccines (live or inactivated) for which a person is eligible at a single clinic visit, unless contraindications exist (ACIP [Kroger 2021]).Special populations:• Altered immunocompetence: Consider deferring immunization during periods of severe immunosuppression (eg, patients receiving chemo/radiation therapy or other immunosuppressive therapy [including high-dose corticosteroids]); may have a reduced response to vaccination. In general, household and close contacts of persons with altered immunocompetence may receive all age-appropriate vaccines. Inactivated vaccines should be administered ≥2 weeks prior to planned immunosuppression when feasible; inactivated vaccines administered during chemotherapy should be readministered after immune competence is regained (ACIP [Kroger 2021]; IDSA [Rubin 2014]). Dosage form specific issues:• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.• Previously vaccinated with Gardasil (quadrivalent): Safety and immunogenicity of Gardasil 9 were assessed in individuals who previously completed a 3-dose vaccination series with Gardasil (quadrivalent). Studies using a mixed regimen of HPV vaccines to assess interchangeability were not performed. Per the ACIP, if the provider does not have available or does not know the HPV product used previously, any gender appropriate product can be used to complete the series (CDC/ACIP [Petrosky 2015]).• Yeast: Product may contain yeast.Other warnings/precautions:• Appropriate use: Use of this vaccine for specific medical and/or other indications (eg, immunocompromising conditions, hepatic or kidney disease, diabetes) is also addressed in the annual ACIP Recommended Immunization Schedules (refer to CDC schedule for detailed information). Specific recommendations for vaccination in immunocompromised patients with asplenia, cancer, HIV infection, cerebrospinal fluid leaks, cochlear implants, hematopoietic stem cell transplant (prior to or after), sickle cell disease, solid organ transplant (prior to or after), or those receiving immunosuppressive therapy for chronic conditions are available from the IDSA (Rubin 2014).• Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval. Vaccines may not be effective if administered during periods of altered immune competence (ACIP [Kroger 2021]). Vaccination is safe for individuals 27 to 45 years of age; however, consider decreased effectiveness and potential for lower cancer prevention in these older ages (ACS [Saslow 2020]; CDC/ACIP [Meites 2019])).• Maximum efficacy: The entire series should be completed for maximum efficacy.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions programAcetaminophen: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of acetaminophen before or during vaccine administration when possible. Acetaminophen is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modificationCladribine: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of cladribine when possible. Patients vaccinated less than 14 days before initiating or during cladribine should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modificationCorticosteroids (Systemic): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Administer vaccines at least 2 weeks prior to immunosuppressive corticosteroids if possible. If patients are vaccinated less than 14 days prior to or during such therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationElivaldogene Autotemcel: May enhance the adverse/toxic effect of Vaccines. Specifically, there may be a greater risk for contracting an infection from any live vaccine. Elivaldogene Autotemcel may diminish the therapeutic effect of Vaccines. Management: Administration of vaccines is not recommended in the 6 weeks before myeloablative conditioning, and until hematologic recovery after elivaldogene autotemcel treatment. Risk X: Avoid combinationFingolimod: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting fingolimod. If vaccinated during fingolimod therapy, revaccinate 2 to 3 months after fingolimod discontinuation. Risk D: Consider therapy modificationImmunosuppressants (Cytotoxic Chemotherapy): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modificationImmunosuppressants (Miscellaneous Oncologic Agents): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modificationImmunosuppressants (Therapeutic Immunosuppressant Agents): May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modificationMethotrexate: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Administer vaccines at least 2 weeks prior to methotrexate initiation, if possible. If patients are vaccinated less than 14 days prior to or during methotrexate therapy, repeat vaccination at least 3 months after therapy if immunocompetence restored. Risk D: Consider therapy modificationPropacetamol: May diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of propacetamol before or during vaccine administration when possible. Propacetamol is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modificationRiTUXimab: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of rituximab when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 6 months after therapy is complete. Risk D: Consider therapy modificationSiponimod: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Avoid administration of vaccines (inactivated) during treatment with siponimod and for 1 month after discontinuation due to potential decreased vaccine efficacy. Risk D: Consider therapy modificationTeplizumab: May diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Vaccination with inactivated or non-replicating vaccines is not recommended in the 2 weeks prior to teplizumab therapy, during treatment, or for 6 weeks following completion of therapy. Risk D: Consider therapy modificationReproductive ConsiderationsPregnancy testing is not required prior to administration of the vaccine (ACOG 2020; CDC/ACIP [Petrosky 2015]).Based on available information, the human papillomavirus vaccine is not expected to decrease female fertility (Christianson 2020; Schmuhl 2020). However, human papillomavirus infection may be associated with infertility in males and females. Vaccination may increase fertility in some patients; however, additional study is needed (Garolla 2018; McInerney 2017; Pereira 2015).Pregnancy ConsiderationsBased on available data, an increased risk of adverse pregnancy outcomes, specifically miscarriage or congenital anomalies, has not been observed following inadvertent administration of the papillomavirus vaccine during pregnancy (ACOG 2020; Kharbanda 2021; Landazabal 2019). However, administration of the vaccine in pregnancy is not recommended. The vaccine series (or completion of the series) should be delayed until pregnancy is completed (ACOG 2020; CDC/ACIP [Petrosky 2015]).Data collection to monitor pregnancy and infant outcomes following exposure to the papillomavirus (9-valent) vaccine is ongoing. A registry has been established for patients exposed to the Gardasil 9 HPV vaccine during pregnancy (1-800-986-8999).Monitoring ParametersScreening for HPV is not required prior to vaccination. Monitor for syncope and hypersensitivity for 15 minutes following administration (ACIP [Kroger 2021]). If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion. Continue recommended anal cancer screening.Females: Gynecologic screening exam, papillomavirus test; screening for cervical cancer should continue per current guidelines following vaccinationMechanism of ActionContains inactive human papillomavirus (HPV) proteins (types 6 L1,11 L1, 16 L1, 18 L1, 31 L1, 33 L1, 45 L1, 52 L1, and 58 L1) which produce neutralizing antibodies to prevent cervical, vulvar, vagin*l, and analcancers, cervical adenocarcinoma, cervical, vagin*l, vulvar, and anal neoplasia, and genital warts caused by HPV. Efficacy of HPV 9-valent vaccine against anogenital diseases related to the vaccine HPV types in humans is thought to be mediated by humoral immune responses induced by the vaccine, although the exact mechanism of protection is unknown.Brand Names: InternationalGardasil 9 (AT, AU, BE, CZ, DE, DK, EE, HK, HR, KR, LT, LV, MY, NL, NZ, PH, PL, PT, RO, SI, SK)For country code abbreviations (show table)Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77(4):593-597. [PubMed 3960626]American Academy of Pediatrics (AAP). In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018.American College of Obstetricians and Gynecologists' Committee on Adolescent Health Care, American College of Obstetricians and Gynecologists' Immunization, Infectious Disease, and Public Health Preparedness Expert Work Group. Human papillomavirus vaccination: ACOG committee opinion, number 809. Obstet Gynecol. 2020;136(2):e15-e21. doi:10.1097/AOG.0000000000004000 [PubMed 32732766]Centers for Disease Control (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm.Centers for Disease Control and Prevention (CDC). Vaccination guidance during a pandemic. Updated October 20, 2020. Available at https://www.cdc.gov/vaccines/pandemic-guidance/index.htmlChristianson MS, Wodi P, Talaat K, Halsey N. Primary ovarian insufficiency and human papilloma virus vaccines: a review of the current evidence. Am J Obstet Gynecol. 2020;222(3):239-244. doi:10.1016/j.ajog.2019.08.045 [PubMed 31479634]Cross GB, Moghaddas J, Buttery J, Ayoub S, Korman TM. Don't aim too high: avoiding shoulder injury related to vaccine administration. Aust Fam Physician. 2016;45(5):303-306. [PubMed 27166466]Einstein MH, Baron M, Levin MJ, et al; HPV-010 Study Group. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin. 2009;5(10):705-719. [PubMed 19684472]Foster SL, Davis MV. Vaccine administration: preventing serious shoulder injuries. J Am Pharm Assoc (2003). 2013;53(1):102-103. doi:10.1331/JAPhA.2013.13503 [PubMed 23636163]Gardasil 9 (human papilloma virus 9-valent vaccine) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; June 2020.Gardasil 9 (human papilloma virus 9-valent vaccine) [prescribing information]. Whitehouse Station, NJ: Merck & Co Inc; August 2021.Garolla A, De Toni L, Bottacin A, et al. Human papillomavirus prophylactic vaccination improves reproductive outcome in infertile patients with HPV sem*n infection: a retrospective study. Sci Rep. 2018;8(1):912. doi:10.1038/s41598-018-19369-z [PubMed 29343824]Isaksson M, Jansson L. Contact allergy to Tween 80 in an inhalation suspension. Contact Dermatitis. 2002;47(5):313. [PubMed 12534540]Kharbanda EO, Vazquez-Benitez G, DeSilva MB, et al. Association of inadvertent 9-valent human papillomavirus vaccine in pregnancy with spontaneous abortion and adverse birth outcomes. JAMA Netw Open. 2021;4(4):e214340. doi:10.1001/jamanetworkopen.2021.4340 [PubMed 33818618]Landazabal CS, Moro PL, Lewis P, Omer SB. Safety of 9-valent human papillomavirus vaccine administration among pregnant women: adverse event reports in the Vaccine Adverse Event Reporting System (VAERS), 2014-2017. Vaccine. 2019;37(9):1229-1234. doi:10.1016/j.vaccine.2018.11.077 [PubMed 30660400]Kroger A, Bahta L, Hunter P. General best practice guidelines for immunization: best practices guidance of the Advisory Committee on Immunization Practices (ACIP). https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. Accessed April 30, 2021.Lucente P, Iorizzo M, Pazzaglia M. Contact sensitivity to Tween 80 in a child. Contact Dermatitis. 2000;43(3):172. [PubMed 10985636]Markowitz LE, Dunne EF, Saraiya M, et al; Centers for Disease Control and Prevention (CDC). Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Recomm Rep. 2014;63(49):1182]. MMWR Recomm Rep. 2014;63(RR-05):1-30. [PubMed 25167164]McInerney KA, Hatch EE, Wesselink AK, et al. The effect of vaccination against human papillomavirus on fecundability. Paediatr Perinat Epidemiol. 2017;31(6):531-536. doi:10.1111/ppe.12408 [PubMed 28881394]Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination – updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2016;65(49):1405-1408. [PubMed 27977643]Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2019;68(32):698-702. doi: 10.15585/mmwr.mm6832a3. [PubMed 31415491]Pereira N, Kucharczyk KM, Estes JL, et al. Human papillomavirus infection, infertility, and assisted reproductive outcomes. J Pathog. 2015;2015:578423. doi:10.1155/2015/578423 [PubMed 26609434]Petrosky E, Bocchini JA Jr, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2015;64(11):300-304. [PubMed 25811679]Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44-e100. [PubMed 24311479]Saslow D, Andrews KS, Manassaram-Baptiste D, Smith RA, Fontham ETH; American Cancer Society Guideline Development Group. Human papillomavirus vaccination 2020 guideline update: American Cancer Society guideline adaptation. CA Cancer J Clin. 2020;70(4):274-280. doi:10.3322/caac.21616 [PubMed 32639044]Schmuhl NB, Mooney KE, Zhang X, Cooney LG, Conway JH, LoConte NK. No association between HPV vaccination and infertility in U.S. females 18-33 years old. Vaccine. 2020;38(24):4038-4043. doi:10.1016/j.vaccine.2020.03.035 [PubMed 32253100]Shelley WB, Talanin N, Shelley ED. Polysorbate 80 hypersensitivity. Lancet. 1995;345(8980):1312-1313. [PubMed 7746084]World Health Organization (WHO). Guiding principles for immunization activities during the COVID-19 pandemic: interim guidance, 26 March 2020. Published March 26, 2020. Available at https://apps.who.int/iris/handle/10665/331590Topic 101845 Version 108.0

CloseLevofloxacin (systemic): Drug informationLevofloxacin (systemic): Drug information(For additional information see "Levofloxacin (systemic): Patient drug information" and see "Levofloxacin (systemic): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningSerious adverse reactions:Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together, including tendinitis and tendon rupture, peripheral neuropathy, and CNS effects. Discontinue levofloxacin immediately and avoid the use of fluoroquinolones in patients who experience any of these serious adverse reactions. Because fluoroquinolones have been associated with serious adverse reactions, reserve levofloxacin for use in patients who have no alternative treatment options for the following indications: uncomplicated urinary tract infection, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis.Exacerbation of myasthenia gravis:Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Avoid levofloxacin in patients with a known history of myasthenia gravis.Brand Names: USLevaquin [DSC]Brand Names: CanadaACT Levofloxacin;APO-Levofloxacin;MINT-Levofloxacin;RIVA-Levofloxacin;SANDOZ Levofloxacin;TEVA-Levofloxacin [DSC]Pharmacologic CategoryAntibiotic, Fluoroquinolone;Antibiotic, Respiratory FluoroquinoloneDosing: AdultAnthraxAnthrax: Note: Consult public health officials for event-specific recommendations.Inhalational exposure (postexposure prophylaxis [PEP]) (alternative agent):Oral: 750 mg every 24 hours for 42 to 60 days.Note: Anthrax vaccine should also be administered to exposed individuals (Ref). Duration of therapy: If the PEP anthrax vaccine series is administered on schedule (for all regimens), antibiotics may be discontinued in immunocompetent adults aged 18 to 65 years at 42 days after initiation of vaccine or 2 weeks after the last dose of the vaccine (whichever comes last and not to exceed 60 days); if the vaccination series cannot be completed, antibiotics should continue for 60 days (Ref). In addition, adults with immunocompromising conditions or receiving immunosuppressive therapy, patients >65 years of age, and patients who are pregnant or breastfeeding should receive antibiotics for 60 days (Ref).Cutaneous (without systemic involvement), treatment (off-label use):Oral: 750 mg every 24 hours for 7 to 10 days after naturally acquired infection; treat for 60 days for bioterrorism-related cases. Note: Patients with cutaneous lesions of the head or neck or extensive edema should be treated for systemic involvement (Ref).Systemic (meningitis excluded), treatment (alternative agent) (off-label use):IV: 750 mg every 24 hours, in combination with other appropriate agents for 2 weeks or until clinically stable, whichever is longer (Ref).Meningitis, treatment (alternative agent) (off-label use):IV: 750 mg every 24 hours, in combination with other appropriate agents for 2 to 3 weeks or until clinically stable, whichever is longer (Ref).Note: Antitoxin should also be administered for patients with suspected systemic anthrax. Following the course of IV combination therapy for systemic anthrax infection (including meningitis), patients exposed to aerosolized spores require oral monotherapy to complete a total antimicrobial course of 60 days (Ref).Bite wound infection, prophylaxis or treatmentBite wound infection, prophylaxis or treatment (animal or human bite) (alternative agent) (off-label use):Oral, IV: 750 mg once daily, in combination with an agent appropriate for anaerobes. Duration of therapy is 3 to 5 days for prophylaxis (Ref); duration of treatment for established infection is typically 5 to 14 days and varies based on patient-specific factors, including clinical response (Ref).Chronic obstructive pulmonary disease, acute exacerbationChronic obstructive pulmonary disease, acute exacerbation: Note: Some experts reserve for outpatients with risk factors for poor outcomes (eg, ≥65 years of age, FEV1 <50% predicted, frequent exacerbations, significant comorbidities) or for inpatients without risk factors for Pseudomonas infection (Ref).Oral, IV: 500 mg once daily (Ref) for 5 to 7 days (Ref); use 750 mg once daily if P. aeruginosa is suspected (Ref).Diabetic foot infectionDiabetic foot infection (off-label use):Note: When used as empiric therapy, levofloxacin should be used in combination with other appropriate agents.Mild to moderate infection: Oral: 500 mg every 24 hours (750 mg every 24 hours if P. aeruginosa is suspected) (Ref).Moderate to severe infection (alternative agent): IV: 750 mg every 24 hours (Ref).Helicobacter pylori eradicationHelicobacter pylori eradication (salvage regimen) (off-label use):Note: Reserve use for levofloxacin susceptible isolates or if the population resistance rate is <15% (Ref).Levofloxacin triple regimen: Oral: Levofloxacin 500 mg once daily, in combination with amoxicillin 750 mg 3 times daily, plus a double-dose proton pump inhibitor twice daily; continue regimen for 14 days (Ref).Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failureIntra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure (off-label use):Note: Empiric oral regimens may be appropriate for patients with mild to moderate infection. Other patients may be switched from IV to oral therapy when clinically improved and able to tolerate an oral diet (Ref).Cholecystitis, acute: IV, Oral: 750 mg once daily (Ref); continue for 1 day after gallbladder removal or until clinical resolution in patients managed nonoperatively (Ref). Note: The addition of anaerobic therapy (eg, metronidazole) is recommended if biliary-enteric anastomosis is present (Ref).Other intra-abdominal infections (eg, perforated appendix, diverticulitis, intra-abdominal abscess): Note: For acute diverticulitis, some experts suggest deferring antibiotics in otherwise healthy patients who are immunocompetent with mild disease (Ref).IV, Oral: 750 mg once daily in combination with metronidazole. Total duration of therapy (which may include transition to oral antibiotics) is 4 to 5 days following adequate source control (Ref); for diverticulitis or uncomplicated appendicitis managed without intervention, duration is 10 to 14 days (Ref).Neutropenia, antibacterial prophylaxis in high-risk patients anticipated to have an ANC ≤100 cells/mm3 for >7 daysNeutropenia (chemotherapy-induced), antibacterial prophylaxis in high-risk patients anticipated to have an ANC ≤100 cells/mm3 for >7 days (off-label use): Oral: 500 or 750 mg once daily (Ref). Some clinicians will provide antibacterial prophylaxis if ANC is anticipated to be <500 cells/mm3 for >7 days (Ref). For hematopoietic cell transplant recipients, begin at the time of stem cell infusion and continue until recovery of neutropenia or until initiation of empiric antibiotic therapy for neutropenic fever (Ref).Odontogenic soft tissue infection, pyogenicOdontogenic soft tissue infection, pyogenic (alternative agent) (off-label use):Note: For patients unable to take beta-lactams (Chow 2022).IV, Oral: 750 mg once daily in combination with metronidazole; continue until clinical resolution, typically for 7 to 14 days. Use in addition to appropriate surgical management (eg, drainage and/or extraction) (Chow 2022).OsteomyelitisOsteomyelitis (off-label use):Oral, IV: 750 mg once daily for ≥6 weeks (Ref).PlaguePlague (Yersinia pestis): Note: Consult public health officials for event-specific recommendations:Treatment: Oral, IV: 750 mg every 24 hours for 7 to 14 days and for at least a few days after clinical resolution (Ref). For plague meningitis, use as part of an appropriate combination regimen (Ref).Postexposure prophylaxis: Oral: 500 to 750 mg once daily for 7 days; use 750 mg once daily in patients who are pregnant (Ref).PneumoniaPneumonia:Community-acquired pneumonia: Outpatients with comorbidities or inpatients:Note: Some experts reserve fluoroquinolones for patients who cannot take other preferred regimens (Ref).Oral, IV: 750 mg once daily. For inpatients with severe pneumonia or risk factors for methicillin-resistant Staphylococcus aureus, use as part of an appropriate combination regimen. Duration is for a minimum of 5 days; a longer course may be required for patients with an immunocompromising condition, severe or complicated infection, or for P. aeruginosa infection. Patients should be clinically stable with normal vital signs prior to discontinuation (Ref).Hospital-acquired or ventilator-associated pneumonia:Note: For empiric therapy, use in combination with other appropriate agents (Ref).Oral, IV: 750 mg every 24 hours. Duration of therapy varies based on disease severity and response to therapy; treatment is typically given for 7 days (Ref).ProstatitisProstatitis:Acute bacterial prostatitis (off-label use): Oral, IV: 500 mg once daily for 4 to 6 weeks (Ref).Chronic bacterial prostatitis: Oral: 500 mg once daily for 4 to 6 weeks (Ref).Prosthetic joint infectionProsthetic joint infection (off-label use): Treatment:Gram-negative bacilli: Oral, IV: 750 mg once daily (Ref).Staphylococcus aureus, oral continuation therapy (following pathogen-specific IV therapy in patients undergoing 1-stage exchange or debridement with retention of prosthesis): Oral: 500 to 750 mg once daily in combination with rifampin; duration is a minimum of 3 months, depending on patient-specific factors (Ref).Chronic suppressive therapy for gram-negative bacilli: Oral: 500 mg once daily (Ref).Rhinosinusitis, acute bacterialRhinosinusitis, acute bacterial (alternative agent):Note: In uncomplicated acute bacterial rhinosinusitis, initial observation and symptom management without antibiotic therapy is appropriate in most patients. Reserve antibiotic therapy for poor follow-up or lack of improvement over the observation period (Ref). Due to risks associated with use, reserve fluoroquinolones for those who have no alternative treatment options (Ref).Oral: 500 mg or 750 mg once daily for 5 to 7 days (Ref).Salmonella infectionSalmonella (nontyphoidal) infection (alternative agent):GI infection: Oral, IV: 500 mg once daily for 3 to 14 days (7 to 14 days in patients with HIV with a CD4 count ≥200 cells/mm3). Immunosuppressed patients (eg, patients with HIV and CD4 count <200 cells/mm3) require longer duration of treatment (eg, weeks to months) and may require a higher dose (eg, 750 mg once daily). Note: Reserve antibiotic treatment for patients with severe illness or at high risk of invasive disease (eg, extremes of age, immunosuppression); reserve parenteral therapy for those who cannot tolerate oral agents (Ref).Bacteremia: Oral, IV: 500 or 750 mg once daily for 14 days. Note: Immunosuppressed patients (eg, HIV-infected with CD4 count <200 cells/mm3) and those with an extraintestinal focus of infection warrant a longer duration of treatment (eg, weeks to months) (Ref).Sexually transmitted infectionsSexually transmitted infections:Cervicitis/urethritis due to Chlamydia trachomatis (alternative agent) (off-label use): Oral: 500 mg once daily for 7 days (Ref).Epididymitis, acute (off-label use):Patients ≥35 years of age and who are at low risk for sexually transmitted diseases (ie, likely caused by enteric organisms): Oral: 500 mg once daily for 10 days. Note: In patients <35 years of age or who are at risk of sexually transmitted diseases, fluoroquinolones are not recommended due to widespread resistance of N. gonorrhoeae to these agents (Ref).Males of any age who practice insertive anal sex (ie, likely caused by sexually transmitted Chlamydia trachomatis or N. gonorrhoeae, and enteric organisms): Oral: 500 mg once daily for 10 days, in combination with a single dose of ceftriaxone (Ref).Pelvic inflammatory disease, outpatient therapy, mild to moderate disease (alternative agent) (off-label use):Note: Reserve for patients who cannot use first-line options and are at low risk for fluoroquinolone-resistant N. gonorrhoeae (eg, prevalence is <5% in the location where the infection was acquired) (Ref).Oral: 500 mg once daily in combination with metronidazole for 14 days (Ref).Shigella GI infectionShigella GI infection (alternative agent) (off-label use): Note: Use only if ciprofloxacin MIC is <0.12 mcg/mL (Ref).Oral: 500 or 750 mg once daily for 3 days; the duration should be extended to 5 to 7 days for those with S. dysenteriae type 1 infection or HIV coinfection (Ref).Skin and skin structure infectionSkin and skin structure infection:Purulent cellulitis or abscess (for patients with or at risk for gram-negative infection): Oral, IV: 750 mg once daily in combination with other appropriate agents. Treat for 5 to 14 days depending on severity and clinical response. Note: Systemic antibiotics are only indicated for treatment of abscess in certain instances (eg, immunocompromised patients, signs of systemic infection, large or multiple abscesses, indwelling device, high risk for adverse outcome with endocarditis) (Ref).Surgical site incisional infection (off-label use):Intestinal or genitourinary tract surgery: IV: 750 mg every 24 hours in combination with metronidazole (Ref).Perineum or axilla surgery: Oral, IV: 750 mg every 24 hours in combination with metronidazole (Ref).Surgical prophylaxisSurgical (preoperative) prophylaxis (alternative agent) (off-label use):IV: 500 mg beginning 120 minutes prior to initial surgical incision; use in combination with other appropriate agents may be warranted (procedure dependent) (Ref). Note: Postoperative prophylaxis is not recommended for clean and clean-contaminated surgeries (Ref).Tuberculosis, drug-resistantTuberculosis, drug-resistant (off-label use):Oral, IV: 750 mg to 1 g once daily in combination with additional appropriate antituberculosis agents (Ref).Duration: Individualize based on rapidity of culture conversion, extent of disease, and patient-specific factors, including clinical response and toxicity (Ref).Urinary tract infectionUrinary tract infection: Cystitis, acute uncomplicated or acute simple cystitis (infection limited to the bladder without signs/symptoms of upper tract, prostate, or systemic infection) (alternative agent): Note: Use is discouraged due to safety concerns and increasing resistance; reserve for those who have no alternative treatment options (Ref). However, for men who have severe symptoms or concern for early prostate involvement, some experts prefer fluoroquinolones (Ref).Oral: 250 mg once daily for 3 days (females) (Ref) or 5 days (males) (Ref).Urinary tract infection, complicated, (including pyelonephritis): Note: If the prevalence of fluoroquinolone resistance is >10%, an initial dose of a long-acting parenteral antimicrobial (eg, ceftriaxone) followed by oral therapy is recommended for outpatients (Ref).Oral, IV: 750 mg once daily for 5 to 7 days (Ref).Missed dose: Administer as soon as possible if ≥8 hours until next scheduled dose; otherwise, wait until next scheduled dose.