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Pronunciation
(vor i KOE na zole)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of invasive aspergillosis; treatment of esophageal candidiasis; treatment of candidemia (in non-neutropenic patients); treatment of disseminated Candida infections of the skin and viscera; treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp (including Fusarium solani) in patients intolerant of, or refractory to, other therapy
Use: Unlabeled/Investigational
Fungal infection prophylaxis in intermediate or high risk neutropenic cancer patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), neutropenic allogeneic hematopoietic stem cell recipients, and patients with significant graft-versus-host disease; empiric antifungal therapy (second-line) for persistent neutropenic fever
Pregnancy Risk Factor
D
Pregnancy Considerations
Voriconazole can cause fetal harm when administered to a pregnant woman. Voriconazole was teratogenic and embryotoxic in animal studies, and lowered plasma estradiol in animal models. Women of childbearing potential should use effective contraception during treatment. Should be used in pregnant woman only if benefit to mother justifies potential risk to the fetus.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Excretion in breast milk has not been investigated; avoid breast-feeding until additional data are available.
Contraindications
Hypersensitivity to voriconazole or any component of the formulation (cross-reaction with other azole antifungal agents may occur but has not been established, use caution); coadministration of CYP3A4 substrates which may lead to QTc prolongation (cisapride, pimozide, or quinidine); coadministration with barbiturates (long acting), carbamazepine, efavirenz (with standard [eg, not adjusted] voriconazole and efavirenz doses), ergot derivatives, rifampin, rifabutin, ritonavir (?800 mg/day), sirolimus, St John's wort
Warnings/Precautions
Concerns related to adverse effects:
• Arrhythmias/QT prolongation: QT interval prolongation has been associated with voriconazole use; rare cases of arrhythmia (including torsade de pointes), cardiac arrest, and sudden death have been reported, usually in seriously ill patients with comorbidities and/or risk factors (eg, prior cardiotoxic chemotherapy, cardiomyopathy, electrolyte imbalance, or concomitant QTc-prolonging drugs). Use with caution in these patient populations; correct electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia) prior to initiating therapy.
• Dermatologic reactions: Rarely, serious cutaneous reactions, including Stevens-Johnson syndrome have been reported with treatment. Consider discontinuing in patients developing a rash. Avoid strong, direct exposure to sunlight; may cause photosensitivity, especially with long-term use.
• Hallucinations: Visual and/or auditory hallucinations have been observed. Possibly dependent on serum concentrations and may be more common with the I.V. formulation.
• Ocular effects: Visual changes, including blurred vision, changes in visual acuity, color perception, and photophobia, are commonly associated with treatment. Patients should be warned to avoid tasks which depend on vision, including operating machinery or driving. Changes are reversible on discontinuation following brief exposure/treatment regimens (?28 days); reversibility following long-term administration has not been evaluated.
Disease-related concerns:
• Hepatic impairment: Serious (and rarely fatal) hepatic toxicity (eg, hepatitis, cholestasis, fulminant failure) has been observed with azole therapy. Use with caution in patients with pre-existing hepatic impairment; monitor liver function closely and dosage adjustment or discontinuation may be warranted.
• Pancreatitis: Monitor pancreatic function in patients (children and adults) at risk for acute pancreatitis (eg, recent chemotherapy or hematopoietic stem cell transplantation). There have been postmarketing reports of pancreatitis in children.
• Renal impairment: Avoid the use of I.V. voriconazole in patients with renal impairment. See “Dosage forms specific issues: Injectable” below. Acute renal failure has been observed in severely ill patients; use with caution in patients receiving concomitant nephrotoxic medications.
Concurrent drug therapy issues:
• High potential for interactions: Use caution in patients taking strong cytochrome P450 inducers, CYP2C9 inhibitors, and major 3A4 substrates (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children <12 years of age.
Dosage form specific issues:
• Injectable: Avoid/limit use of intravenous formulation in patients with renal impairment; intravenous formulation contains excipient cyclodextrin (sulfobutyl ether beta-cyclodextrin), which may accumulate in renal insufficiency. Anaphylactoid-type infusion-related reactions may occur with intravenous dosing. Consider discontinuation of infusion if reaction is severe. Do not infuse concomitantly with blood products or short-term concentrated electrolyte solutions, even if the two infusions are running in separate intravenous lines (or cannulas).