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThe renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.Altered kidney function: Oral, IV:Levofloxacin Dose Adjustments in Altered Kidney FunctionCrCl (mL/minute) If usual recommended dose is 250 mg every 24 hoursIf usual recommended dose is 500 mg every 24 hoursIf usual recommended dose is 750 mg every 24 hoursaaTreatment of tuberculosis: CrCl >30 mL/minute: No dosage adjustment necessary. CrCl <30 mL/minute or on hemodialysis/peritoneal dialysis: Administer 750 mg or 1 g 3 times per week (Ref). Patients receiving hemodialysis 3 times/week: Administer dose after hemodialysis on dialysis days. b Severe infections and GFRCKD-EPI >80 mL/minute/1.73 m2: Monte Carlo simulations suggest a dose of 500 mg every 12 hours may be necessary to obtain pharmacodynamic targets when minimum inhibitory concentration ≥0.5 mg/L (Ref).cWhen scheduled dose falls on a dialysis day, administer post dialysis (Ref).≥50No dosage adjustment necessaryNo dosage adjustment necessaryNo dosage adjustment necessaryb20 to <50No dosage adjustment necessary500 mg initial dose, then 250 mg every 24 hours750 mg every 48 hours<20250 mg every 48 hours (except for uncomplicated UTI, where no dosage adjustment is required)500 mg initial dose, then 250 mg every 48 hours750 mg initial dose, then 500 mg every 48 hoursHemodialysis, intermittent (thrice weekly)c: Dialyzable (21% [4-hour dialysis session utilizing high-flux dialyzers]) (Ref)250 mg every 48 hours (Ref)500 mg initial dose, then either 250 mg every 48 hours (Ref) or 125 mg every 24 hours (Ref) (if daily dosing improves adherence (Ref))750 mg initial dose, then either 500 mg every 48 hours (Ref) or 250 mg every 24 hours (if daily dosing improves adherence (Ref))Peritoneal dialysis250 mg every 48 hours (Ref)500 mg initial dose, then either 250 mg every 48 hours (Ref) or 125 mg every 24 hours (if daily dosing improves adherence [expert opinion derived from Kanamori 2001])750 mg initial dose, then either 500 mg every 48 hours (Ref) or 250 mg every 24 hours (if daily dosing improves adherence (Ref))Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2 ): Augmented renal clearance (ARC) is a condition that occurs in certain critically-ill patients without organ dysfunction and with normal serum creatinine concentrations. Young patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).Note: Dose based on expert opinion derived from Monte Carlo simulations only (Ref).Oral, IV: 750 mg loading dose followed by 500 mg every 12 hours or 1 g every 24 hours.CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations assume high-flux dialyzers and flow rates of ~1,500 to 3,000 mL/hour, and minimal residual kidney function unless otherwise noted. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.CVVH/CVVHD/CVVHDF: Oral, IV:Dose Adjustments in CRRT (CVVH/CVVHD/CVVHDF)If usual recommended dose is 250 mg every 24 hours If usual recommended dose is 500 mg every 24 hoursIf usual recommended dose is 750 mg every 24 hoursNo dosage adjustment necessary (Ref)500 mg initial dose, then 250 mg every 24 hours (Ref) or500 mg every 48 hours (Ref)750 mg initial dose, then 500 mg every 24 hours (Ref) or 750 mg every 48 hours (Ref)PIRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions due to drug accumulation is important.Oral, IV (dialysate flow rate 160 mL/minute, 8-hour session):Dose Adjustments in PIRRTIf usual recommended dose is 250 mg every 24 hours If usual recommended dose is 500 mg every 24 hoursIf usual recommended dose is 750 mg every 24 hoursNo dosage adjustment necessary (Ref)500 mg initial dose, then 250 mg every 24 hours (after PIRRT treatment when possible) (Ref)750 mg every 48 hours (after PIRRT treatment when possible) (Ref)Dosing: Hepatic Impairment: AdultIV, Oral: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). However, dosage adjustment unlikely due to limited hepatic metabolism.Dosing: Pediatric(For additional information see "Levofloxacin (systemic): Pediatric drug information")Note: Concentration of oral suspension may vary (commercially available or extemporaneous compounded); use caution. In pediatric patients, fluoroquinolones are not routinely first-line therapy, but after assessment of risks and benefits, can be considered a reasonable alternative for situations where no safe and effective substitute is available (eg, multidrug resistance) or in situations where the only alternative is parenteral therapy and levofloxacin offers an oral therapy option (Ref).General dosing, susceptible infection (Ref):Infants ≥6 months, Children, and Adolescents:6 months to <5 years: Oral, IV: 8 to 10 mg/kg/dose twice daily.≥5 years: Oral, IV: 10 mg/kg/dose once daily; maximum dose: 750 mg/day.AnthraxAnthrax: Limited data available in infants <6 months of age: Note: Levofloxacin is not preferred therapy for any prophylaxis or treatment regimens; use should be considered when patients are unable to tolerate first-line therapy (eg, ciprofloxacin or others depending upon disease presentation). Although longer durations of therapy are recommended in guidelines in some cases based on risk:benefit assessments (eg, up to 60 days), specific safety data for levofloxacin in pediatric patients is limited to 14 days (Ref).Infants, Children, and Adolescents:Cutaneous, without systemic involvement; treatment (Ref): Appropriate for all strains regardless of penicillin susceptibility or if susceptibility unknown. Treatment duration: 7 to 10 days for naturally-acquired infection, and up to 60 days for biological weapon-related event.<50 kg: Oral: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: Oral: 500 mg every 24 hours.Inhalational (postexposure prophylaxis) (Ref): Reserve levofloxacin use for penicillin-resistant strains or prior to susceptibility testing. Begin therapy as soon as possible after exposure.<50 kg: Oral (preferred), IV: 8 mg/kg/dose every 12 hours for 60 days; maximum dose: 250 mg/dose.≥50 kg: Oral (preferred), IV: 500 mg every 24 hours for 60 days.Systemic anthrax (excluding meningitis); treatment (Ref): Note: A fluoroquinolone is appropriate for all strains regardless of penicillin susceptibility or if susceptibility unknown; ciprofloxacin is preferred.Initial treatment: Use in combination with a protein synthesis inhibitor (eg, clindamycin); continue therapy for at least 14 days or longer until clinical criteria for stability are met.<50 kg: IV: 10 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: IV: 500 mg every 24 hours.Oral step-down therapy: Use in combination with a protein synthesis inhibitor (eg, clindamycin). Duration of therapy to complete treatment course is variable; some patients may require up to 60 days additional prophylaxis from onset of illness.<50 kg: Oral: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: Oral: 500 mg every 24 hours.Systemic anthrax; disseminated infection including meningitis (or when meningitis cannot be ruled out): Initial triple therapy: Use in combination with another bactericidal antimicrobial (beta-lactam or glycopeptide [depending on susceptibility]) and a protein synthesis inhibitor (eg, linezolid); continue therapy for at least 2 to 3 weeks or longer until clinical criteria for stability are met.<50 kg: IV: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: IV: 500 mg every 24 hours.Oral step-down therapy: Use in combination with a protein synthesis inhibitor (eg, clindamycin). Duration of therapy to complete treatment course is variable; some patients may require up to 60 days additional prophylaxis from onset of illness.<50 kg: Oral: 8 mg/kg/dose every 12 hours; maximum dose: 250 mg/dose.≥50 kg: Oral: 500 mg every 24 hour.Bacteremia prophylaxis in patients with acute myeloid leukemia or relapsed acute lymphocytic leukemiaBacteremia prophylaxis in patients with acute myeloid leukemia (AML) or relapsed acute lymphocytic leukemia (ALL): Note: Recommended only during period when patient is severely neutropenic (ie, when absolute neutrophil count [ANC] is <500 cells/mm3) (Ref).Infants ≥6 months and Children <5 years: Oral, IV: 10 mg/kg/dose every 12 hours (Ref).Children ≥5 years and Adolescents: Oral, IV: 10 mg/kg/dose every 24 hours; maximum dose: 750 mg/dose (Ref).Catheter; exit-site or tunnel infectionCatheter (peritoneal dialysis); exit-site or tunnel infection: Infants, Children, and Adolescents: Oral: 10 mg/kg/dose every 48 hours; maximum initial dose: 500 mg; maximum subsequent doses: 250 mg (Ref).Chlamydia trachomatis, urogenital infectionsChlamydia trachomatis, urogenital infections: Adolescents: Oral: 500 mg every 24 hours for 7 days (Ref).Cystic fibrosis pulmonary exacerbationCystic fibrosis pulmonary exacerbation: Limited data available (Ref):Infants ≥6 months, Children, and Adolescents:6 months to <5 years: Oral, IV: 10 mg/kg/dose twice daily.≥5 years: Oral, IV: 10 mg/kg/dose once daily; maximum dose: 750 mg/day.Epididymitis, nongonococcalEpididymitis, nongonococcal: Adolescents: Oral: 500 mg once daily for 10 days (Ref).Mycobacterium avium Complex, severe or disseminated disease, HIV-exposed/-infectedMycobacterium avium Complex, severe or disseminated disease, HIV-exposed/-infected: Adolescents: Oral: 500 mg once daily in combination with other antibiotics (Ref).Otitis media, acuteOtitis media, acute (AOM) (alternative agent): Limited data available: Note: Not recommended for routine empiric use; may be considered for patients with severe penicillin allergy, persistent or recurrent infection, or resistant causative bacteria (Ref).Infants ≥6 months and Children <5 years: Oral: 10 mg/kg/dose every 12 hours for 10 days (Ref).Children ≥5 years and Adolescents: Oral: 10 mg/kg/dose every 24 hours for 10 days; maximum dose: 750 mg/dose (Ref).Pelvic inflammatory diseasePelvic inflammatory disease: Adolescents: Oral: 500 mg once daily for 14 days with or without concomitant metronidazole; Note: Due to resistant organisms, the CDC recommends use as an alternative therapy only if standard parenteral cephalosporin therapy is not feasible and community prevalence, and individual risk of quinolone-resistant gonococcal organisms is low. Culture sensitivity must be confirmed (Ref).Plague, prophylaxis or treatmentPlague (Yersinia pestis), prophylaxis or treatment:Infants ≥6 months, Children, and Adolescents: Note: Begin therapy as soon as possible after exposure:<50 kg: Oral, IV: 8 mg/kg/dose every 12 hours for 10 to 14 days; maximum dose: 250 mg/dose.≥50 kg: Oral, IV: 500 mg every 24 hours for 10 to 14 days.Pneumonia, community-acquiredPneumonia, community-acquired (CAP) (Ref): Note: May consider addition of vancomycin or clindamycin to empiric therapy if community-acquired MRSA suspected. Levofloxacin is not the preferred agent for CAP but may be used as an alternative agent when necessary.Typical pathogens (eg, H. influenzae, S. pneumoniae): Note: Oral administration is generally reserved for mild infections or step-down therapy.Infants ≥6 months and Children <5 years: Oral, IV: 8 to 10 mg/kg/dose every 12 hours; maximum daily dose: 750 mg/day.Children ≥5 years and Adolescents ≤16 years: Oral, IV: 8 to 10 mg/kg/dose once every 24 hours; maximum daily dose: 750 mg/day.Atypical pathogens (eg, Mycoplasma pneumonia or Chlamydia ssp):IV:Infants ≥6 months and Children <5 years: IV: 8 to 10 mg/kg/dose every 12 hours; maximum daily dose: 750 mg/day.Children ≥5 years and Adolescents ≤16 years: IV: 8 to 10 mg/kg/dose once every 24 hours; maximum daily dose: 750 mg/day.Oral: Mild infection/step-down therapy: Adolescents with skeletal maturity: Oral: 500 mg once daily.Rhinosinusitis, acute bacterialRhinosinusitis, acute bacterial: Note: Recommended in the following types of patients: Type I penicillin allergy, after failure of initial therapy or in patients at risk for antibiotic resistance (eg, daycare attendance, age <2 years, recent hospitalization, antibiotic use within the past month) (Ref).Children and Adolescents: Oral, IV: 10 to 20 mg/kg/day divided every 12 to 24 hours for 10 to 14 days; maximum daily dose: 500 mg/day.Surgical prophylaxisSurgical prophylaxis: Children and Adolescents: IV: 10 mg/kg as a single dose 120 minutes prior to procedure; maximum dose: 500 mg/dose; Note: While fluoroquinolones have been associated with an increased risk of tendinopathy/tendon rupture in all ages, use of these agents for single-dose prophylaxis is generally safe (Ref).Tuberculosis, multidrug-resistantTuberculosis (TB), multidrug-resistant: Limited data available: Note: Use in combination with at least 3 to 4 additional anti-TB agents (overall multidrug regimen dependent upon susceptibility profile/patterns) (Ref):Infants, Children, and Adolescents: Oral: 15 to 20 mg/kg/dose once daily; usual maximum daily dose: 1,000 mg/day; higher doses (1,250 to 1,500 mg/day) have been reported in adults (Ref).Urethritis, nongonococcalUrethritis, nongonococcal: Adolescents: Oral: 500 mg every 24 hours for 7 days (Ref).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricInfants, Children, and Adolescents: IV, Oral: The following adjustments have been recommended (Ref). Note: Renally adjusted dose recommendations are based on doses of 5 to 10 mg/kg/dose every 12 hours in ages ≤5 years and 5 to 10 mg/kg/dose every 24 hours in ages >5 years.GFR ≥30 mL/minute/1.73 m2: No adjustment necessaryGFR 10 to 29 mL/minute/1.73 m2: 5 to 10 mg/kg/dose every 24 hoursGFR <10 mL/minute/1.73 m2: 5 to 10 mg/kg/dose every 48 hoursIntermittent hemodialysis: 5 to 10 mg/kg/dose every 48 hours; not removed by hemodialysis; supplemental levofloxacin doses are not requiredPeritoneal dialysis (PD): 5 to 10 mg/kg/dose every 48 hours; not removed by peritoneal dialysis; supplemental levofloxacin doses are not requiredContinuous renal replacement therapy (CRRT): 10 mg/kg/dose every 24 hoursDosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling; has not been studied; however, dosage adjustment unlikely to be necessary due to limited hepatic metabolism.Dosing: Older AdultRefer to adult dosing.Dosing: Obesity: AdultThe recommendations for dosing in patients with obesity are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.Class 1, 2, and 3 obesity (BMI ≥30 kg/m2):IV, Oral: No dosage adjustment necessary (Ref). Dose adjustments based on CrCl in patients with obesity remain the most important approach to ensuring patients receive optimal drug exposure. In patients with BMI ≥40 kg/m2 and CrCl >110 mL/minute, consider using therapeutic drug monitoring (if available) or alternative treatment options (Ref). Refer to adult dosing for indication-specific doses.Rationale for recommendations: Levofloxacin is predominantly eliminated by the kidneys and is the most hydrophilic of the quinolones. Although there are limited data on the pharmaco*kinetics of levofloxacin in patients with BMI ≥30 kg/m2, the data suggest CrCl (particularly measured by co*ckcroft-Gault equation) is the predominant patient factor guiding altered dosing (Ref). In one observational study in patients with BMI ≥40 kg/m2, levofloxacin AUC was not related to any body size metric; however, levofloxacin AUC was associated with CrCl (measured using co*ckcroft-Gault with ideal body weight). A dose of 750 mg may be unlikely to achieve target endpoints in patients with BMI ≥40 kg/m2 and CrCl >110 mL/minute, especially organisms with higher minimum inhibitory concentrations (eg, Pseudomonas sp.) (Ref). A small pharmaco*kinetic study and a separate case study found no clear effects of obesity on levofloxacin dosing requirements, suggesting that weight-based dosing is not required (Ref).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productSolution, Intravenous [preservative free]: Generic: 250 mg/50 mL (50 mL); 500 mg/100 mL (100 mL); 750 mg/150 mL (150 mL); 25 mg/mL (20 mL, 30 mL)Solution, Oral: Generic: 25 mg/mL (10 mL, 100 mL, 200 mL, 480 mL)Tablet, Oral: Levaquin: 500 mg [DSC], 750 mg [DSC]Generic: 250 mg, 500 mg, 750 mgGeneric Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution, Intravenous: Generic: 5 mg/mL (50 mL, 100 mL, 150 mL)Tablet, Oral: Generic: 250 mg, 500 mg, 750 mgMedication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Levaquin tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020634s073lbl.pdf#page=54Administration: AdultOral: Tablets may be administered without regard to meals. Oral solution should be administered at least 1 hour before or 2 hours after meals. Maintain adequate hydration of patient to prevent crystalluria. Administer at least 2 hours before or 2 hours after antacids containing magnesium or aluminum, sucralfate, metal cations (eg, iron), multivitamin preparations with zinc, or didanosine chewable/buffered tablets or the pediatric powder for solution.IV: Infuse 250 to 500 mg IV solution over 60 minutes; infuse 750 mg IV solution over 90 minutes. Too rapid of infusion can lead to hypotension. Avoid administration through an intravenous line with a solution containing multivalent cations (eg, magnesium, calcium). Maintain adequate hydration of patient to prevent crystalluria or cylindruria.Administration: PediatricOral: Maintain adequate hydration to prevent crystalluria or cylindruria. Administer at least 2 hours before or 2 hours after antacids containing magnesium or aluminum, sucralfate, metal cations (eg, iron), multivitamin preparations with zinc, or didanosine chewable/buffered tablets or the pediatric powder for solution.Tablets: May administer without regard to meals.Oral solution: Administer 1 hour before or 2 hours after meals.Missed dose: Administer as soon as possible if ≥8 hours until next scheduled dose; otherwise, wait until next scheduled dose.Parenteral: Administer by slow IV infusion over 60 to 90 minutes (250 to 500 mg over 60 minutes; 750 mg over 90 minutes); avoid rapid or bolus IV infusion due to risk of hypotension. Avoid administration through an intravenous line with a solution containing multivalent cations (eg, magnesium, calcium). Maintain adequate hydration to prevent crystalluria or cylindruria; not for IM, SubQ, or intrathecal administration.Use: Labeled IndicationsTreatment of community-acquired pneumonia, including multidrug-resistant strains of Streptococcus pneumoniae (MDRSP); nosocomial pneumonia; chronic obstructive pulmonary disease, acute exacerbation; rhinosinusitis, acute bacterial (ABRS); prostatitis (chronic bacterial); urinary tract infection (uncomplicated or complicated); acute pyelonephritis; skin or skin structure infections (uncomplicated or complicated); inhalational anthrax (postexposure) to reduce incidence or disease progression; prophylaxis and treatment of plague due to Yersinia pestisLimitations of use: Because fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions (eg, tendinopathy and tendon rupture, peripheral neuropathy, CNS effects), reserve levofloxacin for use in patients who have no alternative treatment options for acute exacerbation of chronic bronchitis, acute bacterial sinusitis, and uncomplicated urinary tract infections.Use: Off-Label: AdultAnthrax; Bite wound infection, prophylaxis or treatment (animal or human bite); Cervicitis or urethritis due to Chlamydia trachomatis infection; Diabetic foot infection; Epididymitis, acute; Helicobacter pylori eradication; Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure; Neutropenia (chemotherapy-induced), antibacterial prophylaxis; Odontogenic soft tissue infection, pyogenic; Osteomyelitis; Pelvic inflammatory disease; Prostatitis (acute bacterial); Prosthetic joint infection; Salmonella (nontyphoidal) infection; Shigella infection; Surgical (preoperative) prophylaxis; Surgical site incisional infection; TuberculosisMedication Safety IssuesSound-alike/look-alike issues:Levaquin may be confused with Levoxyl, Levsin/SL, LovenoxLevoFLOXacin may be confused with levETIRAcetam, levodopa, Levophed, levothyroxineInternational issues:Levaquin [Argentina, Brazil, US, Venezuela] may be confused with Lariam brand name for mefloquine [multiple international markets]Adverse Reactions (Significant): ConsiderationsAortic aneurysm/aortic dissectionFluoroquinolones have been associated with aortic aneurysm and aortic dissection with risk of aortic aneurysm higher than aortic dissection. Overall risk with levofloxacin may be higher than ciprofloxacin and moxifloxacin (Ref).Mechanism: Time-related; upregulation of matrix metalloproteinase (MMP) enzymes capable of damaging components of the extracellular matrix, including collagen and elastin (Ref). MMP-2 and MMP-9 have been shown to play a role in development of aneurysms via degradation of collagen fibril (Ref). May also have a direct effect on the viability of chondrocytes and tenocytes responsible for collagen synthesis, due to generation of reactive oxygen species, caspase activation, and apoptosis (Ref).Onset: Delayed in most cases. Studies evaluating risk generally evaluated the time period of 60 days after the initiation of fluoroquinolone therapy (Ref).Risk factors:• Older adults with peripheral vascular disease or a history of aneurysms, atherosclerosis, hypertension, or genetic conditions predisposing to aortic aneurysm (eg, Marfan syndrome, Ehlers-Danlos syndrome) (Ref)• Longer courses of therapy (>14 days) (Ref)• Severe emotional or physical stress has been correlated to the onset of pain (Ref)Arthropathy/arthralgiaArthropathy, or joint disease, has been observed in both animal and pediatric human studies following treatment with fluoroquinolone antibiotics, including levofloxacin (Ref). In a pooled safety data analysis of ~2,500 pediatric patients, musculoskeletal events including arthralgia were observed more frequently at 2 months and 12 months after treatment with levofloxacin than comparative treatment; no physical joint abnormalities were observed (Ref). Long-term follow-up (up to 5 years) of ~200 of the initial patients demonstrated no difference in musculoskeletal adverse events including ongoing arthropathy, between levofloxacin and comparator (Ref). Arthropathy and arthralgias appear to resolve after discontinuation of treatment with no long-term sequelae (Ref). Though the true incidence is unknown, arthropathy and arthralgia are considered to be infrequent, but potentially serious adverse reactions.Mechanism: Unknown; several hypotheses have been proposed including inhibition of mitochondria DNA synthesis in immature chondrocytes, direct toxic effect of fluoride on cartilage, magnesium chelation and subsequent deficiency in cartilage, and defective proteoglycan and procollagen synthesis with decreased incorporation of tritiated thymidine by chondrocytes (Ref).Onset: Varied; may occur within a day of initiation or months following discontinuation (Ref).Risk factors:• Higher doses (Ref)• Prolonged exposure (Ref)CNS effects/neuroexcitationFluoroquinolones have been associated with a range of psychiatric and neurologic effects, from dizziness and restlessness to toxic psychosis (Ref). More common reactions include confusion, agitation, insomnia, and drowsiness. More severe reactions, including delusions, hallucinations, suicidal ideation, suicidal tendencies, and toxic psychosis are less common (Ref). Neuroexcitation may include seizure in some patients (Ref).Mechanism: GABA binding disruption, NMDA binding alterations, and increased excitatory neurotransmitters (Ref). Mitochondrial dysfunction has been hypothesized to contribute (Ref).Onset: Varied; neuroexcitatory phenomena generally occur in the first week of therapy, often after 2 to 3 days (Ref).Risk factors:• Older adults (Ref)• Kidney impairment with unadjusted or higher doses (Ref)• Concurrent therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with enhanced neuroexcitation (less risk with levofloxacin) (Ref)• Concurrent theophylline (less risk with levofloxacin) (Ref)• History of seizures, seizure disorders, CNS disorders, or concurrent therapy with medications known to lower seizure threshold may increase risk of seizures (Ref)• History of or risk factor for mental illness (eg, depression)Clostridioides difficile infectionClostridioides difficile infection (CDI), including Clostridioides difficile associated diarrhea and Clostridioides difficile colitis, has been reported.Onset: Varied; may start on the first day of antibiotic therapy or up to 3 months postantibiotic (Ref).Risk factors:• Antibiotic exposure (highest risk factor) (Ref)• Type of antibiotic (fluroquinolones among the highest risk) (Ref)• Long durations in a hospital or other health care setting (recent or current) (Ref)• Older adults (Ref)• Immunocompromised conditions (Ref)• A serious underlying condition (Ref)• GI surgery/manipulation (Ref)• Antiulcer medications (eg, proton pump inhibitors and H2 blockers) (Ref)• Chemotherapy (Ref)Glucose regulation/dysglycemiaHyperglycemia and hypoglycemia have been associated with the use of fluoroquinolones, including levofloxacin.Mechanism: Increase in insulin release via blockade of adenosine triphosphate-sensitive potassium channels in the pancreatic beta cells, but the significance at clinical concentrations has been questioned (Ref). Additionally, effects on gluconeogenesis, glucose transport (via expression of GLUT-1), and mitochondrial dysfunction have been implicated (Ref).Onset: Varied; corresponds to the initiation of therapy but may be delayed by 2 to 3 days. Events requiring emergent care or hospitalization occurred between day 3 and day 10 of therapy (Ref).Risk factors:• Patients with diabetes are at highest risk; however, cases in patients without diabetes have been reported (Ref)• Concurrent therapy with hypoglycemic agents, including insulin (Ref)HepatotoxicityLiver injury/drug-induced liver injury: May cause liver injury (hepatotoxicity); both cholestatic and hepatocellular patterns are represented in reported clinical presentations (Ref). Published reports include at least 1 fatal case (Ref).Mechanism: Immunologic reactions account for many events; direct toxicity related to mitochondrial dysfunction and increased oxidative stress may also be responsible for some reactions (Ref).Onset: Varied; acute liver injury generally occurred within 14 days of initiation (most cases within 6 days) range of 1 to 39 days.Risk factors:• Most fatal events occurred in patients ≥65 years of ageHypersensitivity reactions (immediate and delayed)Hypersensitivity reactions include anaphylaxis, nonimmune anaphylaxis (previously called anaphylactoid reactions) (Ref) and delayed cutaneous reactions.Delayed cutaneous reactions include severe dermatologic reactions, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis (Ref). Less severe reactions include fixed drug eruption and bullous pemphigoid reactions (Ref).Immunologically mediated organ-specific reactions include pancreatitis, interstitial nephritis, hemolytic anemia, thrombocytopenia, and some cases of hepatitis (Ref).Mechanism: Nonimmune anaphylaxis results from binding directly to specific receptors (MGPRX2) on mast cells and basophils, causing direct stimulation of histamine release (and other mediators) (Ref). Importantly, these cases may occur without prior exposure. In other cases, anaphylaxis may be mediated by IgE, formed with prior exposure to the drug (Ref).Delayed reactions are mediated by activated T cells. Chemical activation of fluoroquinolones was not required for immune reactions to occur, which implies direct activation (pharmacologic interaction) without covalent binding to host proteins/hapten formation (Ref).Onset: Anaphylaxis (nonimmune and immune): Rapid; may occur within an hour of administration (Ref). Other reactions, particularly various maculopapular cutaneous reactions or organ-specific reactions: Varied; occur after days to weeks of therapy (Ref).Risk factors:• Nonimmune anaphylaxis may be dose and/or infusion rate related (concentration-related) (Ref).Myasthenia gravisFluoroquinolones, including levofloxacin, may cause an exacerbation of myasthenia gravis. Disease exacerbations vary in severity from muscular weakness to severe compromise (myasthenic crisis characterized by acute respiratory failure) (Ref).Mechanism: Neuromuscular blockade is the most frequently cited mechanism, although alterations in mitochondrial energy production has also been suggested as a contributing mechanism (Ref).Onset: Rapid; Within hours of the initiation of therapy with a fluoroquinolone (Ref).Risk factors:• Patients with myasthenia gravis (diagnosed and undiagnosed) (Ref).Peripheral neuropathyFluoroquinolones have been associated with peripheral neuropathy and other effects, including axonal neuropathy and Guillain-Barré syndrome (GBS) (Ref). Associated with many types of disturbances of special senses, including several case reports indicating a very slow recovery and/or permanent state of disability (Ref).Mechanism: Mitochondrial effects related to reactive oxygen species and apoptotic changes (Ref).Onset: Varied; may present as early as the first day of therapy (Ref).Risk factors:• Males (Ref)• Older adults (>60 years of age) (Ref)• Duration of therapy (Ref)• Type 1 diabetes may also be a risk factor (data are limited) (Ref)• History of peripheral neuropathyPhototoxicity/photoallergyPhototoxicity/skin photosensitivity account for a proportion of the overall cutaneous adverse reactions (Ref). Hyperpigmentation (brown-grey) in areas exposed to sunlight has also been reported with levofloxacin (Ref). Levofloxacin is considered a lower risk among the fluoroquinolone class (Ref).Mechanism: Non-dose-related; immunologic. Reactive intermediates are generated by ultraviolet exposure and attach to proteins of Langerhans cells, triggering immune reactions (Ref).Onset: Rapid; in a study with ofloxacin, occurred within 24 hours of initiation and sun exposure (Ref).Risk factors:• Duration and intensity of sun exposure• Cystic fibrosis (Ref)• Prior phototoxic reaction to another fluoroquinolone (Ref)QT prolongationFluoroquinolones may be associated with prolonged QT interval on ECG and ventricular arrhythmias, such as torsades de pointes (TdP). Levofloxacin may have a lower risk than other fluoroquinolones, particularly moxifloxacin (Ref). Change in QTc from baseline for moxifloxacin was found to be +16.34 to 17.83 ms, while the change with levofloxacin was +3.53 to 4.88 ms (Ref).Mechanism: May alter the rapid delayed rectifier potassium current, resulting in prolonged repolarization (Ref). Prolonged repolarization can alter action potentials in cardiac cells and promote arrhythmogenic activity (Ref).Onset: Varied; effect is concentration dependent, initially observed at supra-therapeutic doses (Ref). High dose or accumulation may influence timing/concentrations.Risk factors:Drug-induced QTc prolongation/ TdP (in general)• Females (Ref)• Age >65 years (Ref)• Structural heart disease (eg, history of myocardial infarction or heart failure) (Ref)• History of drug-induced TdP (Ref)• Genetic defects of cardiac ion channels (Ref)• Congenital long QT syndrome (Ref)• Baseline QT interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec (Ref)• Electrolyte disturbances (eg, hypocalcemia, hypokalemia, hypomagnesemia) (Ref)• Bradycardia (Ref)• Hepatic impairment (Ref)• Kidney impairment (Ref)• Loop diuretic use (Ref)• Sepsis (Ref)• Concurrent administration of multiple medications (≥ 2) that prolong the QT interval or increase drug interactions that increase serum drug concentrations of QT prolonging medications (Ref)Tendinopathy/tendon ruptureMay cause tendinopathy or rupture of tendon. Achilles is most commonly cited, but inflammation/rupture of many other tendons (including hand, rotator cuff, biceps, and thumb) has been reported (Ref).Mechanism: Dose and time-related; upregulation of MMPs capable of damaging components of the extracellular matrix, including collagen and elastin (Ref). Direct effect on the viability of chondrocytes and tenocytes responsible for collagen synthesis, due to generation of reactive oxygen species, and caspase activation and apoptosis (Ref).Onset: Varied; per the manufacturer's labeling, tendinopathy or tendon rupture may occur within hours or days of initiation or may be delayed for several months after discontinuation.Risk factors:• Age >60 years (Ref)• Corticosteroid therapy (Ref)• Kidney failure (Ref)• Diabetes mellitus (Ref)• Previous tendon disorders (eg, rheumatoid arthritis) (Ref)• Solid organ transplant recipients (Ref)• Strenuous physical activity (Ref)• Longer duration of therapy and higher dosages (Ref)Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.1% to 10%:Cardiovascular: Chest pain (1%), edema (1%)Dermatologic: Pruritus (1%), skin rash (2%)Gastrointestinal: Abdominal pain (2%), constipation (3%), diarrhea (5%), dyspepsia (2%), nausea (7%), vomiting (2%)Genitourinary: Vaginitis (1%)Infection: Candidiasis (1%)Local: Injection site reaction (1%)Nervous system: Dizziness (3%), headache (6%), insomnia (4%)Respiratory: Dyspnea (1%)<1%:Cardiovascular: Palpitations, phlebitis, syncope, ventricular arrhythmia, ventricular tachycardiaDermatologic: UrticariaEndocrine & metabolic: Hyperglycemia, hyperkalemia, hypoglycemiaGastrointestinal: Anorexia, Clostridioides difficile colitis, esophagitis, gastritis, gastroenteritis, glossitis, pancreatitis, stomatitisGenitourinary: Genital candidiasisHematologic & oncologic: Anemia, granulocytopenia, thrombocytopeniaNervous system: Abnormal dreams, abnormal gait, agitation, anxiety, confusion, depression, drowsiness, hallucination, hypertonia, nightmares, paresthesia, seizure, vertigoNeuromuscular & skeletal: Arthralgia, hyperkinetic muscle activity, myalgia, skeletal pain, tremorRenal: Acute kidney injuryRespiratory: EpistaxisPostmarketing:Cardiovascular: Aortic aneurysm (rare: <1%) (Meng 2018; Pasternak 2018), aortic dissection (rare: <1%) (Meng 2018; Pasternak 2018), hypersensitivity angiitis, hypotension, prolonged QT interval on ECG (rare: <1%) (Teng 2019), tachycardia (rare: <1%), torsades de pointes (rare: <1%) (Teng 2019), vasodilationDermatologic: Acute generalized exanthematous pustulosis, erythema multiforme, hyperpigmentation (rare: <1%) (Connors 2018), phototoxicity (rare: <1%), skin photosensitivity (rare: <1%), Stevens-Johnson syndrome, toxic epidermal necrolysisGastrointestinal: Ageusia, Clostridioides difficile associated diarrhea, dysgeusiaGenitourinary: Casts in urine, crystalluriaHematologic & oncologic: Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, increased INR, leukopenia, pancytopenia, prolonged prothrombin time, thrombotic thrombocytopenic purpuraHepatic: Hepatic failure, hepatotoxicity (idiosyncratic; rare: <1%) (Chalasani 2014; Gulen 2015; Schloss 2018)Hypersensitivity: Anaphylactic shock, anaphylaxis, angioedema, fixed drug eruption, nonimmune anaphylaxis, serum sicknessImmunologic: Drug reaction with eosinophilia and systemic symptoms (Charfi 2015)Nervous system: Abnormal electroencephalogram, altered sense of smell, anosmia, delirium, disorientation, disturbance in attention, encephalopathy (rare), exacerbation of myasthenia gravis, Guillain-Barre syndrome (rare: <1%) (Ali 2014), increased intracranial pressure, memory impairment, nervousness, paranoid ideation, peripheral neuropathy (rare: <1%; may be irreversible), psychosis, restlessness, suicidal ideation, suicidal tendencies, toxic psychosis, voice disorderNeuromuscular & skeletal: Muscular paralysis (musculospiral) (Pan 2017), rhabdomyolysis, rupture of tendon (less frequent: ≥1% to <4%) (van der Linden 2002), tendinopathy (less frequent: ≥1% to <4%) (van der Linden 2002)Ophthalmic: Blurred vision, decreased visual acuity, diplopia, scotoma, uveitisOtic: Hypoacusis, tinnitusRenal: Interstitial nephritisRespiratory: Bronchospasm, hypersensitivity pneumonitisMiscellaneous: Fever, multi-organ failureContraindicationsHypersensitivity to levofloxacin, any component of the formulation, or other quinolonesCanadian labeling: Additional contraindications (not in US labeling): History of tendinopathy or tendon rupture associated with use of any quinolone antimicrobial agentWarnings/PrecautionsConcerns related to adverse effects:• Superinfection: Prolonged use may result in fungal or bacterial superinfection.Disease-related concerns:• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required.Special populations:• Older adult: Adverse effects (eg, hepatotoxicity, tendon rupture, QT changes, aortic dissection) may be increased in the elderly.• G6PD deficiency: Hemolytic reactions may (rarely) occur with fluoroquinolone use in patients with G6PD deficiency (Luzzatto 2020).• Pediatric: Safety of use in pediatric patients for >14 days of therapy has not been studied; increased incidence of musculoskeletal disorders (eg, arthralgia, tendon rupture) has been observed in children.Dosage form specific issues:• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.Warnings: Additional Pediatric ConsiderationsIn pediatric patients, fluoroquinolones are not routinely first-line therapy, but after assessment of risks and benefits, can be considered a reasonable alternative for situations where no safe and effective substitute is available (eg, multidrug resistance) or in situations where the only alternative is parenteral therapy and levofloxacin offers an oral therapy option (AAP [Jackson 2016]).Concentration of oral suspension may vary (commercially available or extemporaneous compound); use caution. Some dosage forms may contain propylene glycol; in neonates, large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).Metabolism/Transport EffectsSubstrate of OAT1/3Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Agents with Blood Glucose Lowering Effects: Quinolones may enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use.Risk C: Monitor therapyAminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).Risk X: Avoid combinationAminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).Risk C: Monitor therapyAmiodarone: Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of Amiodarone.Risk X: Avoid combinationAmisulpride (Oral): May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk C: Monitor therapyAmphetamines: May enhance the cardiotoxic effect of Quinolones. Risk C: Monitor therapyAntacids: May decrease the absorption of Quinolones. Of concern only with oral administration of quinolones. Management: Avoid concurrent administration of quinolones and antacids to minimize the impact of this interaction. Recommendations for optimal dose separation vary by specific quinolone. Risk D: Consider therapy modificationBacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii.Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modificationBCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization).Risk C: Monitor therapyCalcium Salts: May decrease the absorption of Quinolones. Of concern only with oral administration of both agents. Management: Consider administering an oral quinolone at least 2 hours before or 6 hours after the dose of an oral calcium supplement to minimize this interaction. Monitor for decrease therapeutic effects of quinolones during coadministration. Risk D: Consider therapy modificationCholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine.Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combinationCorticosteroids (Systemic): May enhance the adverse/toxic effect of Quinolones. Specifically, the risk of tendonitis and tendon rupture may be increased. Risk C: Monitor therapyDabrafenib: QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of Dabrafenib.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyDelamanid: May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of Delamanid. Management: Avoid concomitant use of delamanid and quinolone antibiotics if possible. If coadministration is considered to be unavoidable, frequent monitoring of electrocardiograms throughout the full delamanid treatment period should occur. Risk D: Consider therapy modificationDidanosine: Quinolones may decrease the serum concentration of Didanosine. Didanosine may decrease the serum concentration of Quinolones.Management: Administer oral quinolones at least 2 hours before or 6 hours after didanosine. Monitor for decreased therapeutic effects of quinolones, particularly if doses cannot be separated as recommended. This does not apply to unbuffered enteric coated didanosine. Risk D: Consider therapy modificationDomperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationFluorouracil Products: QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of Fluorouracil Products.Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyHaloperidol: May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyHydroxychloroquine: May enhance the hyperglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the hypoglycemic effect of Levofloxacin-Containing Products (Systemic). Hydroxychloroquine may enhance the QTc-prolonging effect of Levofloxacin-Containing Products (Systemic). Risk C: Monitor therapyImmune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Risk C: Monitor therapyIron Preparations: May decrease the serum concentration of Quinolones. Management: Give oral quinolones at least several hours before (4 h for moxi- and sparfloxacin, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for lome-, 3 h for gemi-, and 2 h for enox-, levo-, nor-, oflox-, peflox, or nalidixic acid) oral iron. Risk D: Consider therapy modificationLactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol.Risk C: Monitor therapyLanthanum: May decrease the serum concentration of Quinolones. Management: Administer oral quinolone antibiotics at least one hour before or four hours after lanthanum. Risk D: Consider therapy modificationLevoketoconazole: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Levoketoconazole.Risk X: Avoid combinationMagnesium Salts: May decrease the serum concentration of Quinolones. Management: Administer oral quinolones several hours before (4 h for moxi/pe/spar/enox-, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for lome/pe/enox-, 3 h for gemi-, and 2 h for levo-, nor-, or ofloxacin or nalidixic acid) oral magnesium salts. Risk D: Consider therapy modificationMethadone: Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of Methadone.Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationMethoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic).Risk C: Monitor therapyMethylphenidate: May enhance the cardiotoxic effect of Quinolones. Risk C: Monitor therapyMultivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Quinolones. Specifically, polyvalent cations in multivitamin products may decrease the absorption of orally administered quinolone antibiotics. Management: Administer oral quinolones at least 2 hours before, or 6 hours after, the dose of a multivitamin that contains polyvalent cations (ie, calcium, iron, magnesium, selenium, zinc). Monitor for decreased quinolone efficacy. Risk D: Consider therapy modificationMultivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Quinolones. Specifically, minerals in the multivitamin/mineral product may impair absorption of quinolone antibiotics. Management: Administer oral quinolones at least 2 hours before, or 6 hours after, the dose of a multivitamin that contains polyvalent cations (ie, calcium, iron, magnesium, selenium, zinc). Monitor for decreased therapeutic effects of quinolones. Risk D: Consider therapy modificationMycophenolate: Quinolones may decrease the serum concentration of Mycophenolate. Specifically, quinolones may decrease concentrations of the active metabolite of mycophenolate.Risk C: Monitor therapyNadifloxacin: May enhance the adverse/toxic effect of Quinolones. Risk X: Avoid combinationNonsteroidal Anti-Inflammatory Agents: May enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolones. Risk C: Monitor therapyOndansetron: May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyPimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combinationPorfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer.Risk C: Monitor therapyProbenecid: May decrease the excretion of Quinolones. Specifically, probenecid may decreased the renal excretion of quinolone antibiotics. Probenecid may increase the serum concentration of Quinolones. Risk C: Monitor therapyQT-prolonging Antidepressants (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class IA Antiarrhythmics (Highest Risk): Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk).Risk X: Avoid combinationQT-prolonging Class IC Antiarrhythmics (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Class III Antiarrhythmics (Highest Risk): Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk).Risk X: Avoid combinationQT-Prolonging Inhalational Anesthetics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of Levofloxacin-Containing Products (Systemic). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Kinase Inhibitors (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Miscellaneous Agents (Highest Risk): Levofloxacin-Containing Products (Systemic) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk).Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of other QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapyQT-prolonging Strong CYP3A4 Inhibitors (Highest Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Highest Risk).Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: Consider therapy modificationQT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): QT-prolonging Quinolone Antibiotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapySertindole: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combinationSevelamer: May decrease the absorption of Quinolones. Management: Administer oral quinolones at least 2 hours before or 6 hours after sevelamer. Risk D: Consider therapy modificationSodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate.Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modificationStrontium Ranelate: May decrease the serum concentration of Quinolones. Management: In order to minimize any potential impact of strontium ranelate on quinolone antibiotic concentrations, it is recommended that strontium ranelate treatment be interrupted during quinolone therapy. Risk X: Avoid combinationSucralfate: May decrease the serum concentration of Quinolones. Management: Avoid concurrent administration of quinolones and sucralfate to minimize the impact of this interaction. Recommendations for optimal dose separation vary by specific quinolone. Risk D: Consider therapy modificationTacrolimus (Systemic): LevoFLOXacin (Systemic) may enhance the QTc-prolonging effect of Tacrolimus (Systemic). LevoFLOXacin (Systemic) may increase the serum concentration of Tacrolimus (Systemic).Risk C: Monitor therapyTyphoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected.Management: Avoid use of live attenuated typhoid vaccine (Ty21a)in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modificationVerteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin.Risk C: Monitor therapyVitamin K Antagonists (eg, warfarin): Quinolones may enhance the anticoagulant effect of Vitamin K Antagonists.Risk C: Monitor therapyZinc Salts: May decrease the serum concentration of Quinolones. Management: Give oral quinolones at several hours before (4 h for moxi- and sparfloxacin, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for lome-, 3 h for gemi-, and 2 h for enox-, levo-, nor-, pe- or ofloxacin or nalidixic acid) oral zinc salts. Risk D: Consider therapy modificationFood InteractionsAdministration with food prolonged time to peak by ~1 hour and decreased the peak concentration by ~14% and ~25% for the tablet and oral solution, respectively. Management: Tablet may be administered without regard to food; oral solution should be administered at least 1 hour before or 2 hours after food.Pregnancy ConsiderationsLevofloxacin crosses the placenta and can be detected in the amniotic fluid and cord blood (Ozyüncü 2010a; Ozyüncü 2010b).Based on available data, an increased risk of major birth defects, miscarriage, or other adverse fetal and maternal outcomes have not been observed following levofloxacin use during pregnancy (Acar 2019; Yefet 2018; Ziv 2018).Levofloxacin is an alternative agent for treatment of drug-resistant tuberculosis. Active tuberculosis infection is associated with adverse fetal outcomes, including intrauterine growth restriction, low birth weight, preterm birth, and perinatal death (Esmail 2018; Miele 2020), as well as adverse maternal outcomes, including increased risks for anemia and cesarean delivery. Placental transmission may rarely occur with active maternal disease (Miele 2020). Data are limited for use of second-line drugs in pregnancy (ie, fluroquinolones). Individualized regimens should be utilized to treat multidrug-resistant tuberculosis in pregnant patients; evidence to support a specific regimen is not available. Based on susceptibility testing, levofloxacin may be used to treat multidrug-resistant tuberculosis during pregnancy when needed (ATS/CDC/ERS/IDSA [Nahid 2019]; HHS [OI adult 2020]; WHO 2020).Levofloxacin is approved to reduce the incidence or disease progression of inhalational anthrax (postexposure). Untreated anthrax infection during pregnancy is associated with preterm labor, fetal distress, and fetal loss. However, levofloxacin is not the preferred fluoroquinolone for the prophylaxis or treatment of anthrax in pregnant and postpartum patients (Meaney-Delman 2014).Untreated plague (Yersinia pestis) infection in pregnant patients may result in hemorrhage (including postpartum hemorrhage), maternal and fetal death, preterm birth, and stillbirth. Limited data suggest maternal-fetal transmission of Y. pestis can occur if not treated. Pregnant patients should be treated for Y. pestis; parenteral antibiotics are preferred for initial treatment when otherwise appropriate. Levofloxacin is one of the fluoroquinolones recommended for use (in combination with an aminoglycoside) for treating pregnant patients with bubonic, pharyngeal, pneumonic, or septicemic plague. Recommendations for treating pregnant patients with plague meningitis are the same as in nonpregnant patients. Levofloxacin may also be used for pre- and postexposure prophylaxis in pregnant patients exposed to Y. pestis (CDC [Nelson 2021]).Antibiotics other than levofloxacin are recommended for the treatment of uncomplicated urinary tract infections and pyelonephritis during pregnancy (Betschart 2020).Breastfeeding ConsiderationsLevofloxacin is present in breast milk.Breast milk concentrations were measured in a woman receiving levofloxacin for treatment of a septic knee. Therapy was started as levofloxacin 500 mg/day IV for 9 days, followed by 14 days of oral therapy. A total of 26 breast milk samples were taken starting 10 days after the initiation of therapy and continuing after therapy was completed. During therapy, breast milk was expressed, but not fed to her preterm infant (27 weeks estimated gestation age). Steady-state peak milk concentration was 8.2 mcg/mL and occurred 5 hours after the dose. The half-life in the breast milk was approximately 7 hours, but small amounts were still detectable in the milk 65 hours after the last dose (Cahill 2005). Using a milk concentration of 8.2 mcg/mL, the estimated exposure to the breast-feeding infant would be 1.23 mg/kg/day (relative infant dose [RID] 6% based on a therapeutic infant dose of 20 mg/kg/day). In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).Levofloxacin may be considered for use in breastfeeding patients requiring antibiotics for inhalational anthrax (postexposure); according to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. However, patients with active cutaneous anthrax lesions on the breast should avoid direct infant contact; feeding from the affected breast should be avoided until 48 hours after the appropriate antibiotic therapy (Meaney-Delman 2014).For other indications, the manufacturer does not recommend use of levofloxacin in breastfeeding patients during therapy or for 2 days after the last levofloxacin dose due to concerns of potential serious adverse reactions; alternatively, lactating patients can pump and discard breast milk during therapy and for 2 days after the last levofloxacin dose. The risk of articular damage in breastfed infants exposed to other quinolones (ie, ciprofloxacin) is considered low even in children receiving high therapeutic doses. Therefore, some sources do not consider maternal use of these agents to be a reason to discontinue breastfeeding as long as the infant is monitored for GI symptoms (eg, diarrhea) that could occur following antibiotic exposure (Kaplan 2015). Other sources recommend avoiding quinolone antibiotics if alternative agents are available (WHO 2002).The risk for transmission of plague (Yersinia pestis) via breast milk is considered low. Patients with pneumonic plague can breastfeed if both the mother and infant are receiving antibiotic treatment or the infant is receiving postexposure prophylaxis, considering the risk of exposure to the drug via breast milk. If the infant is not being treated, breast milk should be expressed for at least 48 hours of maternal antibiotic therapy to limit person-to-person contact with the infant. The expressed breast milk may be given to the infant. Once maternal clinical improvement is observed, direct breastfeeding may resume (CDC [Nelson 2021]).In general, antibiotics that are present in breast milk may cause non–dose-related modification of bowel flora. Monitor infants for GI disturbances (WHO 2002).Dietary ConsiderationsTablets may be taken without regard to meals. Oral solution should be administered on an empty stomach (at least 1 hour before or 2 hours after a meal).Monitoring ParametersEvaluation of organ system functions (renal, hepatic, and hematopoietic) is recommended periodically during therapy; the possibility of crystalluria should be assessed; WBC and signs of infection, altered mental status, signs and symptoms of tendinopathy (tendon pain, swelling, inflammation, or rupture) or peripheral neuropathy; signs and symptoms of disordered glucose regulation (especially in patients with diabetes mellitus); rash; signs and symptoms of hypersensitivity reaction.Mechanism of ActionAs the S(-) enantiomer of the fluoroquinolone, ofloxacin, levofloxacin, inhibits DNA-gyrase in susceptible organisms thereby inhibits relaxation of supercoiled DNA and promotes breakage of DNA strands. DNA gyrase (topoisomerase II), is an essential bacterial enzyme that maintains the superhelical structure of DNA and is required for DNA replication and transcription, DNA repair, recombination, and transposition.Pharmaco*kineticsAbsorption: Rapid and complete; levofloxacin oral tablet and solution formulations are bioequivalent Distribution: Widely distributed in the body, including blister fluid, skin tissue, macrophages, prostate, and lung tissue; CSF concentrations ~15% of serum concentrations Vd: (Chien 2005):Infants ≥6 months, Children, and Adolescents ≤16 years: Mean range: 1.44 to 1.57 L/kg; reported values not statistically different between pediatric age subgroups; distribution not age-dependent Adults: 1.27 L/kg Protein binding: ~24% to 38%; primarily to albuminMetabolism: Minimally hepaticBioavailability: ~99%Half-life elimination:Infants ≥6 months and Children ≤5 years: ~4 hours (Chien 2005)Children 5 to 10 years: 4.8 hours (Chien 2005)Children 10 to 12 years: 5.4 hours (Chien 2005)Children 12 to 16 years: 6 hours (Chien 2005)Adults: ~6 to 8 hoursAdults, renal impairment: 27 ± 10 hours (CrCl 20 to 49 mL/minute); 35 ± 5 hours (CrCl <20 mL/minute)Time to peak, serum: Oral: 1 to 2 hoursExcretion: Urine (~87% as unchanged drug, <5% as metabolites); feces (<4%)Clearance: IV (Chien 2005): Infants and Children 6 months to 2 years: 0.35 ± 0.13 L/hour/kgChildren 2 to 5 years: 0.32 ± 0.08 L/hour/kgChildren 5 to 10 years: 0.25 ± 0.05 L/hour/kgChildren 10 to 12 years: 0.19 ± 0.05 L/hour/kgChildren 12 to 16 years: 0.18 ± 0.03 L/hour/kgAdults: 0.15 ± 0.02 L/hour/kgPharmaco*kinetics: Additional ConsiderationsRenal impairment: Cl is reduced and half-life prolonged in patients with CrCl less than 50 mL/minute.Anti-infective considerations:Parameters associated with efficacy:Concentration dependent, associated with AUC24/minimum inhibitory concentration (MIC), goal: >87 (90% positive predictive value for pathogen eradication) (Cojutti 2017; Drusano 2004); and Cmax (peak)/MIC, goal ≥12 (clinical and microbiologic cures) (Abdul-Aziz 2020; Preston 1998). Note: In critically ill patients, some experts recommend AUC24/MIC goal >125 to 250 (Abdul-Aziz 2020).Organism specific:S. pneumoniae: AUC24/MIC ≥30 (bactericidal) (Ambrose 2001; Garrison 2003; Lacy 1999; Lister 1999).Mycobacterium tuberculosis: AUC24/MIC ≥146 (bacteriostatic at 24 hours) (Deshpande 2018).Pseudomonas aeruginosa: AUC24/MIC ≥80 (bactericidal) (Griffith 2006).Expected drug exposure in patients with normal renal function:AUC:Adults (multiple dose): AUC24:500 mg daily: Oral: 47.5 ± 6.7 mg•hour/L; IV: 54.6 ± 11.1 mg•hour/L.750 mg daily: Oral: 90.7 ± 17.6 mg•hour/L; IV: 108 ± 34 mg•hour/L.Cmax (peak):Pediatric patients:7 mg/kg (single dose) (Chien 2005):Infants and children 6 months to <5 years of age: Oral: 4.21 to 4.56 mg/L; IV: 5.19 to 6.02 mg/L.Children and adolescents 5 to 16 years of age: Oral: 3.99 to 4.76 mg/L; IV: 6.12 to 7.3 mg/L.15 mg/kg daily (steady state) (Thee 2014):Infants and children <6 years of age: Oral: Median: 6.86 to 7 mg/L (interquartile range: 4.69 to 8.06 mg/L).Children 6 to 8 years of age: Oral: Median: 4.98 mg/L (interquartile range: 4.52 to 7.48 mg/L).Adults (multiple dose):500 mg daily: Oral: 5.7 ± 1.4 mg/L; IV: 6.4 ± 0.8 mg/L.750 mg daily: Oral: 8.6 ± 1.9 mg/L; IV: 12.1 ± 4.1 mg/L.Postantibiotic effect: Bacterial killing continues after levofloxacin concentration falls below the MIC of targeted pathogen and varies based on the organism; generally, 1 to 3 hours (Fu 1992; Houston 1994; Licata 1997; Spangler 1998).Pricing: USSolution (levoFLOXacin in D5W Intravenous)250 mg/50 mL (per mL): $0.04 - $0.18500 mg/100 mL (per mL): $0.03 - $0.15750 mg/150 mL (per mL): $0.02 - $0.10Solution (levoFLOXacin Intravenous)25 mg/mL (per mL): $2.20 - $2.24Solution (levoFLOXacin Oral)25 mg/mL (per mL): $1.40Tablets (levoFLOXacin Oral)250 mg (per each): $0.12 - $17.53500 mg (per each): $0.22 - $20.09750 mg (per each): $0.34 - $36.12Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAbiflox (UA);Adlox (IN);Amlevo (VN);Auxxil (CL, PY);Avoxin (JO);Axoflon (PH);Bacflocin (TW);Bioworld (EG);Bredelin (CR, DO, GT, HN, NI, PA, SV);Conlevo (EC);Corvox (ID);Cravit (CN, HK, ID, JP, MY, PK, SG, TH, TW, VN);Cravox (ID);Elequine (BB, BM, BS, EC, JM, NL, PR, SR, TT);Evocs-III (CR, DO, GT, HN, NI, PA, SV);Evolox (RO);Evoxil (MT);Exacinop (EG);Fenalex (CR, DO, GT, HN, NI, PA, SV);Flexid (HR);Floxacap (ID);Floxel (PH);Floxidin (ID);Floxium (UA);Fovelid (HR);Getzlox (VN);Glevo (ZW);Gravixin (TH);Hailon (CN);Kevork (EG);L-Stafloxin (VN);Lamiwin (TZ);Lecifex (VN);Lecrav (ID);Lectacin (VN);Leflodal (TW);Leflox (BD);Lefloxin (TH);Lefocin (KR);Lemed (HK);LEO (BD);Leroxacin (KR);Lesacin (KR);Levalox (HR);Levaquin (AR, BR, CO, PE);Levflox (PH);Levo (IL);Levobact (PH, UA);Levocin (ID, PH, TH);Levoflox (BH, QA, ZW);Levokacin (KR);Levomac (ET, ZW);Levomicin (KR);Levoquin (HK, PH);Levores (ID, MY);Levox (JO, LK, PH, ZW);Levoxa (MT);Levoxacin (IT);Levoxl (HK);Levunid (PE);Lexacin (HK);Lexlo (BD);Locikline (MY);Lovequin (ID);Loxamox (LB);Lquin (PH);Lufi (LK);LUFI-500 (SG);Matador (BH, LB);Mosardal (ID);Nexquin (TZ);Nirliv (TH);Nirlix (LK);Nofaxin (KR);Olfovel (TH);Omnivox (PH);Pneumocal (PH);Ponaris (PE);Prolecin (ID);Prolecin IV (ID);Quinomed L (AR);Qure (ET);Reskuin (ID);Resquin (LK);Rinvox (ID);Rozoxin (TW);Tavager (IE);Tavanic (AE, AR, AT, BE, BG, BH, BM, BS, CH, CL, CR, CY, CZ, DE, DO, EE, EG, ES, FI, FR, GB, GT, HN, IE, IL, JM, JO, KW, LB, LT, LU, MT, NI, NL, PA, PE, PL, PT, PY, QA, RO, SA, SE, SK, SV, VE);Truxa (EC, UY);Uniflox (BH);Uroflox (EC);Vocin (HK, TH);Voflox (TH);Volequin (ID);VoLox (ID);Voxatic (ID);Wilovex (PH);Xalecin (TH);Zenilev (ID);Zidalex (ID)For country code abbreviations (show table)Abdul-Aziz MH, Alffenaar JC, Bassetti M, et al; Infection Section of European Society of Intensive Care Medicine (ESICM); Pharmaco*kinetic/pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID); Infectious Diseases Group of International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT); Infections in the ICU and Sepsis Working Group of International Society of Antimicrobial Chemotherapy (ISAC). 