• Lactose: Tablets contain lactose; avoid administration in hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
• Sucrose: Suspension contains sucrose; use caution with fructose intolerance, sucrose-isomaltase deficiency, or glucose-galactose malabsorption.
Adverse Reactions
>10%:
Central nervous system: Hallucinations (4% to 12%; auditory and/or visual and likely serum concentration-dependent)
Ocular: Visual changes (dose related; photophobia, color changes, increased or decreased visual acuity, or blurred vision occur in ~21%)
Renal: Creatinine increased (1% to 21%)
2% to 10%:
Cardiovascular: Tachycardia (?2%)
Central nervous system: Fever (?6%), chills (?4%), headache (?3%)
Dermatologic: Rash (?7%)
Endocrine & metabolic: Hypokalemia (?2%)
Gastrointestinal: Nausea (1% to 5%), vomiting (1% to 4%)
Hepatic: Alkaline phosphatase increased (4% to 5%), AST increased (2% to 4%), ALT increased (2% to 3%), cholestatic jaundice (1% to 2%)
Ocular: Photophobia (2% to 3%)
<2% (Limited to important or life-threatening): Acute tubular necrosis, adrenal cortical insufficiency, agranulocytosis, allergic reaction, alopecia, anaphylactoid reaction, anemia (aplastic, hemolytic, macrocytic, megaloblastic, or microcytic), angioedema, anuria, ascites, ataxia, atrial arrhythmia, atrial fibrillation, AV block, bigeminy, bleeding time increased, bone marrow depression, bone necrosis, bradycardia, brain edema, bundle branch block, BUN increased, cardiac arrest, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, chest pain, CHF, cholecystitis, cholelithiasis, chromatopsia, color blindness, coma, confusion, cyanosis, delirium, dementia, depersonalization, depression, diabetes insipidus, diarrhea, DIC, discoid lupus erythematosus, duodenal ulcer perforation, DVT, dyspnea, edema, encephalopathy, endocarditis, eosinophilia, erythema multiforme, exfoliative dermatitis, extrapyramidal symptoms, fixed drug eruption, fulminant hepatic failure, gastrointestinal hemorrhage, GGT/LDH increased, glucose tolerance decreased, grand mal seizure, Guillain-Barré syndrome, hematemesis, hepatic coma, hepatic failure, hepatitis, hepatomegaly, hydronephrosis, hyperbilirubinemia, hypercholesterolemia, hyper-/hypocalcemia, hyper-/hypoglycemia, hyper-/hypomagnesemia, hyper-/hyponatremia, hyper-/hypotension, hyper-/hypothyroidism, hyperkalemia, hyperuricemia, hypophosphatemia, hypoxia, intestinal perforation, intracranial hypertension, jaundice, leukopenia, liver enlarged, lung edema, lymphadenopathy, lymphangitis, maculopapular rash, MI, multiorgan failure, myasthenia, myopathy, nephritis, nephrosis, neuropathy, night blindness, nodal arrhythmia, oculogyric crisis, optic atrophy, optic neuritis, osteomalacia, osteoporosis, palpitation, pancreatitis, pancytopenia, papilledema, paresthesia, peripheral edema, peritonitis, petechia, photosensitivity, pleural effusion, postural hypotension, pruritus, pseudomembraneous colitis, psychosis, pulmonary embolus, purpura, QT interval prolongation, renal dysfunction, renal failure (acute), respiratory distress syndrome, retinal hemorrhage, seizure, sepsis, somnolence, spleen enlarged, Stevens-Johnson syndrome, substernal chest pain, suicidal ideation, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombocytopenia, thrombophlebitis, thrombotic thrombocytopenic purpura, tongue edema, torsade de pointes, toxic epidermal necrolysis, uremia, urinary retention, urticaria, uveitis, vasodilation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, visual field defect
Metabolism/Transport Effects
Substrate of CYP2C9 (major), 2C19 (major), 3A4 (minor); Inhibits CYP2C9 (weak), 2C19 (weak), 3A4 (moderate)
Drug Interactions
Alfentanil: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Alfentanil. Risk D: Consider therapy modification
Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Risk X: Avoid combination
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan dose to 6.25mg and maximum dose to 12.5mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Risk D: Consider therapy modification
Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Risk C: Monitor therapy
Amphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B. Risk C: Monitor therapy
Antineoplastic Agents (Vinca Alkaloids): Voriconazole may enhance the adverse/toxic effect of Antineoplastic Agents (Vinca Alkaloids). Voriconazole may increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Risk D: Consider therapy modification
Aprepitant: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Aprepitant. Risk C: Monitor therapy
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Barbiturates: May decrease the serum concentration of Voriconazole. Exceptions: Methohexital; PENTobarbital; Secobarbital; Thiopental. Risk X: Avoid combination
Benzodiazepines (metabolized by oxidation): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Quazepam. Risk D: Consider therapy modification
Bosentan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Bosentan. Risk C: Monitor therapy
BusPIRone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of BusPIRone. Risk D: Consider therapy modification
Busulfan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Busulfan. Risk C: Monitor therapy
Calcium Channel Blockers: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Exceptions: Clevidipine. Risk D: Consider therapy modification
CarBAMazepine: May decrease the serum concentration of Voriconazole. Risk X: Avoid combination
CarBAMazepine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CarBAMazepine. Risk C: Monitor therapy
Cardiac Glycosides: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Cardiac Glycosides. Risk D: Consider therapy modification