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CloseLevalbuterol: Drug informationLevalbuterol: Drug information(For additional information see "Levalbuterol: Patient drug information" and see "Levalbuterol: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USXopenex;Xopenex Concentrate;Xopenex HFAPharmacologic CategoryBeta2 AgonistDosing: AdultNote: 1.25 mg of levalbuterol base is equivalent to 2.5 mg of albuterol (Lötvall 2001; NAEPP 2007). Nebulized therapy may be preferred for patients who cannot effectively use an inhaler (Lemanske 2021).Asthma, acute exacerbationAsthma, acute exacerbation: Mild to moderate exacerbations (initial home management): Note: Patients with worsening symptoms despite initial care should seek immediate medical attention (GINA 2022).Metered-dose inhaler (45 mcg/actuation): Oral inhalation: 2 to 4 inhalations with spacer every 20 minutes for 3 doses, then every 1 to 4 hours based on response and tolerability (Fanta 2021; Kirenga 2015; NAEPP 2007; Roy 2003).Nebulization solution: Oral inhalation: 1.25 mg every 20 minutes for 3 doses, then every 1 to 4 hours based on response and tolerability (Fanta 2021; GINA 2022; NAEPP 2007; NAEPP 2020).Moderate to severe exacerbations (management in primary or acute care settings): Note: For severe exacerbations, use in combination with an inhaled short-acting muscarinic antagonist and other adjunctive therapies. For patients who have more severe symptoms or who cannot effectively use an inhaler, nebulized therapy may be preferred (Fanta 2021).Metered-dose inhaler (45 mcg/actuation): Oral inhalation: Initial: 4 inhalations with spacer every 20 minutes for 3 doses, then taper based on response and tolerability (eg, to 2 to 4 inhalations every 1 to 4 hours as needed). If insufficient response, may increase to 6 or 8 inhalations/dose (Fanta 2021).Nebulization solution: Oral inhalation: 1.25 to 2.5 mg every 20 minutes for 3 doses, then every 1 to 4 hours as needed based on response and tolerability (Fanta 2021; GINA 2022; NAEPP 2007; NAEPP 2020).Asthma, intermittent symptom reliefAsthma, intermittent symptom relief (alternative agent): Note: Use on an as-needed basis (reliever therapy) rather than regularly scheduled (GINA 2022).Metered-dose inhaler (45 mcg/actuation): Oral inhalation: 2 inhalations with spacer every 4 to 6 hours as needed; in some patients, 1 inhalation every 4 hours as needed may be sufficient (maximum dose: 2 inhalations every 4 hours).Nebulization solution: Oral inhalation: Initial: 0.63 mg to 1.25 mg every 6 to 8 hours as needed, up to 3 doses per 24 hours (maximum dose: 1.25 mg 3 times daily) (Lemanske 2021; manufacturer's labeling).Chronic obstructive pulmonary diseaseChronic obstructive pulmonary disease:Acute exacerbation: Note: Optimal dosing not well defined. Adjust dose according to clinical symptom resolution and tolerability (GOLD 2021; Stoller 2021). Although similar efficacy exists among formulations, some experts prefer nebulized therapy during severe chronic obstructive pulmonary disease exacerbations (Stoller 2021). May combine with an inhaled short-acting muscarinic antagonist (GOLD 2021; Stoller 2021).Nebulization solution: Oral inhalation: 0.63 to 1.25 mg every 1 hour for 2 to 3 doses, then every 2 to 4 hours as needed (Stoller 2021).Metered-dose inhaler (45 mcg/actuation): Oral inhalation: 1 to 2 inhalations every 1 hour for 2 to 3 doses, then every 2 to 4 hours as needed; for patients requiring emergency department or hospital-based care, may increase to 4 inhalations every hour for 2 to 3 doses. For patients requiring mechanical ventilation, up to 8 inhalations may be used if needed (Stoller 2021).Intermittent symptom relief: Note: Use for intermittent symptoms on an as-needed basis rather than regularly scheduled. In patients who have moderate to severe symptoms or who are at high risk of exacerbation, one or more additional long-acting agents should be used for maintenance therapy. May be used in combination with an inhaled short-acting muscarinic antagonist (Ferguson 2021; GOLD 2021).Metered-dose inhaler (45 mcg/actuation): Oral inhalation: 2 inhalations every 4 to 6 hours as needed; in some patients, 1 inhalation every 4 to 6 hours may be sufficient (maximum dose: 2 inhalations every 4 hours).Nebulization solution: Oral inhalation: 0.63 mg 3 times daily at intervals of 6 to 8 hours as needed; dosage may be increased to 1.25 mg 3 times daily as needed with close monitoring for adverse effects (maximum dose: 1.25 mg 3 times daily) (Donohue 2006).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling. Use high doses with caution; drug clearance is decreased.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).Dosing: Pediatric(For additional information see "Levalbuterol: Pediatric drug information")AsthmaAsthma: Note: Scheduled daily levalbuterol use is not recommended for long-term maintenance treatment (GINA 2021; NAEPP 2007). Increasing use or regular use >2 days/week for symptom control (except prevention of exercise-induced bronchospasm) indicates inadequate control and need for additional long-term control therapy (NAEPP 2007; NAEPP 2020).Acute symptom relief: Note:For use as an as-needed reliever therapy for acute symptoms outside of an exacerbation; beta agonists should be used in combination with inhaled corticosteroids (ICS) for acute symptom relief in select patients ≥4 years of age; this may be accomplished by either administering as-needed albuterol immediately followed by ICS or using a combination ICS and formoterol inhaler (Bisgaard 2006; GINA 2021).Metered-dose inhaler: 45 mcg/actuation:Children ≥4 years and Adolescents: Oral inhalation: 2 inhalations every 4 to 6 hours as needed (NAEPP 2007); 1 inhalation every 4 hours may be sufficient in some patients; maximum dose: 2 inhalations every 4 hours (manufacturer's labeling).Nebulization: Limited data available in ages <6 years:Infants and Children ≤4 years: Oral inhalation: 0.31 to 1.25 mg every 4 to 6 hours as needed (NAEPP 2007).Children 5 to <12 years: Oral inhalation: 0.31 to 0.63 mg every 8 hours as needed (NAEPP 2007).Children ≥12 years and Adolescents: Oral inhalation: 0.63 to 1.25 mg every 6 to 8 hours as needed for up to 3 doses per 24 hours (NAEPP 2007; manufacturer's labeling).Acute exacerbation: Note:Use for progressively worsening asthma symptoms not responding to as-needed reliever therapy. Beta agonists are often used in conjunction with systemic glucocorticoids in patients with acute exacerbations.Home management: Note: Patients with severe symptoms or worsening symptoms despite initial care should seek immediate medical attention.Metered-dose inhaler: 45 mcg/actuation:Children ≥4 years and Adolescents: Oral inhalation: 2 to 4 inhalations every 20 minutes as needed for 2 to 3 doses; patients with more severe symptoms may require up to 6 inhalations/dose (NAEPP 2007); if initial response is good, lengthen dosing frequency and administer 2 to 6 inhalations every 3 to 4 hours for 24 to 48 hours (NAEPP 2007).Nebulization: Limited data available in ages <6 years:Infants and Children: Oral inhalation: Usual dose: 0.63 to 1.25 mg every 20 minutes for 3 doses if needed (Hardasmalani 2005; NAEPP 2007); if initial response is good, lengthen dosing frequency and administer 0.63 to 1.25 mg every 3 to 4 hours for 24 to 48 hours; reported range: 0.31 to 1.25 mg/dose (NAEPP 2007).Adolescents: Oral inhalation: Usual dose: 1.25 mg every 20 minutes for 3 doses if needed (Hardasmalani 2005; NAEPP 2007); if initial response is good, lengthen dosing frequency and administer 1.25 mg every 3 to 4 hours for 24 to 48 hours; reported range: 0.63 to 2.5 mg/dose (AAP [Shenoi 2020]; NAEPP 2007).Primary care/acute care management:Metered-dose inhaler: 45 mcg/actuation: Infants, Children, and Adolescents (limited data available in ages <4 years): Oral inhalation: 4 to 8 inhalations every 20 minutes for 3 doses, then every 1 to 4 hours (AAP [Shenoi 2020]; NAEPP 2007).Nebulization (AAP [Shenoi 2020]; NAEPP 2007): Note: Nebulization is preferred for patients who are unable to effectively use a metered-dose inhaler due to age, agitation, or severity of the exacerbation (NAEPP 2007). For severe exacerbations, addition of ipratropium may be considered if poor response to initial aggressive short-acting beta2-agonist (SABA) therapy in an acute care setting (ie, emergency department). Ipratropium has not been shown to provide further benefit (eg, after first 24 hours) once the patient is hospitalized (GINA 2021; NAEPP 2007).Infants and Children: 0.075 mg/kg/dose (minimum dose: 1.25 mg/dose; maximum dose: 2.5 mg/dose) every 20 minutes for 3 doses, then 0.075 to 0.15 mg/kg/dose (maximum dose: 5 mg/dose) every 1 to 4 hours as needed.Adolescents: 1.25 to 2.5 mg every 20 minutes for 3 doses, then 1.25 to 5 mg every 1 to 4 hours as needed.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling. Use high doses with caution; drug clearance is decreased.Dosing: Hepatic Impairment: PediatricThere are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Dosing: Older AdultRefer to adult dosing, starting with lowest dose; titrate cautiously. Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Aerosol, Inhalation, as tartrate [strength expressed as base]: Xopenex HFA: 45 mcg/actuation (15 g)Generic: 45 mcg/actuation (15 g)Nebulization Solution, Inhalation, as hydrochloride [strength expressed as base]: Generic: 0.31 mg/3 mL (3 mL); 0.63 mg/3 mL (3 mL); 1.25 mg/3 mL (3 mL); 1.25 mg/0.5 mL (1 ea, 30 ea)Nebulization Solution, Inhalation, as hydrochloride [strength expressed as base, preservative free]: Xopenex: 0.31 mg/3 mL (3 mL); 0.63 mg/3 mL (3 mL); 1.25 mg/3 mL (3 mL)Xopenex Concentrate: 1.25 mg/0.5 mL (1 ea, 30 ea)Generic: 0.31 mg/3 mL (3 mL); 0.63 mg/3 mL (3 mL); 1.25 mg/3 mL (3 mL); 1.25 mg/0.5 mL (1 ea, 30 ea)Generic Equivalent Available: USYesDosage Forms Considerations Xopenex HFA 15 g canisters contain 200 inhalations. Administration: AdultInhalation: For oral inhalation only.Metered-dose inhaler: Shake well before use, avoid spraying in the eyes. Prime with 4 test sprays prior to first use or if inhaler has not been used for more than 3 days. Clean actuator (mouthpiece) weekly with warm water and air dry thoroughly. A spacer device or valved holding chamber is recommended when using a metered-dose inhaler. Each inhaler contains 200 actuations, discard when the display window shows zero.Nebulization solution: Safety and efficacy were established when administered with the following nebulizers: PARI LC Jet, PARI LC Plus, as well as the following compressors: PARI Master, Dura-Neb 2000, and Dura-Neb 3000. Concentrated solution should be diluted prior to use. Compatibility with other medications (eg, budesonide, ipratropium) in nebulizer has been reported (Burchett 2010; Kamin 2014); also refer to institution-specific policies. Blow-by administration is not recommended, use a mask device if patient unable to hold mouthpiece in mouth for administration.Administration: PediatricOral inhalation: In children <4 years of age, a face mask with either the metered-dose inhaler or nebulizer is recommended (GINA 2021; NAEPP 2007).Metered-dose inhaler: Shake well before use. Prime the inhaler (before first use or if it has not been used for more than 3 days) by releasing 4 test sprays into the air away from the face. Use with a valved spacer in patients ≤5 years of age and spacer with a mask for patients <3 years of age or until proper technique is demonstrated (GINA 2021). Clean actuator (mouthpiece) at least weekly with warm water and air dry thoroughly. The dose indicator tells you how many doses are left; do not immerse cannister in water or use "float test" to determine number of inhalations left. When the indicator turns red and reads "20", the patient should contact the pharmacy for a refill. Discard inhaler when the dose indicator window displays "0".Nebulization: Dilution required for concentrated solution. Safety and efficacy were established when administered with the following nebulizers: PARI LC Jet, PARI LC Plus, as well as the following compressors: PARI Master, Dura-Neb 2000, and Dura-Neb 3000. Blow-by administration is not recommended, use a mask device if patient unable to hold mouthpiece in mouth for administration. Compatibility with other medications (eg, budesonide, ipratropium) in nebulizer has been reported (Burchett 2010; Kamin 2014); also refer to institution-specific policies.Use: Labeled IndicationsBronchospasm: Treatment or prevention of bronchospasm in patients with reversible obstructive airway disease (eg, asthma).Medication Safety IssuesSound-alike/look-alike issues: Xopenex may be confused with XanaxAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%:Central nervous system: Headache (children: 12%)Gastrointestinal: Vomiting (children: 11%)Infection: Viral infection (≤12%)Respiratory: Rhinitis (6% to 11%)>2% to 10%:Cardiovascular: Tachycardia (adolescents and adults: 3%)Central nervous system: Nervousness (adolescents and adults: 3% to 10%), dizziness (adolescents and adults: 3%), migraine (adolescents and adults: 3%), anxiety (adolescents and adults: ≤3%), pain (adolescents and adults: ≤3%)Dermatologic: Skin rash (children: 8%), urticaria (children: 3%)Gastrointestinal: Diarrhea (children: 2% to 6%; adolescents and adults: <2%), dyspepsia (adolescents and adults: ≤3%)Hematologic & oncologic: Lymphadenopathy (≤3%)Neuromuscular & skeletal: Tremor (adolescents and adults: ≤7%), leg cramps (adolescents and adults: ≤3%), weakness (children: 3%), myalgia (≤2%)Respiratory: Pharyngitis (7% to 10%), asthma (9%), cough (adolescents and adults: 4%), sinusitis (adolescents and adults: 4%), flu-like symptoms (adolescents and adults: ≤4%), bronchitis (children: 3%), nasal mucosa swelling (1% to 3%)Miscellaneous: Fever (children: 9%), accidental injury (children 5% to 9%; adolescents and adults: 3%)Frequency not defined:Endocrine & metabolic: Decreased serum potassium, increased heart rate, increased serum glucose, paradoxical bronchospasmHypersensitivity: Hypersensitivity reaction (including bronchospasm, oropharyngeal edema)<2%, postmarketing, and/or case reports: Acne vulgaris, anaphylaxis, angina pectoris, angioedema, atrial fibrillation, cardiac arrhythmia, chest pain, chills, constipation, conjunctivitis, dry throat, dysmenorrhea, dyspnea, ECG abnormality, epistaxis, extrasystoles, eye pruritus, gastroenteritis, gastroesophageal reflux disease, hematuria, hyperesthesia (hand), hypertension, hypokalemia, hypotension, insomnia, metabolic acidosis, nausea, otalgia, paresthesia, pulmonary disease, supraventricular cardiac arrhythmia, syncope, vertigo, voice disorder, vulvovagin*l candidiasis, xerostomiaContraindicationsHypersensitivity to levalbuterol, albuterol, or any component of the formulationWarnings/PrecautionsConcerns related to adverse effects:• Bronchospasm: Rarely, life-threatening paradoxical bronchospasm may occur with use of inhaled bronchodilating agents; this should be distinguished from inadequate response. Discontinue immediately and treat with an alternative therapy. Paradoxical bronchospasm is frequently associated with first use of a new canister or vial.• Hypersensitivity reactions: Immediate hypersensitivity reactions (urticaria, angioedema, rash, bronchospasm, anaphylaxis, oropharyngeal edema) have been reported.Disease-related concerns:• Cardiovascular disease: Use with caution in patients with cardiovascular disease (arrhythmia, coronary insufficiency, or hypertension); beta agonists may cause elevation in blood pressure and heart rate and result in CNS stimulation/excitation. Beta-2 agonists may also increase risk of arrhythmias and electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression.• Diabetes: Use with caution in patients with diabetes mellitus; beta2-agonists may increase serum glucose and aggravate ketoacidosis.• Hyperthyroidism: Use with caution in hyperthyroidism; may stimulate thyroid activity.• Hypokalemia: Use with caution in patients with hypokalemia; beta2-agonists may decrease serum potassium.• Renal impairment: Use with caution in patients with renal impairment; drug clearance is decreased.• Seizures: Use with caution in patients with seizure disorders; beta-agonists may result in CNS stimulation/excitation.Other warnings/precautions:• Appropriate use: Do not exceed recommended dose; serious adverse events, including fatalities, have been associated with excessive use of inhaled sympathomimetics.• Patient information: Patients must be instructed to seek medical attention in cases where acute symptoms are not relieved or a previous level of response is diminished. The need to increase frequency of use may indicate deterioration of asthma, and treatment must not be delayed. A spacer device or valved holding chamber is recommended when using a metered-dose inhaler.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Atomoxetine: May enhance the tachycardic effect of Beta2-Agonists. Risk C: Monitor therapyAtomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapyAtosiban: Beta2-Agonists may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea.Risk C: Monitor therapyBeta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Risk C: Monitor therapyBeta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Risk X: Avoid combinationCannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapyCocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Risk D: Consider therapy modificationDoxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline.Risk C: Monitor therapyGuanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapyHaloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol.Risk C: Monitor therapyKratom: May enhance the adverse/toxic effect of Sympathomimetics. Risk X: Avoid combinationLinezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid.Specific dose adjustment recommendations are not presently available. Risk D: Consider therapy modificationLoop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics.Risk C: Monitor therapyLoxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine.Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation.This does not apply to non-inhaled formulations of loxapine. Risk X: Avoid combinationMethacholine: Beta2-Agonists (Short-Acting) may diminish the therapeutic effect of Methacholine.Management: Hold short-acting beta2 agonists for 6 hours before methacholine use. Risk D: Consider therapy modificationMonoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapyOzanimod: May enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapyQT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk).Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapySolriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol.Risk C: Monitor therapySympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapyTedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapyTheophylline Derivatives: Beta2-Agonists may enhance the adverse/toxic effect of Theophylline Derivatives. Specifically, sympathomimetic effects may be increased. Theophylline Derivatives may enhance the hypokalemic effect of Beta2-Agonists.Risk C: Monitor therapyThiazide and Thiazide-Like Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics.Risk C: Monitor therapyTricyclic Antidepressants: May enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapyPregnancy ConsiderationsMaternal use of beta2 agonists is not associated with an increased risk of fetal malformations (GINA 2022).Uncontrolled asthma is associated with adverse events on pregnancy (increased risk of perinatal mortality, preeclampsia, preterm birth, low birth weight infants, cesarean delivery, and the development of gestational diabetes). Poorly controlled asthma or asthma exacerbations may have a greater fetal/maternal risk than what is associated with appropriately used asthma medications. Maternal treatment improves pregnancy outcomes by reducing the risk of some adverse events (eg, preterm birth and gestational diabetes) (ERS/TSANZ [Middleton 2019]; GINA 2022).Pregnant patients should be treated with a short-acting beta-2 agonist (SABA) for acute asthma exacerbations (GINA 2022). Maternal asthma symptoms should be monitored monthly (ERS/TSANZ [Middleton 2020], GINA 2022). If high doses of a SABA are required within 48 hours of delivery, monitoring of glucose concentrations in the newborn for 24 hours is recommended, especially in preterm infants (GINA 2022). Levalbuterol is not approved for the management of preterm labor.Data collection to monitor pregnancy and infant outcomes associated with asthma and the medications used to treat asthma in pregnancy is ongoing. Health care providers are encouraged to enroll exposed pregnant patients in the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS) (877-311-8972 or http://mothertobaby.org). Patients may also enroll themselves.Breastfeeding ConsiderationsIt is not known if levalbuterol is present in breast milk.According to the manufacturer, the decision to breastfeed during therapy should consider the risk of exposure to the infant, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.Monitoring ParametersAsthma symptoms; FEV1, peak flow, and/or other pulmonary function tests; heart rate, blood pressure, CNS stimulation; arterial blood gases (if condition warrants); serum potassium, serum glucose (in selected patients)Mechanism of ActionRelaxes bronchial smooth muscle by action on beta2-receptors with little effect on heart ratePharmaco*kineticsOnset of action (as measured by a 15% increase in FEV1):Metered-dose inhaler: 5.5 to 10.2 minutes; Peak effect: 76 to 78 minutesNebulization solution: 10 to 17 minutes; Peak effect: 1.5 hoursDuration (as measured by a 15% increase in FEV1):Metered-dose inhaler: 3 to 4 hours (up to 6 hours in some patients)Nebulization solution: 5 to 6 hours (up to 8 hours in some patients)Absorption: A portion of inhaled dose is absorbed to systemic circulationMetabolism: Metabolized primarily in the gastrointestinal tract via SULT1A3 (sulfotransferase)Half-life elimination: 3.3 to 4 hoursTime to peak, serum: Nebulization solution: Children: 0.3 to 0.6 hours, Adults: 0.2 hoursExcretion: Urine (80% to 100%), feces (<20%)Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: Racemic albuterol clearance decreased by 67% in patients with creatinine clearance of 7 to 53 mL/minute.Pricing: USAerosol (Levalbuterol Tartrate Inhalation)45 mcg/ACT (per gram): $4.91Aerosol (Xopenex HFA Inhalation)45 mcg/ACT (per gram): $5.46Nebulization (Levalbuterol HCl Inhalation)0.31 mg/3 mL (per mL): $0.67 - $2.240.63 mg/3 mL (per mL): $0.67 - $2.241.25 mg/0.5 mL (per each): $6.701.25 mg/3 mL (per mL): $0.67 - $2.24Nebulization (Xopenex Concentrate Inhalation)1.25 mg/0.5 mL (per each): $8.54Nebulization (Xopenex Inhalation)0.31 mg/3 mL (per mL): $3.960.63 mg/3 mL (per mL): $3.961.25 mg/3 mL (per mL): $3.96Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalInhawell (TR);Lebusal (TR);Levalin (TR);Levodose (TR);Levolin (IN);Seramar (CO);Ventoplus (AR)For country code abbreviations (show table)Bisgaard H, Le Roux P, Bjåmer D, Dymek A, Vermeulen JH, Hultquist C. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest. 2006;130(6):1733-1743. doi:10.1378/chest.130.6.1733 [PubMed 17166990]Burchett DK, Darko W, Zahra J, Noviasky J, Probst L, Smith A. Mixing and compatibility guide for commonly used aerosolized medications. Am J Health Syst Pharm. 2010;67(3):227-230. doi:10.2146/ajhp080261 [PubMed 20101066]Donohue JF, Parsey MV, Andrews C, et al; Levalbuterol COPD Study Group. Evaluation of the efficacy and safety of levalbuterol in subjects with COPD. COPD. 2006;3(3):125-132. doi:10.1080/15412550600829190 [PubMed 17240614]Fanta CH, Cahill KN. Acute exacerbations of asthma in adults: emergency department and inpatient management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 8, 2021.Ferguson GT. Stable COPD: initial pharmacologic management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 22, 2021.Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. https://ginasthma.org/wp-content/uploads/2021/05/GINA-Main-Report-2021-V2-WMS.pdf. Updated 2021. Accessed December 8, 2021.Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdf. Updated 2022. Accessed September 2, 2022.Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2021 global strategy for prevention, diagnosis, and management of COPD. https://goldcopd.org/2021-gold-reports. Accessed October 22, 2021.Hardasmalani MD, DeBari V, Bithoney WG, Gold N. Levalbuterol versus racemic albuterol in the treatment of acute exacerbation of asthma in children. Pediatr Emerg Care. 2005;21(7):415-419. doi:10.1097/01.pec.0000169433.91196.6a [PubMed 16027572]Kamin W, Erdnüss F, Krämer I. Inhalation solutions--which ones may be mixed? Physico-chemical compatibility of drug solutions in nebulizers--update 2013. J Cyst Fibros. 2014;13(3):243-250. doi:10.1016/j.jcf.2013.09.006 [PubMed 24172851]Kirenga BJ, Schwartz JI, de Jong C, van der Molen T, Okot-Nwang M. Guidance on the diagnosis and management of asthma among adults in resource limited settings. Afr Health Sci. 2015;15(4):1189-1199. doi:10.4314/ahs.v15i4.18 [PubMed 26958020]Lemanske RF, Schauberger E. Beta agonists in asthma: acute administration and prophylactic use. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 31, 2021.Lötvall J, Palmqvist M, Arvidsson P, Maloney A, Ventresca GP, Ward J. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol. 2001;108(5):726-731. doi:10.1067/mai.2001.119152 [PubMed 11692096]Mhanna MJ, Patel JS, Patel S, et al. The Effects of Racemic Albuterol Versus Levalbuterol in Very Low Birth Weight Infants. Pediatr Pulmonol. 2009;44(8):778-783. [PubMed 19598281]Middleton PG, Gade EJ, Aguilera C, et al. ERS/TSANZ Task Force Statement on the management of reproduction and pregnancy in women with airways diseases. Eur Respir J. 2020;55(2):1901208. doi:10.1183/13993003.01208-2019 [PubMed 31699837]Milgrom H, Skoner DP, Bensch G, et al. Low-Dose Levalbuterol in Children With Asthma: Safety and Efficacy in Comparison With Placebo and Racemic Albuterol. J Allergy Clin Immunol. 2001;108(6):938-945. [PubMed 11742271]National Asthma Education and Prevention Program (NAEPP); National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthgdln_1.pdf. Published 2007.National Asthma Education and Prevention Program (NAEPP); National Heart, Lung, and Blood Institute. 2020 focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/2020-focused-updates-asthma-management-guidelines. Published December 2020.Roy SR, Milgrom H. Managing outpatient asthma exacerbations. Curr Allergy Asthma Rep. 2003;3(2):179-189. doi:10.1007/s11882-003-0032-7 [PubMed 12562559]Shenoi RP, Timm N; Committee on Drugs; Committee on Pediatric Emergency Medicine. Drugs used to treat pediatric emergencies. Pediatrics. 2020;145(1):e20193450. [PubMed 31871244]Stoller JK. COPD exacerbations: management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 22, 2021.Xopenex (levalbuterol) [prescribing information]. Lake Forest, IL: Akorn; January 2019.Xopenex HFA (levalbuterol) [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals Inc; February 2017.Xopenex inhalation solution concentrate (levalbuterol) [prescribing information]. Lake Forest, IL: Akorn Inc; January 2019.Topic 10215 Version 341.0