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciclesonide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ciclesonide. Specifically, concentrations of the active des-ciclesonide metabolite may be increased. Risk C: Monitor therapy
Cilostazol: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Cilostazol. Risk D: Consider therapy modification
Cinacalcet: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Cinacalcet. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Cisapride: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Cisapride. Risk X: Avoid combination
Colchicine: 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. Risk D: Consider therapy modification
Conivaptan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Conivaptan. Risk X: Avoid combination
Corticosteroids (Orally Inhaled): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Corticosteroids (Orally Inhaled). Exceptions: Beclomethasone; Flunisolide; Triamcinolone. Risk C: Monitor therapy
Corticosteroids (Systemic): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Corticosteroids (Systemic). Risk C: Monitor therapy
CycloSPORINE: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification
CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Darunavir: May decrease the serum concentration of Voriconazole. Risk X: Avoid combination
Diclofenac: Voriconazole may increase the serum concentration of Diclofenac. Risk D: Consider therapy modification
Didanosine: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Enteric coated didanosine capsules are not expected to affect these antifungals. Risk D: Consider therapy modification
Docetaxel: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Docetaxel. Risk D: Consider therapy modification
Dofetilide: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Dofetilide. Risk X: Avoid combination
Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Risk X: Avoid combination
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Risk C: Monitor therapy
Eletriptan: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Eletriptan. Risk D: Consider therapy modification
Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Risk X: Avoid combination
Eplerenone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Eplerenone. Risk D: Consider therapy modification
Ergot Derivatives: Voriconazole may increase the serum concentration of Ergot Derivatives. Risk X: Avoid combination
Erlotinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Erlotinib. Risk C: Monitor therapy
Eszopiclone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Eszopiclone. Risk C: Monitor therapy
Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Risk X: Avoid combination
FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Risk D: Consider therapy modification
Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4mg daily in patients who are also receiving strong CYP3A4 inhibitors. Risk D: Consider therapy modification
Fosaprepitant: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Fosaprepitant. Specifically, concentrations of aprepitant are likely to be increased. Risk C: Monitor therapy
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Gefitinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Gefitinib. Risk C: Monitor therapy
Grapefruit Juice: May increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This specifically applies to oral antifungal administration, and the interaction may be different depending on specific dosage form being used. Risk C: Monitor therapy
Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Risk X: Avoid combination
HMG-CoA Reductase Inhibitors: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of HMG-CoA Reductase Inhibitors. Exceptions: Fluvastatin; Rosuvastatin. Risk D: Consider therapy modification
Imatinib: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Imatinib. Risk C: Monitor therapy
Irinotecan: Antifungal Agents (Azole Derivatives, Systemic) may enhance the adverse/toxic effect of Irinotecan. Risk D: Consider therapy modification
Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Risk D: Consider therapy modification
Lopinavir: May decrease the serum concentration of Voriconazole. Risk X: Avoid combination
Losartan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Losartan. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Macrolide Antibiotics: May decrease the metabolism of Antifungal Agents (Azole Derivatives, Systemic). Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Macrolide Antibiotics. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification
Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: When used with a strong CYP3A4 inhibitor, the adult dose of maraviroc should be decreased to 150 mg twice daily. Risk D: Consider therapy modification
Methadone: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Methadone. Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Risk X: Avoid combination
Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Risk X: Avoid combination
Oral Contraceptive (Estrogens): Voriconazole may decrease the metabolism of Oral Contraceptive (Estrogens). Oral Contraceptive (Estrogens) may increase the serum concentration of Voriconazole. Risk C: Monitor therapy
Oral Contraceptive (Progestins): Voriconazole may decrease the metabolism of Oral Contraceptive (Progestins). Oral Contraceptive (Progestins) may increase the serum concentration of Voriconazole. Risk C: Monitor therapy
Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
Phenytoin: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Phosphodiesterase 5 Inhibitors: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Phosphodiesterase 5 Inhibitors. Risk D: Consider therapy modification
Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Pimozide: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Pimozide. Risk X: Avoid combination