ClosePolysaccharide-iron complex: Drug informationPolysaccharide-iron complex: Drug information(For additional information see "Polysaccharide-iron complex: Patient drug information" and see "Polysaccharide-iron complex: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)Brand Names: USEZFE 200 [OTC];Ferrex 150 [OTC];Ferric x-150 [OTC];IFerex 150 [OTC];Myferon 150 [OTC] [DSC];NovaFerrum 50 [OTC] [DSC];NovaFerrum Pediatric Drops [OTC];NovaFerrum [OTC];Nu-Iron [OTC];Poly-Iron 150 [OTC]Pharmacologic CategoryIron PreparationsDosing: AdultNote: Dosage expression: Dose is expressed in terms of elemental iron; the strength of each capsule or concentration of liquid represents the amount of elemental iron (eg, a 150 mg capsule contains 150 mg of elemental iron). Formulation: Enteric-coated and slow/sustained-release preparations are generally not preferred due to poor absorption (Hershko 2014; Liu 2012). Route of administration: IV iron replacement is preferred over oral replacement in several clinical situations (eg, poor GI absorption, lack of response to or poor tolerability of oral iron, chronic kidney disease, active inflammatory bowel disease, cancer, chronic or extensive blood loss) (Auerbach 2021).Iron deficiency or iron deficiency anemiaIron deficiency or iron deficiency anemia: Oral: 50 to 200 mg of elemental iron (1 tablet or equivalent as liquid) once every other day or on Monday, Wednesday, and Friday (Liu 2012; Stoffel 2017; Stoffel 2020; Stoltzfus 1998; WHO 2001). Note: Daily dosing has been shown to result in decreased absorption but may be reasonable in some individuals to improve adherence (Auerbach 2021; Stoffel 2017; Stoffel 2020).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosing adjustments provided in the manufacturer’s labeling.Dosing: Hepatic Impairment: AdultThere are no dosing adjustments provided in the manufacturer’s labeling.Dosing: Pediatric(For additional information see "Polysaccharide-iron complex: Pediatric drug information")Note: Multiple concentrations of polysaccharide iron complex oral liquid exist; close attention must be paid to the concentration when ordering and administering polysaccharide iron complex; incorrect selection or substitution of one polysaccharide iron complex liquid for another without proper dosage volume adjustment may result in serious over- or underdosing.Note: Dosages are expressed in terms of elemental iron.Dietary supplementationDietary supplementation: Note: Refer to product-specific labeling for approved pediatric ages.Infants and Children <12 years: Oral liquid: Oral: 15 mg elemental iron daily.Children ≥12 years and Adolescents: Oral: 50 mg elemental iron daily.Iron deficiency anemia, preventionIron deficiency anemia, prevention: AAP recommendations: Infants ≥4 months (exclusively fed human milk or human milk provides >50% of nutrition without iron fortified food): Oral: 1 mg elemental iron/kg/day; supplementation should be continued until sufficient iron is provided in complementary foods (AAP [Baker 2010]).WHO recommendations:Areas where anemia prevalence is ≥40%:Infants ≥6 months and Children <2 years: Oral: 10 to 12.5 mg elemental iron daily for 3 consecutive months in a year (WHO 2016b).Children 2 to <5 years: Oral: 30 mg elemental iron daily for 3 consecutive months in a year (WHO 2016b).Children ≥5 to 12 years: Oral: 30 to 60 mg elemental iron daily for 3 consecutive months in a year (WHO 2016b).Adolescent menstruating patients (nonpregnant patients of reproductive potential): Oral: 30 to 60 mg elemental iron daily for 3 consecutive months in a year (WHO 2016a).Areas where anemia prevalence 20% to <40%: Weekly intermittent dosing:Children 2 to <5 years: Oral: 25 mg elemental iron once weekly for 3 consecutive months, then alternating 3 months off supplementation, 3 months on supplementation (WHO 2011).Children 5 to 12 years: Oral: 45 mg elemental iron once weekly for 3 consecutive months, then alternating 3 months off supplementation, 3 months on supplementation (WHO 2011).Iron deficiency anemia, treatmentIron deficiency anemia, treatment: Infants, Children, and Adolescents: Oral: Initial: 3 mg elemental iron/kg/day as a single daily dose (Kazal 2002; Oski 1993; Powers 2017; Reeves 1985) up to 60 to 120 mg elemental iron once daily (AAP [Kleinman 2019]); higher doses may be needed in select patients; dosage range: 3 to 6 mg elemental iron/kg/day in 1 to 3 divided doses; usual maximum daily dose: 150 to 200 mg elemental iron/day (ASPEN [Corkins 2015]; Kliegman 2020; Zlotkin 2001); once-daily administration may be preferred for ease of administration and adherence (Zlotkin 2001). Studies in iron-depleted adults suggest that iron absorption may be improved by less frequent dosing (alternate-day dosing, or once daily versus multiple daily doses) (Moretti 2015; Stoffel 2017).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no dosing adjustments provided in the manufacturer's labeling.Dosing: Hepatic Impairment: PediatricThere are no dosing adjustments provided in the manufacturer's labeling.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productCapsule, Oral: EZFE 200: 200 mg [non-toxic; contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]Ferrex 150: 150 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c red #40(allura red ac)aluminum lake, fd&c yellow #5 (tartrazine)aluminum lake]Ferric x-150: 150 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #5 (tartrazine)]IFerex 150: 150 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]Myferon 150: 150 mg [DSC]NovaFerrum 50: 50 mg [DSC]Nu-Iron: 150 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]Poly-Iron 150: 150 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c red #40(allura red ac)aluminum lake, fd&c yellow #5 (tartrazine)aluminum lake]Generic: 150 mgLiquid, Oral: NovaFerrum: Polysaccharide-iron complex 125 mg and cholecalciferol 100 units per 5 mL (180 mL) [contains sodium benzoate]NovaFerrum Pediatric Drops: 15 mg/mL (120 mL) [alcohol free, dye free, gluten free, lactose free, sodium free, sugar free; contains sodium benzoate; raspberry-grape flavor]Generic Equivalent Available: USMay be product dependentAdministration: AdultOral: Shake liquid well prior to administration.Administration: PediatricOral: Administer with water or juice prior to breakfast and/or between meals for maximum absorption (Kliegman 2020; Oski 1993); may administer with food if GI upset occurs; do not administer with milk or milk products (Powers 2017). Shake liquid well prior to administration.Use: Labeled IndicationsIron deficiency or iron-deficiency anemia: Management (prevention and treatment) of iron-deficiency anemia.Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.>10%: Gastrointestinal: Constipation, darkening of stools, epigastric pain, gastrointestinal irritation, nausea, stomach cramps, vomiting1% to 10%:Gastrointestinal: Dental discoloration, diarrhea, heartburnGenitourinary: Urine discoloration<1%, postmarketing, and/or case reports: Local irritationContraindicationsKnown hypersensitivity to polysaccharide-iron complex or any component of the formulations; hemochromatosis; hemosiderosisDocumentation of allergenic cross-reactivity for other iron-containing products is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.Warnings/PrecautionsConcerns related to adverse effects:• Stool discoloration: Oral iron preparations commonly cause dark or black stools; patients should be informed of the effect.Special populations:• Pediatric: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age. Keep this product out of the reach of children. In case of accidental overdose call the poison control center immediately.Dosage form specific issues: • Oral iron formulations: Immediate-release oral iron products are preferred for treatment of iron deficiency anemia; enteric-coated and slow-/sustained-release preparations are not desired due to poor absorption (Hershko 2014; Liu 2012).• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions and intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.• Excipient: Some formulations may contain tartrazine, which is associated with allergic-type reactions. Although rare, hypersensitivity is more frequently seen in individuals with aspirin allergy.Other warnings/precautions:• Appropriate use: Investigate type of anemia and potential underlying causes (eg, recurrent blood loss) prior to initiating iron supplementation.Warnings: Additional Pediatric ConsiderationsConsider all iron sources when evaluating the dose of iron, including combination products, infant formulas, and liquid nutritional supplements.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Alpha-Lipoic Acid: Iron Preparations may decrease the absorption of Alpha-Lipoic Acid. Alpha-Lipoic Acid may decrease the absorption of Iron Preparations.Management: Separate administration of alpha-lipoic acid from that of any iron-containing compounds by several hours. If alpha-lipoic acid is given 30 minutes before breakfast, then administer oral iron-containing products at lunch or dinner. Risk D: Consider therapy modificationAntacids: May decrease the absorption of Iron Preparations. Management: No action is likely necessary for the majority of patients who only use antacids intermittently or occasionally. Consider separating doses of oral iron and antacids in patients who require chronic use of both agents and monitor for reduced iron efficacy. Risk D: Consider therapy modificationBaloxavir Marboxil: Polyvalent Cation Containing Products may decrease the serum concentration of Baloxavir Marboxil.Risk X: Avoid combinationBictegravir: Iron Preparations may decrease the serum concentration of Bictegravir.Management: Bictegravir, emtricitabine, and tenofovir alafenamide can be administered with iron preparations under fed conditions, but coadministration with or 2 hours after an iron preparation is not recommended under fasting conditions. Risk D: Consider therapy modificationBisphosphonate Derivatives: Polyvalent Cation Containing Products may decrease the serum concentration of Bisphosphonate Derivatives.Management: Avoid administration of oral medications containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Risk D: Consider therapy modificationCabotegravir: Polyvalent Cation Containing Products may decrease the serum concentration of Cabotegravir.Management: Administer polyvalent cation containing products at least 2 hours before or 4 hours after oral cabotegravir. Risk D: Consider therapy modificationCefdinir: Iron Preparations may decrease the serum concentration of Cefdinir. Red-appearing, non-bloody stools may also develop due to the formation of an insoluble iron-cefdinir complex.Management: Avoid concurrent cefdinir and oral iron when possible. Separate doses by at least 2 hours if combined. Iron-containing infant formulas do not appear alter cefdinir pharmaco*kinetics, but red-appearing, non-bloody stools may develop when combined. Risk D: Consider therapy modificationDeferiprone: Polyvalent Cation Containing Products may decrease the serum concentration of Deferiprone.Management: Separate administration of deferiprone and oral medications or supplements that contain polyvalent cations by at least 4 hours. Risk D: Consider therapy modificationDimercaprol: May enhance the nephrotoxic effect of Iron Preparations. Risk X: Avoid combinationDolutegravir: Iron Preparations may decrease the serum concentration of Dolutegravir.Management: Administer dolutegravir at least 2 hours before or 6 hours after oral iron. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral iron. Alternatively, dolutegravir and oral iron can be taken together with food. Risk D: Consider therapy modificationEltrombopag: Polyvalent Cation Containing Products may decrease the serum concentration of Eltrombopag.Management: Administer eltrombopag at least 2 hours before or 4 hours after oral administration of any polyvalent cation containing product. Risk D: Consider therapy modificationElvitegravir: Polyvalent Cation Containing Products may decrease the serum concentration of Elvitegravir.Management: Administer elvitegravir 2 hours before or 6 hours after the administration of polyvalent cation containing products. Risk D: Consider therapy modificationEntacapone: Iron Preparations may decrease the serum concentration of Entacapone.Management: Consider separating doses of the agents by 2 or more hours to minimize the effects of this interaction. Monitor for decreased therapeutic effects of levodopa during concomitant therapy, particularly if doses cannot be separated. Risk D: Consider therapy modificationFerric Hydroxide Polymaltose Complex: May decrease the serum concentration of Iron Preparations. Specifically, the absorption of oral iron salts may be reduced. Management: Do not administer intravenous (IV) ferric hydroxide polymaltose complex with other oral iron preparations. Therapy with oral iron preparations should begin 1 week after the last dose of IV ferric hydroxide polymaltose complex. Risk D: Consider therapy modificationLevodopa: Iron Preparations may decrease the serum concentration of Levodopa. Only applies to oral iron preparations.Management: Consider separating doses of the agents by 2 or more hours to minimize the effects of this interaction. Monitor for decreased therapeutic effects of levodopa during concomitant therapy, particularly if doses cannot be separated. Risk D: Consider therapy modificationLevothyroxine: Iron Preparations may decrease the serum concentration of Levothyroxine.Management: Separate oral administration of iron preparations and levothyroxine by at least 4 hours.Separation of doses is not required with parenterally administered iron preparations or levothyroxine. Risk D: Consider therapy modificationMethyldopa: Iron Preparations may decrease the serum concentration of Methyldopa.Management: Consider separating doses of methyldopa and orally administered iron preparation by 2 or more hours. Monitor for decreased efficacy of methyldopa if an oral iron preparation is initiated/dose increase, or increased efficacy if discontinued/dose decreased. Risk D: Consider therapy modificationPenicillAMINE: Polyvalent Cation Containing Products may decrease the serum concentration of PenicillAMINE.Management: Separate the administration of penicillamine and oral polyvalent cation containing products by at least 1 hour. Risk D: Consider therapy modificationPhosphate Supplements: Iron Preparations may decrease the absorption of Phosphate Supplements.Management: Administer oral phosphate supplements as far apart from the administration of an oral iron preparation as possible to minimize the significance of this interaction. Risk D: Consider therapy modificationQuinolones: Iron Preparations may decrease the serum concentration of Quinolones.Management: Give oral quinolones at least several hours before (4 h for moxi- and sparfloxacin, 2 h for others) or after (8 h for moxi-, 6 h for cipro/dela-, 4 h for lome-, 3 h for gemi-, and 2 h for enox-, levo-, nor-, oflox-, peflox, or nalidixic acid) oral iron. Risk D: Consider therapy modificationRaltegravir: Polyvalent Cation Containing Products may decrease the serum concentration of Raltegravir.Management: Administer raltegravir 2 hours before or 6 hours after administration of the polyvalent cations. Dose separation may not adequately minimize the significance of this interaction. Risk D: Consider therapy modificationRoxadustat: Polyvalent Cation Containing Products may decrease the serum concentration of Roxadustat.Management: Administer roxadustat at least 1 hour after the administration of oral polyvalent cation containing products. Risk D: Consider therapy modificationTetracyclines: May decrease the absorption of Iron Preparations. Iron Preparations may decrease the serum concentration of Tetracyclines. Management: Avoid this combination if possible. Administer oral iron preparations at least 2 hours before, or 4 hours after, the dose of the oral tetracycline derivative. Monitor for decreased therapeutic effect of oral tetracycline derivatives. Risk D: Consider therapy modificationTrientine: Polyvalent Cation Containing Products may decrease the serum concentration of Trientine.Management: Avoid concomitant use of trientine and polyvalent cations. If oral iron supplements are required, separate the administration by 2 hours. For other oral polyvalent cations, give trientine 1 hour before, or 1 to 2 hours after the polyvalent cation. Risk D: Consider therapy modificationUnithiol: May diminish the therapeutic effect of Polyvalent Cation Containing Products. Risk X: Avoid combinationPregnancy ConsiderationsIron transfer to the fetus is regulated by the placenta (BSH [Pavord 2020]; NAS 2020).Maternal iron requirements increase during pregnancy. Untreated iron deficiency and iron-deficiency anemia (IDA) in pregnant patients are associated with adverse pregnancy outcomes, including low birth weight, preterm birth, and increased perinatal mortality (ACOG 2021; BSH [Pavord 2020]). Maternal iron deficiency is also associated with fatigue, increased risk of postpartum depression, and possibly postpartum hemorrhage (BSH [Pavord 2020]).Oral and parenteral iron are effective at replacing iron stores in pregnant patients (ACOG 2021). Most studies note iron therapy improves maternal hematologic parameters; however, data related to clinical outcomes in the mother and neonate are limited (FIGO 2019; NAS 2020; USPSTF [Siu 2015]). Use of low-dose supplemental iron is recommended for all pregnant patients beginning in the first trimester or first prenatal visit to prevent anemia at term (ACOG 2021).A product containing a ferrous salt may be preferred for the oral management of IDA in pregnancy (BSH [Pavord 2020]). Iron supplementation is recommended for 3 months once hemoglobin is within the normal range, and at least 6 weeks postpartum to replenish maternal iron stores (BSH [Pavord 2020]; FIGO 2019). Iron supplementation is recommended in addition to use of prenatal vitamins in pregnant patients diagnosed with IDA (ACOG 2021). Enteric-coated and slow/sustained-release preparations may be less effective due to decreased absorption, and use should be avoided (ACOG 2021; BSH [Pavord 2020]).Breastfeeding ConsiderationsIron is present in breast milk.Endogenous iron concentrations in breast milk vary by postpartum age and are lower than concentrations in the maternal plasma (Dorea 2000; Emmett 1997). Breast milk concentrations of iron are maintained in lactating patients with mild to moderate iron-deficiency anemia (IDA), but concentrations decrease if IDA is moderate to severe (El-Farrash 2012) or severe (Kumar 2008).Iron deficiency and IDA are associated with adverse effects in postpartum patients (eg, altered cognition, depression, fatigue) that may influence interactions with the infant. Iron supplementation in the postpartum patient should be initiated as soon as possible following delivery when gestational anemia is a concern. All postpartum patients at risk of gestational anemia (regardless of breastfeeding status) may be given oral iron with or without folic acid for 6 to 12 weeks postpartum to reduce the risk of anemia. A product containing a ferrous salt may be preferred (WHO 2016c). Oral iron therapy is recommended for postpartum patients with uncorrected anemia at delivery who are hemodynamically stable and are asymptomatic or have only mild symptoms; treatment should continue for at least 3 months (BSH [Pavord 2020]).Dietary ConsiderationsDietary sources of iron include beans, cereal (enriched), clams, beef, lentils, liver, oysters, shrimp, and turkey. Foods that enhance dietary absorption of iron include broccoli, grapefruit, orange juice, peppers and strawberries. Foods that decrease dietary absorption of iron include coffee, dairy products, soy products, spinach, and tea.Dietary reference intake (elemental iron) (IOM 2001):0 to 6 months: Adequate intake: 0.27 mg elemental iron daily.7 to 12 months: Recommended dietary allowance (RDA): 11 mg elemental iron daily.1 to 3 years: RDA: 7 mg elemental iron daily.4 to 8 years: RDA: 10 mg elemental iron daily.9 to 13 years: RDA: 8 mg elemental iron daily.14 to 18 years: RDA:Males: 11 mg elemental iron daily.Females: 15 mg elemental iron daily.Pregnancy: 27 mg elemental iron daily.Lactation: 10 mg elemental iron daily.19 to 50 years: RDA:Males: 8 mg elemental iron daily.Females: 18 mg elemental iron daily.Pregnancy: 27 mg elemental iron daily.Lactation: 9 mg elemental iron daily.≥50 years: RDA: 8 mg elemental iron daily.Pharmaco*kineticsOnset of action: Hematologic response: Red blood cells form within 3 to 10 days; similar onset as parenteral iron salts; Maximum effect: Peak reticulocytosis occurs in 5 to 10 days, and hemoglobin values increase within 2 to 4 weeks Absorption: Oral: Iron is absorbed in the duodenum and upper jejunum; in persons with normal iron stores 10% of an oral dose is absorbed; this is increased to 20% to 30% in persons with inadequate iron stores; food and achlorhydria will decrease absorptionProtein binding: To transferrinExcretion: Urine, sweat, sloughing of intestinal mucosa, and by mensesPricing: USCapsules (EZFE 200 Oral)434.8 (200 Fe) mg (per each): $0.41Capsules (Ferrex 150 Oral)150 mg (per each): $0.15Capsules (IFerex 150 Oral)150 mg (per each): $0.34Capsules (Nu-Iron Oral)150 mg (per each): $0.51Capsules (Poly-Iron 150 Oral)150 mg (per each): $0.14Capsules (Polysaccharide Iron Complex Oral)150 mg (per each): $0.28Liquid (Hematex Oral)100 mg/5 mL (per mL): $0.08Liquid (NovaFerrum Oral)125 mg/5 mL (per mL): $0.14Liquid (NovaFerrum Pediatric Drops Oral)15 mg/mL (per mL): $0.19Tablets (Hematex Iron Complex Oral)150 mg (per each): $0.30Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalDafuten (TW);Ferich (TW);Ferricure (BE, LB, LK);Hemonia (TW);Hong Yuan Da (CN);Irome (TW);Niferex (CN, GB)For country code abbreviations (show table)Agostoni C, Buonocore G, Carnielli VP, et al. 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Nutrition. 2000;16(3):209-220. doi:10.1016/s0899-9007(99)00287-7 [PubMed 10705077]El-Farrash RA, Ismail EA, Nada AS. Cord blood iron profile and breast milk micronutrients in maternal iron deficiency anemia. Pediatr Blood Cancer. 2012;58(2):233-238. doi: 10.1002/pbc.23184. [PubMed 21548016]Emmett PM, Rogers IS. Properties of human milk and their relationship with maternal nutrition. Early Hum Dev. 1997;49(suppl):S7-S28. doi:10.1016/s0378-3782(97)00051-0 [PubMed 9363415]EZFE 200 (polysaccharide-iron complex) [prescribing information]. Chattanooga, TN: R.A. McNeil Co; November 2010.Ferrex 150 (polysaccharide-iron complex) [prescribing information]. Boca Raton, FL: Breckenridge Pharmaceutical Inc; November 2016.FIGO Working Group on Good Clinical Practice in Maternal-Fetal Medicine. Good clinical practice advice: iron deficiency anemia in pregnancy. 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Nelson Textbook of Pediatrics. 21st ed. Philadelphia, PA: Saunders Elsevier; 2020.Kumar A, Rai AK, Basu S, et al. Cord blood and breast milk iron status in maternal anemia. Pediatrics. 2008;121(3):e673-e677. doi: 10.1542/peds.2007-1986. [PubMed 18310187]Lapillonne A, Bronsky J, Campoy C, et al. Feeding the late and moderately preterm infant: a position paper of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2019;69(2):259-270. doi:10.1097/MPG.0000000000002397 [PubMed 31095091]Liu K, Kaffes AJ. Iron deficiency anaemia: a review of diagnosis, investigation and management. Eur J Gastroenterol Hepatol. 2012;24(2):109-116. doi:10.1097/MEG.0b013e32834f3140 [PubMed 22157204]Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126(17):1981-1989. doi:10.1182/blood-2015-05-642223 [PubMed 26289639]Myferon 150 (polysaccharide-iron complex) [prescribing information]. Richmond, IN: M.E. Pharmaceuticals Inc; February 2014.National Academies of Sciences, Engineering, and Medicine. Nutrition During Pregnancy and Lactation: Exploring New Evidence: Proceedings of a Workshop. The National Academies Press; 2020. https://doi.org/10.17226/25841.National Institutes of Health (NIH). Iron fact sheet for health professionals. https://ods.od.nih.gov/factsheets/Iron-HealthProfessional/. Published March 30, 2021. Accessed October 28, 2021.NovaFerrum 125 (polysaccharide-iron complex) [prescribing information]. Corpus Christi, TX: Gensavis Pharmaceuticals Inc; October 2013.NovaFerrum 50 (polysaccharide-iron complex) [prescribing information]. Corpus Christi, TX: Gensavis Pharmaceuticals Inc; October 2013.NovaFerrum pediatric drops (polysaccharide-iron complex) [prescribing information]. Corpus Christi, TX: Gensavis Pharmaceuticals, LLC; June 2006.Nu-Iron (polysaccharide-iron complex) [prescribing information]. Solon, OH: DSE Healthcare Solutions LLC; January 2020.Oski FA. Iron deficiency in infancy and childhood. N Engl J Med. 1993;329(3):190-193. doi:10.1056/NEJM199307153290308 [PubMed 8515791]Pavord S, Daru J, Prasannan N, Robinson S, Stanworth S, Girling J; BSH Committee. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol. 2020;188(6):819-830. doi:10.1111/bjh.16221 [PubMed 31578718]Poly-Iron (polysaccharide-iron complex) [prescribing information]. Madison MS: Cypress Pharmaceutical Inc; March 2011.Powers JM, Buchanan GR, Adix L, Zhang S, Gao A, McCavit TL. Effect of low-dose ferrous sulfate vs iron polysaccharide complex on hemoglobin concentration in young children with nutritional iron-deficiency anemia: a randomized clinical trial. JAMA. 2017;317(22):2297-2304. doi:10.1001/jama.2017.6846 [PubMed 28609534]Rao R, Georgieff MK. Iron therapy for preterm infants. Clin Perinatol. 2009;36(1):27-42. [PubMed 19161863]Recommendations to Prevent and Control Iron Deficiency in the United States. Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47(RR-3):1-29. [PubMed 9563847]Reeves JD, Yip R. Lack of adverse side effects of oral ferrous sulfate therapy in 1-year-old infants. Pediatrics. 1985;75(2):352-355. [PubMed 3969339]Schrier SL, Auerbach M. Treatment of iron deficiency anemia in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 25, 2019.Siu AL; US Preventive Services Task Force. Screening for iron deficiency anemia and iron supplementation in pregnant women to improve maternal health and birth outcomes: US Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2015;163(7):529-36. doi:10.7326/M15-1707 [PubMed 26344176]Stoffel NU, Cercamondi CI, Brittenham G, et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol. 2017;4(11):e524-e533. doi:10.1016/S2352-3026(17)30182-5 [PubMed 29032957]Stoffel NU, Zeder C, Brittenham GM, Moretti D, Zimmermann MB. Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women. Haematologica. 2020;105(5):1232-1239. doi:10.3324/haematol.2019.220830 [PubMed 31413088]Stoltzfus RJ, Dreyfuss ML, eds; International Nutritional Anemia Consultative Group. Guidelines for the use of iron supplements to prevent and treat iron deficiency anemia. https://www.who.int/nutrition/publications/micronutrients/guidelines_for_Iron_supplementation.pdf?ua=1. Published 1998. Accessed March 20, 2019.Unger SL, Fenton TR, Jetty R, Critch JN, O'connor DL. Iron requirements in the first 2 years of life. Paediatr Child Health. 2019;24(8):555-556. doi:10.1093/pch/pxz148 [PubMed 31844396]United Nations Children's Fund, United Nations University, World Health Organization. Iron deficiency anaemia assessment, prevention, and control. A guide for programme managers, 2001.World Health Organization (WHO). Iron deficiency anaemia: assessment, prevention, and control. A guide for programme managers. https://www.ihs.org.in/SHG/WHO-Anemia%20detection%20guidelines.pdf. Published 2001.World Health Organization (WHO): Guideline: Daily Iron Supplementation in Adult Women and Adolescent Girls. Geneva, Switzerland: World Health Organization; 2016a. https://www.ncbi.nlm.nih.gov/books/NBK361888/. [PubMed 27195351]World Health Organization (WHO): Guideline: Daily Iron Supplementation in Infants and Children. Geneva, Switzerland: World Health Organization; 2016b. https://www.ncbi.nlm.nih.gov/books/NBK362032/. [PubMed 27195348]World Health Organization (WHO): Guideline: Iron supplementation in postpartum women. Geneva: World Health Organization; 2016c. [PubMed 27583315]Zlotkin S, Arthur P, Antwi KY, Yeung G. Randomized, controlled trial of single versus 3-times-daily ferrous sulfate drops for treatment of anemia. Pediatrics. 2001;108(3):613-616. doi:10.1542/peds.108.3.613 [PubMed 11533326]Topic 10222 Version 249.0