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Risk C: Monitor therapy
Protease Inhibitors: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Protease Inhibitors. Protease Inhibitors may increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Management: Limit indinavir to 600mg every 8 hours with itraconazole or ketoconazole. When used with ritonavir, limit ketoconazole to 200mg/day. Tipranavir labeling recommends limiting fluconazole, itraconazole, and ketoconazole to 200mg with tipranavir/ritonavir. Risk D: Consider therapy modification
Proton Pump Inhibitors: May increase the serum concentration of Voriconazole. Risk C: Monitor therapy
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QuiNIDine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of QuiNIDine. Management: Itraconazole, voriconazole, and posaconazole are specifically contraindicated with quinidine. Use of quinidine with any azole antifungal may require quinidine dose adjustment and should be done with caution and close monitoring. Risk X: Avoid combination
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Ramelteon: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ramelteon. Risk C: Monitor therapy
Ranolazine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ranolazine. Risk X: Avoid combination
Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Risk X: Avoid combination
Repaglinide: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Repaglinide. Management: Concurrent use of an azole antifungal with both repaglinide and gemfibrozil should be avoided. Risk C: Monitor therapy
Reverse Transcriptase Inhibitors (Non-Nucleoside): May decrease the serum concentration of Voriconazole. Voriconazole may increase the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Management: Efavirenz and voriconazole should not be coadministered at standard doses. Concurrent therapy is acceptable if voriconazole is dosed at 400 mg every 12 hours and efavirenz is dosed at 300 mg daily throughout the course of therapy. Exceptions: Delavirdine; Etravirine. Risk D: Consider therapy modification
Rifamycin Derivatives: Voriconazole may increase the serum concentration of Rifamycin Derivatives. Rifamycin Derivatives may decrease the serum concentration of Voriconazole. Risk X: Avoid combination
Rifamycin Derivatives: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Rifamycin Derivatives. Only rifabutin appears to be affected. Rifamycin Derivatives may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Risk D: Consider therapy modification
Ritonavir: May increase the metabolism of Voriconazole. High-dose ritonavir (400 mg every 12 hours) is contraindicated. Use caution with lower doses. Risk X: Avoid combination
Rivaroxaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rivaroxaban. Risk X: Avoid combination
Saccharomyces boulardii: Antifungal Agents may diminish the therapeutic effect of Saccharomyces boulardii. Risk D: Consider therapy modification
Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Risk X: Avoid combination
Saxagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Saxagliptin. Management: Limit saxagliptin dosage to 2.5 mg/day and monitor for increased saxagliptin levels/effects (e.g., hypoglycemia) with concomitant use of a strong CYP3A4 inhibitor. Monitor for decreased saxagliptin levels/effects if discontinuing CYP3A4 inhibitor. Risk D: Consider therapy modification
Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Risk X: Avoid combination
Sirolimus: Voriconazole may increase the serum concentration of Sirolimus. Risk X: Avoid combination
Solifenacin: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Solifenacin. Risk D: Consider therapy modification
Sorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sorafenib. Risk C: Monitor therapy
St Johns Wort: May decrease the serum concentration of Voriconazole. Risk X: Avoid combination
Sucralfate: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Risk C: Monitor therapy
Sunitinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Sunitinib. Risk D: Consider therapy modification
Tacrolimus: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tacrolimus. Risk D: Consider therapy modification
Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Erectile dysfunction: tadalafil max = 2.5 mg/day (daily use) or 10 mg/72 hrs (as needed use). Avoid use of tadalafil for treatment of pulmonary arterial hypertension in patients also receiving a strong CYP3A4 inhibitor. Risk D: Consider therapy modification
Temsirolimus: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are likely to be increased more substantially than those of the parent temsirolimus. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tolterodine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tolterodine. This is likely only of concern in CYP2D6-deficient patients (ie, "poor metabolizers") Risk D: Consider therapy modification
Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination
Trimetrexate: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Trimetrexate. Risk C: Monitor therapy
Venlafaxine: Voriconazole may enhance the adverse/toxic effect of Venlafaxine. Voriconazole may increase the serum concentration of Venlafaxine. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Voriconazole may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ziprasidone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ziprasidone. Risk C: Monitor therapy
Zolpidem: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Zolpidem. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Food: May decrease voriconazole absorption. Voriconazole should be taken 1 hour before or 1 hour after a meal. Avoid grapefruit juice (may decrease voriconazole levels).
Herb/Nutraceutical: St John's wort may decrease voriconazole levels; concurrent use with voriconazole is contraindicated.
Storage
Powder for injection: Store at 15°C to 30°C (59°F to 86°F). Reconstituted solutions are stable for up to 24 hours under refrigeration at 2°C to 8°C (36°F to 46°F).
Powder for oral suspension: Store at 2°C to 8°C (36°F to 46°F). Reconstituted oral suspension may be stored at 15°C to 30°C (59°F to 86°F).
Tablets: Store at 15°C to 30°C (59°F to 86°F).
Reconstitution
Powder for injection: Reconstitute 200 mg vial with 19 mL of sterile water for injection (use of automated syringe is not recommended). Resultant solution (20 mL) has a concentration of 10 mg/mL. Prior to infusion, must dilute to 0.5-5 mg/mL with NS, LR, D5WLR, D5W1/2NS, D5W, D5W with KCl 20 mEq, 1/2NS, or D5WNS. Do not dilute with 4.2% sodium bicarbonate infusion.
Powder for oral suspension: Add 46 mL of water to the bottle to make 40 mg/mL suspension. Discard unused portion after 14 days.
Compatibility
Stable in NS, LR, D5WLR, D5W1/2NS, D5W, D5W with KCl 20 mEq, 1/2NS, or D5WNS. Do not infuse concomitantly into same line or cannula with other drug infusions, including TPN. May be infused simultaneously with TPN through a separate I.V. line.
Incompatible: Do not infuse simultaneously with blood products.
Mechanism of Action
Interferes 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.
Pharmacodynamics/Kinetics
Absorption: Well absorbed after oral administration; administration of crushed tablets is considered bioequivalent to whole tablets
Distribution: Vd: 4.6 L/kg
Protein binding: 58%
Metabolism: Hepatic, via CYP2C19 (major pathway) and CYP2C9 and CYP3A4 (less significant); saturable (may demonstrate nonlinearity)
Bioavailability: 96%
Half-life elimination: Variable, dose-dependent
Time to peak: Oral: 1-2 hours; 0.5 hours (crushed tablet)
Excretion: Urine (as inactive metabolites; <2% as unchanged drug)
Dosage
Usual dosage ranges:
Children <12 years: Dosage not established
Children ?12 years and Adults:
Oral: 100-300 mg every 12 hours
I.V.: 6 mg/kg every 12 hours for 2 doses; followed by maintenance dose of 4 mg/kg every 12 hours
Indication-specific dosing: Children ?12 years and Adults:
Aspergillosis, invasive, including disseminated and extrapulmonary infection: Duration of therapy should be a minimum of 6-12 weeks or throughout period of immunosuppression:
I.V.: Initial: Loading dose: 6 mg/kg every 12 hours for 2 doses; followed by maintenance dose of 4 mg/kg every 12 hours
Oral: May consider oral therapy in place of I.V. with dosing of 4 mg/kg (rounded up to convenient tablet dosage form) every 12 hours; however, I.V. administration is preferred in serious infections since comparative efficacy with the oral formulation has not been established.