CloseStreptomycin: Drug informationStreptomycin: Drug information(For additional information see "Streptomycin: Patient drug information" and see "Streptomycin: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningToxicity:The risk of severe neurotoxic reactions is sharply increased in patients with impaired renal function or prerenal azotemia. These include disturbances of vestibular and cochlear function, optic nerve dysfunction, peripheral neuritis, arachnoiditis, and encephalopathy. The incidence of clinically detectable, irreversible vestibular damage is particularly high in patients treated with streptomycin.Renal function should be monitored carefully; patients with renal impairment and/or nitrogen retention should receive reduced doses. The peak serum concentration in individuals with kidney damage should not exceed 20 to 25 mcg/mL.The concurrent or sequential use of other neurotoxic and/or nephrotoxic drugs with streptomycin, including neomycin, kanamycin, gentamicin, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, tobramycin, and cyclosporine should be avoided.The neurotoxicity of streptomycin can result in respiratory paralysis from neuromuscular blockage, especially when the drug is given soon after the use of anesthesia or muscle relaxants.The administration of streptomycin in parenteral form should be reserved for patients where adequate laboratory and audiometric testing facilities are available during therapy.Brand Names: CanadaStreptomycinPharmacologic CategoryAntibiotic, Aminoglycoside;Antitubercular AgentDosing: AdultNote: Route of administration: Manufacturer’s labeling states for IM administration only; however, IV administration (off-label route) has been described (Morris 1994; Peloquin 1992; Tanoira 2014).Aminoglycoside dosing weight: For underweight patients (ie, total body weight [TBW] < ideal body weight [IBW]), calculate the dose based on TBW. For nonobese patients (ie, TBW 1 to 1.25 × IBW), calculate the dose based on TBW or IBW. TBW may be preferred in nonobese patients who may have increased volume of distribution (eg, critically ill). For obese patients (ie, TBW > 1.25 × IBW), calculate the dose based on 40% adjusted body weight (IBW + [0.4 × (TBW-IBW)]) (Blackburn 2015; Drew 2020). Therapeutic drug monitoring: Monitoring of serum concentrations is recommended to ensure efficacy and avoid toxicity; confirm availability of rapid streptomycin serum concentrations. Timing and frequency of concentration monitoring is individualized based on dosing and monitoring strategy (AHA [Baddour 2015]; Drew 2020; Park 2015; Zhu 2001).Usual dosage range: IM, IV: 15 to 30 mg/kg/day or 1 to 2 g daily.Indication-specific dosing:BrucellosisBrucellosis: IM, IV: 1 g once daily in combination with doxycycline. Duration depends on extent of disease; streptomycin is usually given for the first 14 to 21 days of therapy, followed by doxycycline monotherapy (Ariza 2007; Bosilkovski 2020; Hasanjani Roushan 2006; Skalsky 2008). Note: Additional agents or other regimens are preferred for neurobrucellosis, endocarditis, and infection in pregnant women (Bosilkovski 2020).EndocarditisEndocarditis (alternate agent):Enterococcus spp. (native or prosthetic valve, susceptible to penicillin and streptomycin/resistant to gentamicin): IM, IV: 7.5 mg/kg every 12 hours in combination with ampicillin or penicillin; Duration of therapy: 4 weeks (native valve and symptoms present <3 months); ≥6 weeks (native valve and symptoms present ≥3 months or prosthetic valve). Note: For native valve endocarditis due to ampicillin-susceptible E. faecalis, a combination regimen that does not contain streptomycin is preferred (AHA [Baddour 2015]).Mycobacterial infectionMycobacterial (nontuberculous) (M. avium complex) infection (off-label use):Pulmonary disease (severe nodular/bronchiectatic or cavitary disease) (adjunctive agent): IM, IV: 10 to 15 mg/kg once daily or 15 to 25 mg/kg 3 times weekly (ATS/ERS/ESCMID/IDSA [Daley 2020]; Peloquin 2004) or 10 to 15 mg/kg 3 times weekly (Kasperbauer 2020) or 15 mg/kg once daily (usual maximum dose: 1 g) for 1 month then 15 mg/kg 3 times weekly (BTS [Haworth 2017]). Give streptomycin as part of an appropriate combination regimen for the first 2 to 3 months of therapy (ATS/ERS/ESCMID/IDSA [Daley 2020]). Note: For older adults or patients who require >6 months of parenteral therapy, some experts recommend empiric dose reduction (BTS [Haworth 2017]).Pulmonary disease (cavitary or severe bronchiectatic or acid-fast bacilli smear-positive respiratory samples) or systemic illness in patients with cystic fibrosis (adjunctive agent): IM, IV: 15 mg/kg once daily (maximum: 1 g daily) as part of an appropriate combination regimen (CFF/ECFS [Floto 2016]).Disseminated disease in patients with HIV with CD4 count <50 cells/mm3, high mycobacterial loads (ie, >2 log colony-forming units/mL of blood), or in the absence of effective antiretroviral therapy (adjunctive agent): IM, IV: 1 g once daily as part of an appropriate combination regimen (HHS [OI adult 2019]).Plague, treatmentPlague (Yersinia pestis), treatment: Note: Consult public health officials for event-specific recommendations.IM, IV: 1 g every 12 hours for 7 to 14 days and for at least a few days after clinical resolution (CDC [Nelson 2021]; Stout 2022).TuberculosisTuberculosis (alternative agent): IM, IV: 15 mg/kg once daily or 25 mg/kg 3 times weekly (ATS/CDC/ERS/IDSA [Nahid 2019]; ATS/CDC/IDSA [Nahid 2016]).TularemiaTularemia (alternative agent): IM: 1 g twice daily for ≥10 days depending on severity (CDC 2019; WHO 2007).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling; however, the following adjustments have been recommended:Aronoff 2007: Note: Recommendations are based on doses of 1 to 2 g every 6 to 12 hours (1 g once daily for tuberculosis):CrCl >50 mL/minute: No dosage adjustment necessary.CrCl 10 to 50 mL/minute: Administer every 24 to 72 hours.CrCl <10 mL/minute: Administer every 72 to 96 hours.End-stage renal disease (ESRD):Intermittent hemodialysis (IHD): One-half the recommended dose administered after hemodialysis on dialysis days. Note: Dosing dependent on the assumption of 3 times weekly complete IHD sessions.Peritoneal dialysis (PD): Administration via PD fluid: 20 to 40 mg/L (20 to 40 mcg/mL) of PD fluid.CRRT: Administer every 24 to 72 hours; monitor levels. Note: Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate).ATS/CDC/IDSA [Nahid 2016]:Tuberculosis:CrCl ≥30 mL/minute: No dosage adjustment necessary.CrCl <30 mL/minute: 15 mg/kg/dose 2 to 3 times weekly.ESRD on IHD: 15 mg/kg/dose 2 to 3 times weekly. Give after dialysis if given on day of dialysis.Dosing: Hepatic Impairment: AdultThere are no dosage adjustments provided in the manufacturer’s labeling.Dosing: Pediatric(For additional information see "Streptomycin: Pediatric drug information")Note: IM route preferred; consider use of IV route if IM therapy not tolerated. Monitor serum drug concentrations.General dosing, combination therapy for susceptible infection: Infants, Children, and Adolescents:Manufacturer's labeling: IM: 20 to 40 mg/kg/day in divided doses every 6 to 12 hours; maximum dose: 1,000 mg/dose; maximum daily dose: 2,000 mg/dayAlternate dosing: IM, IV: 20 to 30 mg/kg/day divided every 12 hours; maximum daily dose: 1,000 mg/day (Bradley 2015)Endocarditis, Enterococcal, resistant to gentamicinEndocarditis, Enterococcal, resistant to gentamicin: Infants, Children, and Adolescents: IM, IV: 20 to 30 mg/kg/day divided every 12 hours; maximum daily dose: 2,000 mg/day; used in combination with other antibiotics, adjust dose to target concentrations (AHA [Baddour] 2005)Mycobacterium avium complex, treatmentMycobacterium avium complex, treatment: Limited data available: Adolescents: IM, IV: 1,000 mg once daily as part of combination therapy (HHS [Adult] 2016)Mycobacterium ulceransMycobacterium ulcerans (Buruli ulcers): Limited data available: Infants, Children, and Adolescents: IM: 15 mg/kg once daily; maximum daily dose: 1,000 mg/day; used in combination with rifampin for 8 weeks, or may use this combination for 4 weeks, followed by 4 weeks of rifampin-claithromycin combination therapy (WHO 2012)PlaguePlague: Infants, Children, and Adolescents: IM, IV: 30 mg/kg/day divided every 12 hours for 10 days; maximum daily dose: 2,000 mg/day (Red Book [AAP 2015]; WHO 2009)Tuberculosis; active infection; treatment; multidrug-resistant or meningitisTuberculosis; active infection; treatment (second-line therapy); multidrug-resistant (MDR) or meningitis: Note: Always use as part of a multidrug regimen. Any regimens using less than once daily dosing should administer dosing as directly observed therapy (DOT). Treatment regimens for MDR TB are variable depending upon sensitivity and clinical response. Streptomycin frequency and dosing differs depending on treatment regimen selected; consult current drug-sensitive TB guidelines for detailed information (ATS/CDC/IDSA [Nahid 2016]; Schaaf 2015).Primary pulmonary disease:Once daily therapy:Infants, Children, and Adolescents <15 years weighing ≤40 kg: Note: Suggested expert dosing range is large and variable (Schaaf 2015); IM, IV: 15 to 40 mg/kg/dose once daily; some experts recommend an initial dose range of 15 to 20 mg/kg/dose once daily; maximum daily dose: 1,000 mg/day; monitor serum concentrations (ATS/CDC/IDSA [Nahid 2016]; Schaaf 2015; WHO, 2009a). Note: Some clinicians suggest every 12-hour dosing may be utilized (Berenberg 1951; Bradley 2015).Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: IM, IV: 15 mg/kg/dose once daily; maximum daily dose: 1,000 mg/day; monitor serum concentrations (ATS/CDC/IDSA [Nahid 2016]; Pérez Tanoira 2014)Three-times-weekly DOT: Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: IM, IV: 25 mg/kg/dose three times weekly; maximum dose: 1,000 mg/dose (ATS/CDC/IDSA [Nahid 2016]Twice weekly DOT: Infants, Children, and Adolescents <15 years weighing ≤40 kg: IM, IV: 25 to 30 mg/kg/dose twice weekly; maximum dose: 1,000 mg/dose (ATS/CDC/IDSA [Nahid 2016])Meningitis (independent of HIV-status): Infants, Children, and Adolescents: Note: Suggested expert dosing range is large and variable (Schaaf 2015): IM, IV: 15 to 40 mg/kg/dose once daily; some experts recommend an initial dose range of 15 to 20 mg/kg/dose once daily; maximum daily dose: 1,000 mg/day; monitor serum concentrations (ATS/CDC/IDSA [Nahid 2016]; DHHS [pediatric] 2013; Red Book [AAP 2015]; Schaaf 2015)TularemiaTularemia: Infants, Children, and Adolescents: IM: 15 mg/kg/dose twice daily for 10 days; maximum daily dose: 2,000 mg/day (WHO 2007)Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricThere are no adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended (Aronoff 2007):Infants, Children, and Adolescents: Note: Renally adjusted dose recommendations are based on doses of 20 to 40 mg/kg/day every 24 hours. Monitor serum concentrations.GFR 30 to 50 mL/minute/1.73 m2: Administer 7.5 mg/kg/dose every 24 hoursGFR 10 to 29 mL/minute/1.73 m2: Administer 7.5 mg/kg/dose every 48 hoursGFR <10 mL/minute/1.73 m2: Administer 7.5 mg/kg/dose every 72 to 96 hoursIntermittent hemodialysis (IHD): Administer 7.5 mg/kg/dose every 72 to 96 hoursPeritoneal dialysis (PD): Administer 7.5 mg/kg/dose every 72 to 96 hoursContinuous renal replacement therapy (CRRT): Administer every 24 hours; monitor levels. Note: Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate).Dosing: Hepatic Impairment: PediatricThere are no adjustments provided in the manufacturer's labeling.Dosing: Older AdultDose reductions are recommended by the manufacturer in patients >60 years of age.M. avium complex disease: IM/IV: 8 to 10 mg/kg 2 to 3 times weekly (maximum dose for >50 years of age: 500 mg) (ATS/IDSA [Griffith 2007]) or 10 mg/kg once daily for the first month followed by 15 mg/kg 3 times weekly (maximum dose for >59 years of age: 750 mg) (BTS [Haworth 2017]).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution Reconstituted, Intramuscular [preservative free]: Generic: 1 g (1 ea)Generic Equivalent Available: USYesDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Solution Reconstituted, Intramuscular: Generic: 1 g (5 mL)Administration: AdultIM: Inject deep IM into large muscle mass; midlateral thigh muscle or upper outer quadrant of buttocks; rotate injection sites.IV (off-label route): After dilution in admixture, infuse over 30 to 60 minutes (Morris 1994; Peloquin 1992; Tanoira 2014)Administration: PediatricParenteral: IM: Inject deep IM into a large muscle mass; rotate injection sitesIV: After further dilution, infuse over 30 to 60 minutes (Morris 1994; Peloquin 1992; Pérez Tanoira 2014) Use: Labeled IndicationsTuberculosis:Treatment of tuberculosis, in combination with other appropriate antituberculosis agents, when the primary agents are contraindicated because of toxicity or intolerance.Nontuberculosis infections:Treatment of infections caused by susceptible bacteria that are not amenable to therapy with less potentially toxic agents, including sensitive Yersinia pestis (plague); Francisella tularensis (tularemia); Brucella; Klebsiella granulomatis (donovanosis, granuloma inguinale); Haemophilus ducreyi (chancroid); Haemophilus influenzae (in respiratory, endocardial, and meningeal infections, concomitantly with another antibacterial agent); Klebsiella pneumoniae pneumonia (concomitantly with another antibacterial agent); Escherichia coli, Proteus spp., Klebsiella aerogenes (formerly Enterobacter aerogenes), K. pneumoniae, and Enterococcus faecalis in urinary tract infections; Streptococcus viridans; E. faecalis (in endocardial infections, concomitant with penicillin); and gram-negative bacillary bacteremia (concomitant with another antibacterial agent).Use: Off-Label: AdultMycobacterium avium complex infectionMedication Safety IssuesSound-alike/look-alike issues: Streptomycin may be confused with streptozocinAdverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Frequency not defined.Cardiovascular: HypotensionCentral nervous system: Drug fever, facial paresthesia, headache, neurotoxicityDermatologic: Exfoliative dermatitis, skin rash, urticariaGastrointestinal: Nausea, vomitingGenitourinary: Azotemia, nephrotoxicityHematologic & oncologic: Eosinophilia, hemolytic anemia, leukopenia, pancytopenia, thrombocytopeniaHypersensitivity: Anaphylaxis, angioedemaNeuromuscular & skeletal: Arthralgia, tremor, weaknessOphthalmic: AmblyopiaOtic: Auditory ototoxicity, vestibular ototoxicityRespiratory: Dyspnea<1%, postmarketing, and/or case reports: DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), toxic epidermal necrolysisContraindicationsHypersensitivity to streptomycin, other aminoglycosides, or any component of the formulationWarnings/PrecautionsConcerns related to adverse effects:• Neuromuscular blockade and respiratory paralysis: [US Boxed Warning]: May cause neuromuscular blockade and respiratory paralysis; especially when given soon after anesthesia or muscle relaxants.• Neurotoxicity: [US Boxed Warning]: May cause neurotoxicity, including disturbances of vestibular and cochlear function, optic nerve dysfunction, peripheral neuritis, arachnoiditis, and encephalopathy; usual risk factors include pre-existing renal impairment, concomitant neuro-/nephrotoxic medications. Ototoxicity is proportional to the amount of drug given and the duration of treatment. Tinnitus or vertigo may be indications of vestibular injury and impending bilateral irreversible damage. Baseline and periodic caloric stimulation and audiometric tests are recommended with prolonged therapy. Discontinue treatment if signs of ototoxicity occur.• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.Disease-related concerns:• Hearing impairment: Use with caution in patients with pre-existing vertigo, tinnitus, or hearing loss.• Neuromuscular disorders: Use with caution in patients with neuromuscular disorders, including myasthenia gravis.• Renal impairment:[US Boxed Warning]: May cause nephrotoxicity. Use with caution in patients with renal impairment; dose adjustment necessary in patients with renal impairment and/or nitrogen retention. Monitor renal function closely; peak serum concentrations should not surpass 20 to 25 mcg/mL in patients with renal impairment.Concurrent drug therapy issues:• Neurotoxic and/or nephrotoxic drugs: [US Boxed Warning]: Avoid concomitant or sequential use with other neurotoxic and/or nephrotoxic drugs (eg, neomycin, kanamycin, gentamicin, paromomycin, polymyxin B, colistin, tobramycin, cyclosporine).Dosage form specific issues:• Sulfite sensitivity: Some formulations may contain sodium metabisulfite; may cause allergic reactions including anaphylaxis or asthma exacerbations (some life-threatening) in susceptible patients.Other warnings/precautions:• Appropriate use: [US Boxed Warning]: Parenteral form should be used only where appropriate audiometric and laboratory testing facilities are available. IM injections should be administered in a large muscle well within the body to avoid peripheral nerve damage and local skin reactions.Metabolism/Transport EffectsNone known.Drug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Aminoglycosides: May enhance the nephrotoxic effect of other Aminoglycosides. Aminoglycosides may enhance the neurotoxic effect of other Aminoglycosides. Risk X: Avoid combinationAmphotericin B: May enhance the nephrotoxic effect of Aminoglycosides. Amphotericin B may enhance the neurotoxic effect of Aminoglycosides. Risk C: Monitor therapyAtaluren: May enhance the adverse/toxic effect of Aminoglycosides. Specifically, an increased risk of nephrotoxicity may occur with the concomitant use of ataluren and aminoglycosides. Risk X: Avoid combinationBacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii.Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modificationBacitracin (Systemic): Streptomycin may enhance the nephrotoxic effect of Bacitracin (Systemic).Risk X: Avoid combinationBCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical).Risk X: Avoid combinationBCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization).Risk C: Monitor therapyBisphosphonate Derivatives: Aminoglycosides may enhance the hypocalcemic effect of Bisphosphonate Derivatives.Risk C: Monitor therapyBotulinum Toxin-Containing Products: Aminoglycosides may enhance the neuromuscular-blocking effect of Botulinum Toxin-Containing Products.Risk C: Monitor therapyCapreomycin: May enhance the neuromuscular-blocking effect of Aminoglycosides. Risk C: Monitor therapyCARBOplatin: May enhance the nephrotoxic effect of Aminoglycosides. Aminoglycosides may enhance the ototoxic effect of CARBOplatin. Especially with higher doses of carboplatin. Risk C: Monitor therapyCephalosporins: May enhance the nephrotoxic effect of Aminoglycosides. Cephalosporins may decrease the serum concentration of Aminoglycosides. Risk C: Monitor therapyCholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine.Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combinationCISplatin: May enhance the nephrotoxic effect of Aminoglycosides. CISplatin may enhance the neurotoxic effect of Aminoglycosides. Risk X: Avoid combinationColistimethate: Aminoglycosides may enhance the nephrotoxic effect of Colistimethate. Aminoglycosides may enhance the neuromuscular-blocking effect of Colistimethate.Management: Avoid coadministration of colistimethate and aminoglycosides whenever possible due to the risk of nephrotoxicity and neuromuscular blockade. If coadministration cannot be avoided, monitor renal and neuromuscular function. Risk D: Consider therapy modificationCyclizine: May enhance the ototoxic effect of Aminoglycosides. Risk C: Monitor therapyCycloSPORINE (Systemic): Aminoglycosides may enhance the nephrotoxic effect of CycloSPORINE (Systemic).Risk C: Monitor therapyDistigmine: Aminoglycosides may diminish the therapeutic effect of Distigmine.Risk C: Monitor therapyFoscarnet: May enhance the nephrotoxic effect of Aminoglycosides. Risk X: Avoid combinationImmune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors.Risk C: Monitor therapyLactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol.Risk C: Monitor therapyLoop Diuretics: May enhance the adverse/toxic effect of Aminoglycosides. Specifically, nephrotoxicity and ototoxicity. Risk C: Monitor therapyMannitol (Systemic): May enhance the nephrotoxic effect of Aminoglycosides. Risk X: Avoid combinationMecamylamine: Aminoglycosides may enhance the neuromuscular-blocking effect of Mecamylamine.Risk X: Avoid combinationMethoxyflurane: Aminoglycosides may enhance the nephrotoxic effect of Methoxyflurane.Risk X: Avoid combinationNetilmicin (Ophthalmic): Aminoglycosides may enhance the nephrotoxic effect of Netilmicin (Ophthalmic).Risk X: Avoid combinationNeuromuscular-Blocking Agents: Aminoglycosides may enhance the therapeutic effect of Neuromuscular-Blocking Agents.Risk C: Monitor therapyNonsteroidal Anti-Inflammatory Agents: May decrease the excretion of Aminoglycosides. Data only in premature infants. Risk C: Monitor therapyOxatomide: May enhance the ototoxic effect of Aminoglycosides. Risk C: Monitor therapyPenicillins: May decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Risk C: Monitor therapyPolymyxin B: May enhance the nephrotoxic effect of Aminoglycosides. Polymyxin B may enhance the neurotoxic effect of Aminoglycosides. Risk X: Avoid combinationSodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate.Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modificationTacrolimus (Systemic): Aminoglycosides may enhance the nephrotoxic effect of Tacrolimus (Systemic).Risk C: Monitor therapyTenofovir Products: Aminoglycosides may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides.Risk C: Monitor therapyTyphoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected.Management: Avoid use of live attenuated typhoid vaccine (Ty21a)in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modificationVancomycin: May enhance the nephrotoxic effect of Aminoglycosides. Vancomycin may enhance the neurotoxic effect of Aminoglycosides. Management: Consider avoiding coadministration of aminoglycosides and vancomycin unless clinically indicated. If coadministered, monitor closely for signs of nephrotoxicity and neurotoxicity. Risk D: Consider therapy modificationReproductive ConsiderationsEvaluate pregnancy status prior to treatment of multidrug resistant tuberculosis in patients who could become pregnant. Patients who could become pregnant should use effective contraception during treatment for multidrug resistant tuberculosis (Esmail 2018).Pregnancy ConsiderationsStreptomycin crosses the placenta.Streptomycin may cause fetal harm if administered to a pregnant patient. There are multiple reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy.Streptomycin is approved for the treatment of tuberculosis. Active tuberculosis infection is associated with adverse fetal outcomes including intrauterine growth restriction, low birth weight, preterm birth, and perinatal death (Esmail 2018; Miele 2020) as well as adverse maternal outcomes, including increased risks for anemia and cesarean delivery. Placental transmission may rarely occur with active maternal disease (Miele 2020). The treatment of multidrug resistant tuberculosis in pregnant patients should be individualized; evidence to support a specific regimen is not available (ATS/CDC/ERS/IDSA [Nahid 2019]; WHO 2020). When second-line agents are needed for the treatment of multidrug resistant tuberculosis during pregnancy, aminoglycosides should be avoided when alternative agents are effective (ATS/CDC/ERS/IDSA [Nahid 2019]). Streptomycin is not the preferred agent when an aminoglycoside is required for the treatment of tuberculosis during pregnancy (HHS [OI adult 2019]).Untreated plague (Yersinia pestis) infection in pregnant patients may result in hemorrhage (including postpartum hemorrhage), maternal and fetal death, preterm birth, and stillbirth. Limited data suggest maternal-fetal transmission of Y. pestis can occur if not treated. Pregnant patients should be treated for Y. pestis; parenteral antibiotics are preferred for initial treatment when otherwise appropriate. Streptomycin is an alternative aminoglycoside recommended for use (in combination with a fluroquinolone) for treating pregnant patients with bubonic, pharyngeal, pneumonic, or septicemic plague (CDC [Nelson 2021]).Breastfeeding ConsiderationsStreptomycin is present in breast milk.Aminoglycosides have poor oral bioavailability (Edson 1991), which may limit systemic absorption via breast milk.Streptomycin is considered compatible with breastfeeding. In general, antibiotics that are present in breast milk may cause non-dose-related modification of bowel flora. Monitor infants for GI disturbances, such as thrush and diarrhea (WHO 2002). Patients with multidrug resistant tuberculosis and a sputum smear-positive test should avoid breastfeeding when possible (Esmail 2018).Monitoring ParametersBaseline and periodic hearing tests (audiograms), clinical assessment for vertigo and tinnitus, BUN, creatinine, serum electrolytes; serum drug concentrations should be monitored in all patients (ATS/CDC/ERS/IDSA [Nahid 2019]).Reference RangeTherapeutic:Peak: Daily dosing: 20 to 35 mcg/mL (35 to 45 mcg/mL for mycobacterial disease); Three times weekly dosing: 65 to 80 mcg/mL (AHA [Baddour 2015]; ATS/ERS/ESCMID/IDSA [Daley 2020]; BTS [Haworth 2017]; CFF/ECFS [Floto 2016]; Edson 1991; Peloquin 2004; Zhu 2001).Trough: <5 mcg/mL (AHA [Baddour 2015]; BTS [Haworth 2017]; CFF/ECFS [Floto 2016]; Edson 1991; Zhu 2001).Supratherapeutic: Trough: >10 mcg/mL.Mechanism of ActionInhibits bacterial protein synthesis by binding directly to the 30S ribosomal subunits causing faulty peptide sequence to form in the protein chainPharmaco*kineticsAbsorption: Oral: Poorly absorbed; IM: Well absorbed Distribution: Distributes into most body tissues and fluids except the brain; small amounts enter the CSF only with inflamed meninges Protein binding: 34% Half-life elimination: Newborns: 4 to 10 hours; Adults: ~2 to 4.7 hours; prolonged with renal impairmentTime to peak: IM: Within 1 to 2 hoursExcretion: Urine (29% to 89% as unchanged drug); small amount (1%) excreted in bile, saliva, sweat, and tearsPricing: USSolution (reconstituted) (Streptomycin Sulfate Intramuscular)1 g (per each): $93.75Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAmbistryn-S (IN);Bio-Strep (ZA);Estrepto-Monaxin (MX);Solustrep (ZA);Strepiovit (LK);Strepto (TH);Strepto-Hefa (DE);Streptocin (MY);Streptomycinum (PL);Streptosol (ZW);Stretopen (BD)For country code abbreviations (show table)Abughali N, Van der Kuyp F, Annable W, Kumar ML. Congenital tuberculosis. Pediatr Infect Dis J. 1994;13(8):738-741. doi:10.1097/00006454-199408000-00012 [PubMed 7970976 ]Ad Hoc Committee of the Scientific Assembly on Microbiology, Tuberculosis, and Pulmonary Infections. Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children. Clin Infect Dis. 1995;21:9-27.American Academy of Pediatrics (AAP). Streptomycin. In: Kimberlin DW, Brady MT, Jackson MA, Long SA, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. American Academy of Pediatrics; 2015.American Academy of Pediatrics Committee on Infectious Diseases. Chemotherapy for tuberculosis in infants and children. Pediatrics. 1992;89(1):161-5. [PubMed 1728006]American Thoracic Society (ATS); CDC; Infectious Diseases Society of America. Treatment of tuberculosis. MMWR Recomm Rep. 2003;52(RR-11):1-77. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm [PubMed 12836625]Ariza J, Bosilkovski M, Cascio A, et al. Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations. PLoS Med. 2007;4(12):e317. doi:10.1371/journal.pmed.0040317 [PubMed 18162038]Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. American College of Physicians; 2007.Arguedas AG, Wehrle PP. New Concepts for Antimicrobial Use in Central Nervous System Infections. Semin Pediatr Infect Dis. 1991;2(1):36-42.Baddour LM, Wilson WR, Bayer AS, et al; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435-1486. doi:10.1161/CIR.0000000000000296 [PubMed 26373316]Balyan FR, Taibah A, De Donato G, et al. Titration streptomycin therapy in Meniere's disease: long-term results. Otolaryngol Head Neck Surg. 1998;118(2):261-266. doi:10.1016/S0194-5998(98)80028-4 [PubMed 9482564]Begg EJ, Barclay ML. Aminoglycosides - 50 Years On. Br J Clin Pharmacol. 1995;39(6):597-603. [PubMed 7654476]Berenberg W, Cook CD, Twinam CW. Streptomycin in pulmonary tuberculosis in children. J Am Med Assoc. 1951;145(14):1044-1048. doi:10.1001/jama.1951.02920320018005 [PubMed 14803304]Blackburn LM, Tverdek FP, Hernandez M, Bruno JJ. First-dose pharmaco*kinetics of aminoglycosides in critically ill haematological malignancy patients. Int J Antimicrob Agents. 2015;45(1):46‐53. doi:10.1016/j.ijantimicag.2014.09.006 [PubMed 25455848]Blumberg HM, Burman WJ, Chaisson RE, et al. 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[PubMed 12556935]Park SI, Oh J, Jang K, et al. Pharmaco*kinetics of second-line antituberculosis drugs after multiple administrations in healthy volunteers. Antimicrob Agents Chemother. 2015;59(8):4429‐4435. doi:10.1128/AAC.00354-15 [PubMed 25987620]Passeron T, Ndir M, Aubron C, et al. Drug rash with eosinophilia and systemic symptoms (DRESS) due to streptomycin. Acta Derm Venerol. 2004;84(1):92-93. doi:10.1080/00015550310006095 [PubMed 15040497]Peloquin CA. Shortages of antimycobacterial drugs. N Engl J Med. 1992;326(10):714. doi:10.1056/NEJM199203053261018 [PubMed 1736124]Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clin Infect Dis. 2004;38(11):1538‐1544. doi:10.1086/420742 [PubMed 15156439]Pérez Tanoira R, Sánchez-Patán F, Jiménez Girón A, Fernández Roblas R, Esteban J, Fernández Guerrero ML. Tolerance and safety of intravenous streptomycin therapy in patients with tuberculosis. 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Population pharmaco*kinetics of intravenous and intramuscular streptomycin in patients with tuberculosis. Pharmacotherapy. 2001;21(9):1037‐1045. doi:10.1592/phco.21.13.1037.34625 [PubMed 11560193]Topic 10238 Version 199.0

CloseRosiglitazone (United States: Not available): Drug informationRosiglitazone (United States: Not available): Drug information(For additional information see "Rosiglitazone (United States: Not available): Patient drug information" and see "Rosiglitazone (United States: Not available): Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningCongestive heart failure:Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of rosiglitazone and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain; dyspnea; and/or edema). If these signs and symptoms develop, manage the heart failure according to current standards of care. Furthermore, consider discontinuation or dose reduction of rosiglitazone.Rosiglitazone is not recommended in patients with symptomatic heart failure. Initiation of rosiglitazone in patients with established New York Heart Association (NYHA) class III or IV heart failure is contraindicated.Myocardial infarction: A meta-analysis of 52 clinical trials (mean duration, 6 months; 16,995 total patients), most of which compared rosiglitazone with placebo, showed rosiglitazone to be associated with a statistically significant increased risk of myocardial infarction (MI). Three other trials (mean duration, 46 months; 14,067 total patients) comparing rosiglitazone with some other approved oral antidiabetic agents or placebo showed a statistically nonsignificant increased risk of MI and a statistically nonsignificant decreased risk of death. There have been no clinical trials directly comparing the cardiovascular risk of rosiglitazone and pioglitazone, another thiazolidinedione, but in a separate trial, pioglitazone (when compared with placebo) did not show an increased risk of MI or death.Brand Names: USAvandia [DSC]Brand Names: CanadaAvandia [DSC]Pharmacologic CategoryAntidiabetic Agent, ThiazolidinedioneDosing: AdultNote: Avandia has been discontinued in the United States for >1 year.Note: May require a dose reduction of insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia; consider stopping insulin or reducing insulin dose (ADA/EASD [Davies 2018]; manufacturer's labeling).Diabetes mellitus, type 2, treatmentDiabetes mellitus, type 2, treatment:Note: May be used as an adjunctive agent or alternative monotherapy for select patients, including those in whom initial therapy with lifestyle intervention and metformin failed, or cannot take metformin, particularly when avoidance of hypoglycemia is desirable. Pioglitazone may have a more favorable cardiovascular profile compared to rosiglitazone; use of any thiazolidinedione has been associated with an increased risk of heart failure, and risk is increased with concomitant insulin use (AACE/ACE [Garber 2020]; ADA 2021).Oral: Initial: 4 mg/day as a single dose or in 2 divided doses If response is inadequate after 8 to 12 weeks of treatment, the dosage may be increased to 8 mg/day as a single dose or in 2 divided doses daily; maximum dose: 8 mg/day. Per some clinical trial data, 4 mg twice daily may lower fasting plasma glucose and HbA1c more effectively than 8 mg once daily.Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: AdultNo dosage adjustment necessary. Dosing: Hepatic Impairment: AdultHepatic impairment prior to initiation: There are no dosage adjustments provided in the manufacturer's labeling. Clearance is significantly lower in hepatic impairment; therapy should not be initiated if the patient exhibits active liver disease or increased transaminases (ALT >2.5 times the upper limit of normal) at baseline.Hepatic impairment during therapy: Discontinue therapy if ALT is persistently >3 times ULN or jaundice occurs.Dosing: Pediatric(For additional information see "Rosiglitazone (United States: Not available): Pediatric drug information")Note: Avandia has been discontinued in the United States for >1 year.Diabetes mellitus, type 2Diabetes mellitus, type 2: Limited data available: Note:Rosiglitazone is not recommended for the management of type 2 diabetes mellitus (T2DM) in children and adolescents; if thiazolidinedione therapy is required, other agents are preferred (ADA 2022b; ISPAD [Shah 2022]).Children ≥10 years and Adolescents: Oral: Initial: 2 mg twice daily; then increase to 4 mg twice daily after 8 weeks. Dosing presented was used in 233 pediatric patients as part of a larger multicenter comparative trial of treatments (n=699) in which rosiglitazone in combination with metformin was more effective than metformin alone or metformin and lifestyle changes at maintaining glycemic control (Copeland 2011; TODAY Study Group 2007; TODAY Study Group 2012).Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricBased on experience in adults, no dosage adjustment necessary.Dosing: Hepatic Impairment: PediatricChildren ≥10 years and Adolescents:Hepatic impairment prior to initiation: There are no dosage adjustments provided in the manufacturer's labeling. Clearance is significantly lower in hepatic impairment; based on recommendations in adults, therapy should not be initiated if the patient exhibits active liver disease or increased transaminases (ALT >2.5 times ULN) at baseline.Hepatic impairment during therapy: Based on recommendations in adults, discontinue therapy if ALT is persistently >3 times ULN or jaundice occurs.Dosing: Older AdultRefer to adult dosing.Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productTablet, Oral: Avandia: 2 mg [DSC], 4 mg [DSC]Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.[DSC] = Discontinued productTablet, Oral: Avandia: 2 mg [DSC], 4 mg [DSC], 8 mg [DSC]Generic: 2 mg, 4 mg, 8 mgProduct AvailabilityAvandia has been discontinued in the United States for >1 year.Prescribing and Access RestrictionsHealth Canada requires written informed consent for new and current patients receiving rosiglitazone.Medication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm085922.pdf, must be dispensed with this medication.Administration: AdultOral: May be administered without regard to meals.Administration: PediatricOral: May be taken without regard to meals.Use: Labeled IndicationsDiabetes mellitus, type 2, treatment: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.Medication Safety IssuesSound-alike/look-alike issues:Avandia may be confused with Avalide, Coumadin, PrandinHigh alert medication:This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.International issues:Avandia [US, Canada, and multiple international markets] may be confused with Avanza brand name for mirtazapine [Australia]Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.Note: As reported in monotherapy studies; the rate of certain adverse reactions (eg, anemia, edema, hypoglycemia) may be higher with some combination therapies. Rare cases of hepatocellular injury have been reported in men in their 60s within 2 to 3 weeks after initiation of rosiglitazone therapy. LFTs in these patients revealed severe hepatocellular injury which responded with rapid improvement of liver function and resolution of symptoms upon discontinuation of rosiglitazone. Patients were also receiving other potentially hepatotoxic medications (Al-Salman 2000; Freid 2000).>10%: Endocrine & metabolic: Increased HDL cholesterol, increased LDL cholesterol, increased serum cholesterol (total), weight gain1% to 10%:Cardiovascular: Edema (5%), hypertension (4%); cardiac failure (≤3% in patients receiving insulin; incidence likely higher in patients with pre-existing cardiac failure), ischemic heart disease (3%; incidence likely higher in patients with pre-existing CAD)Central nervous system: Headache (6%)Endocrine & metabolic: Hypoglycemia (1% to 3%; combination therapy with insulin: 12% to 14%)Gastrointestinal: Diarrhea (3%)Hematologic & oncologic: Anemia (2%)Neuromuscular & skeletal: Bone fracture (≤9%; incidence greater in females; usually upper arm, hand, or foot), arthralgia (5%), back pain (4% to 5%)Respiratory: Upper respiratory tract infection (4% to 10%), nasopharyngitis (6%)Miscellaneous: Trauma (8%)<1%, postmarketing, and/or case reports: Anaphylaxis, angina pectoris, angioedema, blurred vision, cardiac arrest, coronary artery disease, coronary thrombosis, decreased HDL cholesterol, decreased hematocrit, decreased hemoglobin, decreased visual acuity, decreased white blood cell count, dyspnea, hepatic failure, hepatitis, increased serum bilirubin, increased serum transaminases, jaundice (reversible), macular edema, myocardial infarction, pleural effusion, pruritus, pulmonary edema, skin rash, Stevens-Johnson syndrome, thrombocytopenia, urticaria, weight gain (rapid, excessive; usually due to fluid accumulation)ContraindicationsUS labeling: Hypersensitivity to rosiglitazone or any component of the formulation; NYHA Class III/IV heart failure (initiation of therapy)Canadian labeling: Hypersensitivity to rosiglitazone or any component of the formulation; any stage of heart failure (eg, NYHA Class I, II, III, IV); serious hepatic impairment; pregnancy Warnings/PrecautionsConcerns related to adverse effects:• Edema: Dose-related edema may occur. Use with caution in patients with edema; may increase plasma volume and/or cause fluid retention. Monitor for signs/symptoms of heart failure.• Fractures: Increased incidence of bone fractures in females treated with rosiglitazone was observed during analysis of long-term trial; majority of fractures occurred in the upper arm, hand and foot (differing from the hip or spine fractures usually associated with postmenopausal osteoporosis). Consider risk of fracture prior to initiation and during use.• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including rosiglitazone, may cause or exacerbate congestive heart failure; closely monitor for signs and symptoms of congestive heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases. If heart failure develops, treat accordingly and consider dose reduction or discontinuation. Not recommended for use in any patient with symptomatic heart failure. Initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure. A higher frequency of cardiovascular events has been noted in patients with NYHA class I or II heart failure treated with rosiglitazone. Use may also be associated with an increased risk of angina and MI. Use with caution in patients at risk for cardiovascular events and monitor closely. Discontinue if any deterioration in cardiac status occurs.• Hematologic effects: May decrease hemoglobin, hematocrit, and/or WBC count (slight); effects may be related to increased plasma volume and/or dose-related. Changes in hemoglobin and hematocrit generally occurred during the first 3 months after initiation of therapy and after dose increases. Use with caution in patients with anemia.• Hypoglycemia: The risk of hypoglycemia is increased when rosiglitazone is combined with other hypoglycemic agents; dosage adjustment of concomitant hypoglycemic agents may be necessary.• Macular edema: Has been reported with thiazolidinedione use, including rosiglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. In addition to regular ophthalmic exams, diabetic patients with visual symptoms should receive prompt ophthalmic evaluation. Improvement in macular edema may occur with discontinuation of therapy.• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.Disease-related concerns:• Bariatric surgery:– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Melissas 2013).– Weight gain: Evaluate risk vs benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).• Hepatic impairment: Use with caution in patients with elevated transaminases (AST or ALT); do not initiate in patients with active liver disease or ALT >2.5 times the upper limit of normal (ULN) at baseline; evaluate patients with ALT ≤2.5 times ULN at baseline or during therapy for cause of enzyme elevation; during therapy, if ALT >3 times ULN, reevaluate levels promptly and discontinue if elevation persists or if jaundice occurs at any time during use.• Ischemic heart disease: Do not initiate in patients with stable ischemic heart disease due to an increased risk of cardiovascular complications (Fihn 2012).• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).Other warnings/precautions:• Appropriate use: Not indicated for use in patients with type 1 diabetes mellitus or with diabetic ketoacidosis (DKA).• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.Metabolism/Transport EffectsSubstrate of CYP2C8 (major), CYP2C9 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Abiraterone Acetate: May enhance the hyperglycemic effect of Thiazolidinediones. Risk C: Monitor therapyAlpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyAndrogens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyAtazanavir: May increase the serum concentration of Rosiglitazone. Risk C: Monitor therapyBeta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyBeta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyBortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyCholestyramine Resin: May decrease the serum concentration of Rosiglitazone. Management: Administer rosiglitazone at least 2 hours prior to cholestyramine in order to minimize the likelihood of an interaction, and monitor patients closely for evidence of reduced rosiglitazone effectiveness. Risk D: Consider therapy modificationCYP2C8 Inducers (Moderate): May decrease the serum concentration of Rosiglitazone. Risk C: Monitor therapyCYP2C8 Inhibitors (Strong): May increase the serum concentration of Rosiglitazone. Risk C: Monitor therapyDirect Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyEtilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyGuanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapyHyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyHypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents.Risk C: Monitor therapyInhibitors of the Proton Pump (PPIs and PCABs): May enhance the adverse/toxic effect of Thiazolidinediones. Specifically, the risk of osteoporosis or fracture may be increased. Risk C: Monitor therapyInsulins: May enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Risk X: Avoid combinationLetermovir: May increase the serum concentration of Rosiglitazone. Risk C: Monitor therapyLumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapyMaitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyMonoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyPegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyPregabalin: May enhance the fluid-retaining effect of Thiazolidinediones. Risk C: Monitor therapyProthionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapyQuinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapyRitodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapySalicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapySelective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapySulfonylureas: Thiazolidinediones may enhance the hypoglycemic effect of Sulfonylureas.Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Risk D: Consider therapy modificationThiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapyVasodilators (Organic Nitrates): May enhance the adverse/toxic effect of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses. Risk C: Monitor therapyReproductive ConsiderationsThiazolidinediones may cause ovulation in anovulatory premenopausal patients, increasing the risk of unintended pregnancy.Thiazolidinediones are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)Pregnancy ConsiderationsRosiglitazone crosses the placenta (Chan 2005).Inadvertent use early in pregnancy has been reported, although in the majority of cases, the medication was stopped as soon as pregnancy was detected (Chan 2005; Kalyoncu 2005; Yaris 2004).Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2021; Blumer 2013).Agents other than rosiglitazone are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).Breastfeeding ConsiderationsIt is not known if rosiglitazone is present in breast milk.According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the motherDietary ConsiderationsIndividualized medical nutrition therapy (MNT) based on American Diabetes Association recommendations is an integral part of therapy.Monitoring ParametersFasting blood glucose.HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).Liver enzymes (prior to initiation of therapy, then periodically thereafter); evaluate patients with ALT ≤2.5 times ULN at baseline or during therapy for cause of enzyme elevation. Patients with an elevation in ALT >3 times ULN during therapy should be rechecked as soon as possible. If the ALT levels remain >3 times ULN, therapy with rosiglitazone should be discontinued.Signs and symptoms of fluid retention or heart failure (periodically and with dose adjustments); weight gain (periodically and with dose adjustments); ophthalmic exams (at least every 1 to 2 years, or more frequently if symptoms dictate) (ADA 2020); fractures/fracture risk.Reference RangeRecommendations for glycemic control in patients with diabetes:Nonpregnant adults (ADA 2021):HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).Older adults (≥65 years of age) (ADA 2021):Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).Classification of hypoglycemia (ADA 2021):Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.Mechanism of ActionThiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity. Rosiglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.Pharmaco*kineticsOnset of action: Delayed; Maximum effect: Up to 12 weeks Distribution: Vdss (apparent): 17.6 L Protein binding: 99.8%; primarily albumin Metabolism: Hepatic (99%) via CYP2C8; minor metabolism via CYP2C9 Bioavailability: 99% Half-life elimination: 3 to 4 hours; prolonged by approximately 2 hours in patients with moderate-to-severe hepatic impairmentTime to peak, plasma: 1 hour; delayed with food Excretion: Urine (~64%) and feces (~23%) as metabolitesPharmaco*kinetics: Additional ConsiderationsHepatic function impairment: In moderate to severe liver disease (Child-Pugh class B or C), unbound oral Cl was significantly lower, Cmax and AUC were increased 2- and 3-fold, respectively.Sex: Mean oral Cl in women was approximately 6% lower.Body weight: Cl and steady-state Vd increase with increased body weight.Pricing: USTablets (Avandia Oral)2 mg (per each): $4.574 mg (per each): $6.78Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalAlgor (PY);Avaglit (EG);Avandia (AE, AR, AT, BB, BE, BG, BM, BO, BR, BS, BZ, CH, CL, CR, CZ, DE, DK, DO, EC, ET, FI, FR, GB, GR, GT, GY, HK, HN, ID, IE, IL, IT, JM, JO, KR, KW, MX, NI, NL, NO, NZ, PA, PH, PK, PL, PR, PT, RU, SA, SE, SG, SR, SV, TH, TR, TT, UY, VE, VN);Diaglinex (PE);Reglit (PE);Rezult (IN);Rosidexx (EG);Rosix (CO);Rosizone (TW);Rovendia (TW);Vidya (TW);Xilan (PY)For country code abbreviations (show table)2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767 [PubMed 30693946]Alexopoulos AS, Blair R, Peters AL. Management of preexisting diabetes in pregnancy: a review. JAMA. 2019;321(18):1811-1819. doi:10.1001/jama.2019.4981 [PubMed 31087027]Al-Salman J, Arjomand H, Kemp DG, et al. Hepatocellular Injury in a Patient Receiving Rosiglitazone. A Case Report. Ann Intern Med. 2000;132(2):121-124. [PubMed 10644273]American College of Obstetricians and Gynecologists (ACOG) practice bulletin no. 201: pregestational diabetes mellitus. Obstet Gynecol. 2018;132(6):e228-e248. doi: 10.1097/AOG.0000000000002960. [PubMed 30461693]American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131(2):e49-e64. [PubMed 29370047]American Diabetes Association (ADA). Standards of medical care in diabetes 2016. Diabetes Care. 2016;39(suppl 1):S1-S113. [PubMed 24357209]American Diabetes Association (ADA). Standards of medical care in diabetes–2021. Diabetes Care. 2021;44(suppl 1):S1-S232. https://care.diabetesjournals.org/content/44/Supplement_1. Accessed January 13, 2021.American Diabetes Association (ADA) Professional Practice Committee, Draznin B, Aroda VR, et al. 6. Glycemic targets: standards of medical care in diabetes-2022. Diabetes Care. 2022a;45(suppl 1):S83-S96. doi:10.2337/dc22-S006 [PubMed 34964868]American Diabetes Association Professional Practice Committee, Draznin B, Aroda VR, et al. 14. Children and adolescents: standards of medical care in diabetes-2022. Diabetes Care. 2022b;45(suppl 1):S208-S231. doi:10.2337/dc22-S014 [PubMed 34964865]Apovian CM, Aronne LJ, Bessesen DH, et al; Endocrine Society. Pharmacological management of obesity: an Endocrine Society clinical practice guideline [published correction appears in J Clin Endocrinol Metab. 2015;100(5):2135-2136]. J Clin Endocrinol Metab. 2015;100(2):342-362. doi:10.1210/jc.2014-3415 [PubMed 25590212]Avandia (rosiglitazone) [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; November 2020.Avandia (rosiglitazone) [product monograph]. Mississauga, Ontario: GlaxoSmithKline; October 2017.Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(11):4227-4249. [PubMed 24194617]Chan LY, Yeung JH, Lau TK. Placental Transfer of Rosiglitazone in the First Trimester of Human Pregnancy. Fertil Steril. 2005;83(4):955-958. [PubMed 15820806]Copeland KC, Zeitler P, Geffner M, et al. Characteristics of Adolescents and Youth With Recent-Onset Type 2 Diabetes: The TODAY Cohort at Baseline. J Clin Endocrinol Metab. 2011;96(1):159-167. [PubMed 20962021]Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701. doi:10.2337/dci18-0033 [PubMed 30291106]DeFronzo RA. Pharmacologic Therapy for Type 2 Diabetes Mellitus. Ann Intern Med. 1999;131(4):281-303. [PubMed 10454950]Egan AM, Dow ML, Vella A. A review of the pathophysiology and management of diabetes in pregnancy. Mayo Clin Proc. 2020;95(12):2734-2746. doi:10.1016/j.mayocp.2020.02.019 [PubMed 32736942]Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on Women's Health Aspects of Polycystic Ovary Syndrome (PCOS): The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28-38. [PubMed 22153789]Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126(25):3097-3137. [PubMed 23166211]Forman LM, Simmons DA, Diamond RH. Hepatic Failure in a Patient Taking Rosiglitazone. Ann Intern Med. 2000;132(2):118-121. [PubMed 10644272]Freid J, Everitt D, Boscia J. Rosiglitazone and Hepatic Failure. Ann Intern Med. 2000;132(2):164-166.Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2020 executive summary. Endocr Pract. 2020;26(1):107-139. doi:10.4158/CS-2019-0472 [PubMed 32022600]Kahn SE, Haffner SM, Heise MA, et al. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy. N Engl J Med. 2006;355(23):2427-2443. [PubMed 17145742]Kalyoncu NI, Yaris F, Ulku C, et al. A Case of Rosiglitazone Exposure in the Second Trimester of Pregnancy. Reprod Toxicol. 2005;19(4):563-564. [PubMed 15749272]Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2020;98(supp 4):S1-S115. doi:10.1016/j.kint.2020.06.019 [PubMed 32998798]Kirkman M, Briscoe VJ, Clark N, et al. Diabetes in Older Adults: A Consensus Report. J Am Geriatr Soc. 2012;60(12):2342-2356. doi:10.1111/jgs.12035 [PubMed 23106132]LeRoith D, Biessels GJ, Braithwaite SS, et al. Treatment of diabetes in older adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2019;104(5):1520-1574. doi:10.1210/jc.2019-00198 [PubMed 30903688]Liu S, Huang T, Sahud MA, “Rosiglitazone-Induced Immune Thrombocytopenia,” Platelets, 2006, 17(3):143-8. [PubMed 16702039]Mechanick JI, Apovian C, Brethauer S, et al. Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures - 2019 update: cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, the Obesity Society, American Society for Metabolic & Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Surg Obes Relat Dis. 2020;16(2):175-247. doi:10.1016/j.soard.2019.10.025 [PubMed 31917200]Melissas J, Leventi A, Klinaki I, et al. Alterations of global gastrointestinal motility after sleeve gastrectomy: a prospective study. Ann Surg. 2013;258(6):976-982. doi: 10.1097/SLA.0b013e3182774522. [PubMed 23160151]Practice Committee of American Society for Reproductive Medicine, "Use of Insulin-Sensitizing Agents in the Treatment of Polycystic Ovary Syndrome," Fertil Steril, 2008, 90(5 Suppl):S69-73. [PubMed 19007650]Shah AS, Zeitler PS, Wong J, et al. ISPAD clinical practice consensus guidelines 2022: type 2 diabetes in children and adolescents. Pediatr Diabetes. 2022;23(7):872-902. doi:10.1111/pedi.13409 [PubMed 36161685]TODAY Study Group, Zeitler P, Epstein L, et al, "Treatment Options for Type 2 Diabetes in Adolescents and Youth: A Study of the Comparative Efficacy of Metformin Alone or in Combination With Rosiglitazone or Lifestyle Intervention in Adolescents With Type 2 Diabetes," Pediatr Diabetes, 2007, 8(2):74-87. [PubMed 17448130]TODAY Study Group, Zeitler P, Hirst K, et al, "A Clinical Trial to Maintain Glycemic Control in Youth With Type 2 Diabetes," N Engl J Med, 2012, 366(24):2247-56. [PubMed 22540912]Yaris F, Yaris E, Kadioglu M, et al, "Normal Pregnancy Outcome Following Inadvertent Exposure to Rosiglitazone, Gliclazide, and Atorvastatin in a Diabetic and Hypertensive Woman," Reprod Toxicol, 2004, 18(4):619-21. [PubMed 15135857]Topic 10249 Version 253.0