Scedosporiosis, fusariosis: I.V.: Initial: Loading dose: 6 mg/kg every 12 hours for 2 doses; followed by maintenance dose of 4 mg/kg every 12 hours
Candidemia and other deep tissue
Candida
infections: I.V.: Initial: Loading dose 6 mg/kg every 12 hours for 2 doses; followed by maintenance dose of 3-4 mg/kg every 12 hours
Endophthalmitis, fungal (unlabeled use, Pappas, 2009): I.V.: 6 mg/kg every 12 hours for 2 doses, then 3-4 mg/kg every 12 hours
Esophageal candidiasis: Oral:
Patients <40 kg: 100 mg every 12 hours; maximum: 300 mg/day
Patients ?40 kg: 200 mg every 12 hours; maximum: 600 mg/day
Note: Treatment should continue for a minimum of 14 days, and for at least 7 days following resolution of symptoms.
Conversion to oral dosing:
Patients <40 kg: 100 mg every 12 hours; increase to 150 mg every 12 hours in patients who fail to respond adequately
Patients ?40 kg: 200 mg every 12 hours; increase to 300 mg every 12 hours in patients who fail to respond adequately
Dosage adjustment in patients unable to tolerate treatment:
I.V.: Dose may be reduced to 3 mg/kg every 12 hours
Oral: Dose may be reduced in 50 mg decrements to a minimum dosage of 200 mg every 12 hours in patients weighing ?40 kg (100 mg every 12 hours in patients <40 kg)
Dosage adjustment in patients receiving concomitant CYP450 enzyme inducers or substrates:
Cyclosporine: Reduce cyclosporine dose by 1/2 and monitor closely.
Efavirenz: Oral: Increase maintenance dose of voriconazole to 400 mg every 12 hours and reduce efavirenz dose to 300 mg once daily
Phenytoin:
I.V.: Increase maintenance dosage to 5 mg/kg every 12 hours
Oral: Increase dose to 400 mg every 12 hours in patients ?40 kg (200 mg every 12 hours in patients <40 kg)
Dosage adjustment in renal impairment: In patients with Clcr <50 mL/minute, accumulation of the intravenous vehicle (cyclodextrin) occurs. After initial I.V. loading dose, oral voriconazole should be administered to these patients, unless an assessment of the benefit:risk to the patient justifies the use of I.V. voriconazole. Monitor serum creatinine and change to oral voriconazole therapy when possible.
Hemodialysis: Oral dosage adjustment not required; I.V. dosing not recommended since cyclodextrin vehicle is cleared at half the rate of voriconazole and may accumulate
Dosage adjustment in hepatic impairment:
Mild-to-moderate hepatic dysfunction (Child-Pugh class A and B): Following standard loading dose, reduce maintenance dosage by 50%
Severe hepatic impairment: Should only be used if benefit outweighs risk; monitor closely for toxicity
Administration: Oral
Administer 1 hour before or 1 hour after a meal.
Administration: I.V.
Infuse over 1-2 hours (rate not to exceed 3 mg/kg/hour). Do not infuse concomitantly into same line or cannula with other drug infusions, including TPN.
Monitoring Parameters
Hepatic function at initiation and during course of treatment; renal function; serum electrolytes (particularly calcium, magnesium and potassium) prior to therapy initiation; visual function (visual acuity, visual field and color perception) if treatment course continues >28 days; may consider obtaining voriconazole trough level in patients failing therapy or exhibiting signs of toxicity; pancreatic function (in patients at risk for acute pancreatitis)
Dietary Considerations
Oral: Should be taken 1 hour before or 1 hour after a meal. Voriconazole tablets contain lactose; avoid administration in hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. Suspension contains sucrose; use caution with fructose intolerance, sucrose-isomaltase deficiency, or glucose-galactose malabsorption.
Patient Education
Do not take any new medication during therapy unless approved by prescriber. I.V.: You will be monitored during intravenous administration; report immediately any pain, swelling, redness at infusion site, difficulty breathing or swallowing, back pain, itching, or other adverse effects. Oral: Take full course of medication as ordered. Preferable to take on empty stomach 1 hour before or 1 hour after a meal. Maintain adequate hydration unless instructed to restrict fluid intake. You may experience headache, dizziness, blurred vision, photophobia, or changes in visual acuity (use caution when driving or engaging in tasks that require alertness until response to drug is known; vision changes are reversible shortly after treatment is completed or discontinued); nausea, vomiting, or abdominal pain (small frequent meals, frequent mouth care, sucking lozenges, chewing gum may help). Report immediately any change in vision. Report unusual tiredness, flu-like feelings, skin rash or itching, dark urine, light colored stool, yellowing of skin or eyes; fever; chest pain or rapid heartbeat; or any other persistent side effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant while taking this drug. Fetal harm can occur. Consult prescriber for appropriate contraceptive measures. Breast-feeding is not recommended.