CloseBrexpiprazole: Drug informationBrexpiprazole: Drug information(For additional information see "Brexpiprazole: Patient drug information" and see "Brexpiprazole: Pediatric drug information")For abbreviations, symbols, and age group definitions used in Lexicomp (show table)ALERT: US Boxed WarningIncreased mortality in elderly patients with dementia-related psychosis:Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.Suicidal thoughts and behaviors:Antidepressants increased the risk of suicidal thoughts and behavior in patients aged 24 years and younger in short-term studies. Monitor closely for clinical worsening and for emergence of suicidal thoughts and behaviors. The safety and efficacy of brexpiprazole have not been established in pediatric patients with major depressive disorder.Brand Names: USRexultiBrand Names: CanadaRexultiPharmacologic CategorySecond Generation (Atypical) AntipsychoticDosing: AdultAgitation/aggression and psychosis associated with dementia, severe or refractoryAgitation/aggression and psychosis associated with dementia, severe or refractory (alternative agent) (off-label use):Note: For short-term adjunctive use while addressing underlying cause(s) of severe symptoms. In patients without a clinically significant response after an adequate trial (eg, up to 4 weeks), taper and withdraw therapy. Only continue in patients with demonstrated benefit; attempt to taper and withdraw at regular intervals (eg, within 4 months of initiation). Patients with dementia with Lewy bodies are at increased risk for severe adverse reactions; caution is required even with low doses (APA [Reus 2016]).Oral: Initial: 0.25 mg once daily for 3 days, then 0.5 mg once daily for 10 days, then 1 mg once daily for 2 weeks, then increase to target dose of 2 mg once daily (Grossberg 2020).Major depressive disorderMajor depressive disorder (unipolar) (adjunct to antidepressants): Oral: Initial: 0.5 mg or 1 mg once daily; titrate at weekly intervals based on response and tolerability to 1 mg once daily (if initial dose is 0.5 mg), followed by 2 mg once daily; maximum daily dose: 3 mg.SchizophreniaSchizophrenia: Oral: Initial: 1 mg once daily for 4 days, titrate based on response and tolerability to 2 mg once daily for 3 days, followed by 4 mg once daily on day 8; target dose: 2 to 4 mg/day; maximum daily dose: 4 mg.Dosage adjustment for CYP2D6 poor metabolizers: Administer 1/2 of the usual dose; in patients also taking moderate/strong CYP3A4 inhibitors, administer 1/4 of the usual dose.Dosage adjustment with concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Discontinuation of therapy: In the treatment of chronic psychiatric disease, switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (APA [Keepers 2020]; Lambert 2007; Moncrieff 2020; Post 2020).Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include: cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Stroup 2022).Dosing: Kidney Impairment: AdultCrCl ≥60 mL/minute: No dosage adjustment necessary.CrCl <60 mL/minute: Maximum dose:Major depressive disorder: 2 mg once dailySchizophrenia: 3 mg once dailyHemodialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, removal by dialysis unlikely since brexpiprazole is highly protein bound.Dosing: Hepatic Impairment: AdultMild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer’s labeling.Moderate to severe impairment (Child-Pugh class B or C): Maximum dose:Major depressive disorder: 2 mg once dailySchizophrenia: 3 mg once dailyDosing: Pediatric(For additional information see "Brexpiprazole: Pediatric drug information")SchizophreniaSchizophrenia:Adolescents <18 years: Oral: Initial: 0.5 mg once daily for 4 days (days 1 to 4); titrate to 1 mg once daily for 3 days (days 5 to 7), followed by 2 mg once daily on day 8 based on response and tolerability; target dose range: 2 to 4 mg once daily; maximum daily dose: 4 mg/day.Adolescents ≥18 years: Oral: Initial: 1 mg once daily for 4 days (days 1 to 4); titrate to 2 mg once daily for 3 days (days 5 to 7), followed by 4 mg once daily on day 8 based on response and tolerability; target dose range: 2 to 4 mg once daily; maximum daily dose: 4 mg/day.Discontinuation of therapy:Adolescents: American Academy of Child and Adolescent Psychiatry (AACAP), American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), National Institute for Health and Care Excellence (NICE), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (AACAP [McClellan 2007]; APA [Lehman 2004]; Cerovecki 2013; CPA 2005; NICE 2013; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months and the APA guidelines recommend reducing the dose by 10% each month (APA [Lehman 2004]; CPA 2005). Continuing antiparkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). When switching antipsychotics, three strategies have been suggested: Cross titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited and results are conflicting (Cerovecki 2013; Remington 2005).Dosage adjustment with concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.Dosing: Kidney Impairment: PediatricAdolescents:CrCl ≥60 mL/minute: No dosage adjustment necessary.CrCl <60 mL/minute:Schizophrenia: Oral: Maximum dose: 3 mg once daily.Hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, removal by dialysis unlikely since brexpiprazole is highly protein bound.Dosing: Hepatic Impairment: PediatricAdolescents:Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer's labeling.Moderate to severe impairment (Child-Pugh class B or C):Maximum dose: Schizophrenia: Oral: 3 mg once daily.Dosing: Older AdultRefer to adult dosing. Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia or psychosis. Titrate dosage slowly and monitor carefully (Howard 2000).Dosage Forms: USExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Rexulti: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg [contains corn starch]Generic Equivalent Available: USNoDosage Forms: CanadaExcipient information presented when available (limited, particularly for generics); consult specific product labeling.Tablet, Oral: Rexulti: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg [contains corn starch]Tablet Therapy Pack, Oral: Rexulti: 0.5 & 1 MG (14 ea) [contains corn starch]Medication Guide and/or Vaccine Information Statement (VIS)An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:Rexulti: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205422s005lbl.pdf#page=27Administration: AdultOral: Administer with or without food.Administration: PediatricOral: Administer with or without food.Use: Labeled IndicationsMajor depressive disorder (unipolar): Adjunctive treatment in adults for the treatment of major depressive disorder.Schizophrenia: Treatment of schizophrenia in pediatric patients ≥13 years of age and adults.Use: Off-Label: AdultAgitation/aggression and psychosis associated with dementia, severe or refractoryMedication Safety IssuesOlder Adult: High-Risk Medication:Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions, or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible In addition, antipsychotics should be used with caution in the elderly due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2019]).Adverse ReactionsThe following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.>10%:Endocrine & metabolic: Increased serum triglycerides (<500 mg/dL: 9% to 13%; ≥500 mg/dL: <1%), weight gain (3% to 11%)Nervous system: Akathisia (4% to 14%; dose related)1% to 10%:Dermatologic: Hyperhidrosis (≥1%)Endocrine & metabolic: Decreased cortisol (3% to 4%), increased serum prolactin (≥1%)Gastrointestinal: Abdominal pain (≥1%), constipation (2% to 3%), diarrhea (3%), dyspepsia (3% to 6%), flatulence (≥1%), increased appetite (3%), nausea (≥1%), sialorrhea (≥1%), xerostomia (≥1%)Genitourinary: Urinary tract infection (≥1%)Nervous system: Abnormal dreams (≥1%), anxiety (2% to 4%), dizziness (2% to 5%), drowsiness (4% to 6%), drug-induced extrapyramidal reaction (5% to 6%), fatigue (3% to 5%), headache (9%), insomnia (≥1%), restlessness (2% to 4%; dose-related), sedated state (2% to 3%)Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (2% to 4%), myalgia (≥1%), tremor (2% to 5%)Ophthalmic: Blurred vision (≥1%)Respiratory: Nasopharyngitis (3% to 7%)<1%: Cardiovascular: Orthostatic hypotension, syncopeFrequency not defined:Endocrine & metabolic: HyperglycemiaNervous system: Dystonia, suicidal ideation, suicidal tendenciesPostmarketing:Endocrine & metabolic: Diabetes mellitus, dyslipidemiaNervous system: Impulse control disorder (including pathological gambling, increased libido, shopping, eating), neuroleptic malignant syndromeContraindicationsHypersensitivity (eg, anaphylaxis, facial swelling, rash, urticaria) to brexpiprazole or any component of the formulationWarnings/PrecautionsConcerns related to adverse reactions:• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC/ANC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.• Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of antipsychotics for the unapproved use in elderly patients with dementia-related psychosis.• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).• Dyslipidemia: Has been reported with atypical antipsychotics; risk profile may differ between agents. In clinical trials, the incidence of hypertriglyceridemia observed with brexpiprazole was greater than observed with placebo, while changes in fasting total cholesterol, LDL, and HDL were similar.• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer disease), particularly in patients >75 years (Herzig 2017; Maddalena 2004).• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Keepers 2020]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability.• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. All patients should be monitored for symptoms of hyperglycemia (eg, polydipsia, polyuria, polyphagia, weakness). Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar (FBS) and periodic assessment of glucose regulation. Hyperglycemia may resolve with discontinuation of antipsychotic; some patients may require treatment of diabetes after discontinuation of therapy.• Impulse control disorders: Has been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, uncontrolled sexual urges, uncontrolled spending, binge or compulsive eating, and/or other intense urges. Patients with prior history of impulse control issues may be at increased risk. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in most, but not all, cases.• Neuroleptic malignant syndrome: Neuroleptic malignant syndrome (NMS) has been associated with use of antipsychotic agents, including brexpiprazole; monitor for mental status changes, fever, muscle rigidity and/or autonomic instability, elevated creatinine phosphokinase, rhabdomyolysis, and/or acute renal failure. Discontinue treatment immediately if NMS is suspected and initiate symptomatic treatment and monitoring.• Orthostatic hypotension: May cause orthostatic hypotension; increased risk at initiation of therapy or during dose escalation. Use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (patients who are antipsychotic-naive or have cerebrovascular disease, cardiovascular disease, hypovolemia, dehydration, or are taking concurrent medication use which may predispose to hypotension/bradycardia). Consider using lower starting dosages and slower titrations in these patients.• Temperature regulation: Antipsychotic use has been associated with impaired core body temperature regulation; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitoring of weight is recommended.Disease-related concerns:• Dementia: Most deaths in elderly patients with dementia-related psychosis treated with antipsychotics appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. (APA [Reus 2016]).• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment needed if CrCl <60 mL/minute.• Seizures: Use with caution in patients at risk of seizures or with conditions that potentially lower the seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.Dosage form specific issues:• Lactose: Tablets may contain lactose; avoid use in patients with galactose intolerance or glucose-galactose malabsorption.Other warnings/precautions:• Discontinuation of therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternate feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).Metabolism/Transport EffectsSubstrate of CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potentialDrug InteractionsNote: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed).For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapyAgents With Seizure Threshold Lowering Potential: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased. Risk C: Monitor therapyAjmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapyAlcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).Risk C: Monitor therapyAlizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyAmifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine.Risk C: Monitor therapyAmisulpride (Oral): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome or increased QTc interval may be increased. Risk C: Monitor therapyAmphetamines: Antipsychotic Agents may enhance the adverse/toxic effect of Amphetamines. Antipsychotic Agents may diminish the stimulatory effect of Amphetamines.Risk C: Monitor therapyAntidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.Risk C: Monitor therapyAnti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist).Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modificationAntipsychotic Agents: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased.Risk C: Monitor therapyArtemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapyAzelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBlonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin.Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modificationBlood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapyBrexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone.Risk C: Monitor therapyBrimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyBromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combinationBromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationBuprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine.Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modificationBuPROPion: Brexpiprazole may enhance the adverse/toxic effect of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase the serum concentration of Brexpiprazole.Management: Reduce brexpiprazole dose to 50% of usual dose with bupropion; reduce to 25% of usual if used with both bupropion and a strong or moderate CYP3A4 inhibitor. These recommendations do not apply if treating major depressive disorder. Monitor for seizures. Risk D: Consider therapy modificationCabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combinationCannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.Risk C: Monitor therapyChlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modificationChlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapyClofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapyCNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapyCYP2D6 Inhibitors (Moderate): May increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose when treating indications other than major depressive disorder. Risk C: Monitor therapyCYP2D6 Inhibitors (Strong): May increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with strong CYP2D6 inhibitors, reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor; these recommendations do not apply if treating major depressive disorder Risk D: Consider therapy modificationCYP3A4 Inducers (Moderate): May decrease the serum concentration of Brexpiprazole. Risk C: Monitor therapyCYP3A4 Inducers (Strong): May decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Decrease brexpiprazole to original dose over 1 to 2 weeks if the strong CYP3A4 inducer is discontinued. Risk D: Consider therapy modificationCYP3A4 Inhibitors (Moderate): May increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Risk C: Monitor therapyCYP3A4 Inhibitors (Strong): May increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose 50% with strong CYP3A4 inhibitors; reduce to 25% of usual if used with both a strong CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer. Risk D: Consider therapy modificationDaridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationDeutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapyDexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine.Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modificationDexmethylphenidate-Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined.Risk C: Monitor therapyDifelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyDoxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants isnot recommended. Risk C: Monitor therapyDroperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modificationEsketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyFexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationFlunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine.Risk X: Avoid combinationFlunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modificationFusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combinationGuanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine.Risk C: Monitor therapyHydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modificationIohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased.Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modificationIomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased.Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modificationIopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased.Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modificationKava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyKratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationLemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modificationLithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapyLofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMagnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyMequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine.Management: Consider alternatives to one of these agents when possible.While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modificationMethotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modificationMetoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combinationMetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE.Risk C: Monitor therapyMetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapyMinocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyOlopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOpioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists.Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationOrphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine.Risk X: Avoid combinationOxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combinationOxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products.Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modificationOxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE.Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modificationParaldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde.Risk X: Avoid combinationPeginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapyPerampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyPiribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents.Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid combinationProcarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyQuinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide.Risk C: Monitor therapyRopeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased.Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modificationRufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapySerotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapySodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities.Risk C: Monitor therapySt John's Wort: May decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with St John's wort, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Decrease brexpiprazole to original dose over 1 to 2 weeks if St John's wort is discontinued. Risk D: Consider therapy modificationSulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride.Risk X: Avoid combinationSuvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant.Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary.Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modificationTetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapyThalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide.Risk X: Avoid combinationTrimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyValerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapyZolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem.Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg formen who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modificationPregnancy ConsiderationsAntipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (Yonkers 2009). The ACOG recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy is limited and routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to a typical antipsychotic that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008).Health care providers are encouraged to enroll women exposed to brexpiprazole during pregnancy in the National Pregnancy Registry for Atypical Antipsychotics (866-961-2388 or http://www.womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/).Breastfeeding ConsiderationsIt is not known if brexpiprazole is present in breast milk. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.Monitoring ParametersFrequency of Antipsychotic Monitoringa,bMonitoring parameterFrequency of monitoringCommentsAdherenceEvery visitBlood chemistries (electrolytes, renal function, liver function, TSH)AnnuallyCBCAs clinically indicatedCheck frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropeniaExtrapyramidal symptomsEvery visit; 4 weeks after initiation and dose change; annually. Use a formalized rating scale at least annually or every 6 months if high riskcFall riskEvery visitFasting plasma glucose/HbA1c12 weeks after initiation and dose change; annuallyCheck more frequently than annually if abnormal. Follow diabetes guidelines.Lipid panel12 weeks after initiation and dose change; annuallyCheck more frequently than annually if abnormal. Follow lipid guidelines.Mental status and alertnessEvery visitMetabolic syndrome historyAnnuallyEvaluate for personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular diseaseProlactinAsk about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported.Hyperprolactinemia symptoms: Changes in menstruation, libido, gynecomastia, development of galactorrhea, and erectile and ejacul*tory functionTardive dyskinesiaEvery visit; annually. Use a formalized rating scale at least annually or every 6 months if high riskdVital signs (BP, orthostatics, temperature, pulse, signs of infection)Every visit (at least weekly during first 3 to 4 weeks of treatment); 4 weeks after dose change.Weight/Height/BMI8 and 12 weeks after initiation and dose change; quarterlyConsider monitoring waist circumference at baseline and annually, especially in patients with or at risk for metabolic syndrome.Consider changing antipsychotic if BMI increases by ≥1 unit.Some experts recommend checking weight and height at every visit.a For all monitoring parameters, it is appropriate for check at baseline and when clinically relevant (based on symptoms or suspected ADRs) in addition to the timeline.b ADA 2004; APA [Keepers 2020]; de Hert 2011; Gugger 2011; manufacturer’s labeling.c Risk factors for extrapyramidal symptoms (EPS) include prior history of EPS, high doses of antipsychotics, young age (children and adolescents at higher risk than adults), and dopaminergic affinity of individual antipsychotic.d Risk factors for tardive dyskinesia include age >55 years; females; White or African ethnicity; presence of a mood disorder, intellectual disability, or CNS injury; and past or current EPS.Reference RangeTiming of serum samples: Draw trough just before next dose (Hiemke 2018).Therapeutic reference range: 40 to 140 ng/mL (Hiemke 2018). Note: Dosing should be based on therapeutic response as opposed to serum concentrations; however, therapeutic drug monitoring can be used to confirm adherence (APA [Keepers 2020]).Laboratory alert level: 280 ng/mL (Hiemke 2018).Mechanism of ActionBrexpiprazole exhibits partial agonist activity for 5-HT1A and D2 receptors and antagonist activity for 5-HT2A receptors.Pharmaco*kineticsOnset of action: Oral:Major depressive disorder, unipolar: Initial effects may be observed within 1 week with continued improvements over 6 to 12 weeks (Wen 2014).Schizophrenia: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).Distribution: Vd: IV: 1.56 L/kgProtein binding: >99%, primarily to serum albumin and alpha1-acid glycoproteinMetabolism: Hepatic, primarily by CYP3A4 and CYP2D6; major metabolite, DM-3411 (inactive)Bioavailability: 95%Half-life elimination: Terminal: Brexpiprazole: 91 hours; DM-3411: 86 hoursTime to peak, plasma: Within 4 hoursExcretion: Feces (46%, ~14% of the total dose as unchanged drug); urine (25%, <1% of the total dose as unchanged drug)Pharmaco*kinetics: Additional ConsiderationsAltered kidney function: AUC was increased in patients with renal impairment (CrCl <60 mL/minute) compared to patients with normal renal function.Hepatic function impairment: AUC increased in patients with moderate to severe hepatic impairment.CYP2D6 poor metabolizers: Increased Cmax is observed in CYP2D6 poor metabolizers compared to normal CYP2D6 metabolizers.Pricing: USTablets (Rexulti Oral)0.25 mg (per each): $53.300.5 mg (per each): $53.301 mg (per each): $53.302 mg (per each): $53.303 mg (per each): $53.304 mg (per each): $53.30Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursem*nt or purchasing functions or considered to be an exact price for a single product and/or manufacturer.Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions.In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data.Pricing data is updated monthly.Brand Names: InternationalRexulti (AU, CH, HK, JP, TW);Rxulti (HR, PL)For country code abbreviations (show table)2019 American Geriatrics Society Beers Criteria Update Expert Panel. 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