Geriatric Considerations
The manufacturer reports that median voriconazole plasma concentrations were increased in patients 65 years and older compared to those 65 years and younger. The recommendation that a dose adjustment is not needed for the elderly was based on a similar safety profile between young and older patients.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: Based on high oral bioavailability, switching between I.V. and oral administration is appropriate when clinically indicated. Infusions of blood products and any electrolyte supplementation must not occur simultaneously with intravenous voriconazole. Voriconazole I.V. must not be infused into the same line or cannula concomitantly with other drug infusions.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Voriconazole is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.
Dental Comment
Voriconazole is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Voriconazole is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.
Mental Health: Effects on Mental Status
May cause abnormal dreams, agitation, amnesia, anxiety, confusion, delirium, dementia, depersonalization, depression, dizziness, encephalopathy, euphoria, insomnia, psychosis, somnolence, suicidal ideation
Mental Health: Effects on Psychiatric Treatment
Contraindicated with CYP3A4 substrates which may lead to QTc prolongation (pimozide); coadministration with barbiturates (long acting), carbamazepine, and ergot alkaloids. Blurred vision is common; use caution with anticholinergic agents. Concurrent use with benzodiazepines that are oxidatively metabolized (alprazolam, diazepam, temazepam, triazolam, and midazolam) may result in elevated benzodiazepine serum concentrations and potential risk for toxicity. Buspirone and zolpidem serum concentrations may be increased with concurrent use. St John's wort may decrease voriconazole levels; monitor.
Nursing: Physical Assessment/Monitoring
Evaluate hepatic function, renal function, and allergy history prior to beginning therapy. Assess all other pharmacological or herbal products patient may be taking for potential interactions or toxicity. Assess results of laboratory tests, therapeutic effectiveness (according to purpose for use), and adverse response (eg, vision changes [photophobia, changed visual acuity, blurred vision], hepatic toxicity [increased liver enzymes, jaundice], tachycardia, dermatologic reactions) on a regular basis. Teach patient proper use, possible side effects/appropriate interventions, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
VFEND®: 200 mg 200 mg [contains cyclodextrin]
Powder for oral suspension:
VFEND®: 200 mg/5 mL (70 mL) [contains sodium benzoate and sucrose; orange flavor]
Tablet:
VFEND®: 50 mg, 200 mg
References
Breit SM, Hariprasad SM, Mieler WF, et al, “Management of Endogenous Fungal Endophthalmitis With Voriconazole and Caspofungin,” Am J Ophthalmol, 2005, 139(1):135-40.
Dodds-Ashley ES, Zaas AK, Fang AF, et al, “Comparative Pharmacokinetics of Voriconazole Administered Orally as Either Crushed or Whole Tablets,” Antimicrob Agents Chemother, 2007, 51(3):877-80.
Durand ML, Kim IK, D'Amico DJ, et al, “Successful Treatment of Fusarium Endophthalmitis with Voriconazole and Aspergillus Endophthalmitis With Voriconazole Plus Caspofungin,” Am J Ophthalmol, 2005, 140(3):552-4.
Hariprasad SM, Mieler WF, Holz ER, et al, “Determination of Vitreous, Aqueous, and Plasma Concentration of Orally Administered Voriconazole in Humans,” Arch Ophthalmol, 2004, 122(1):42-7.
Herbrecht R, Denning DW, Patterson TF, et al, "Voriconazole Versus Amphotericin B for Primary Therapy of Invasive Aspergillosis," N Engl J Med, 2002, 347(6):408-15.
Kullberg BJ, Sobel JD, Ruhnke M, et al, “Voriconazole Versus a Regimen of Amphotericin B Followed by Fluconazole for Candidaemia in Non-Neutropenic Patients: A Randomised Non-Inferiority Trial,” Lancet, 2005, 366(9495):1435-42.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Prevention and Treatment of Cancer-Related Infections,” Version 1.2008. Available at http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf.
Pappas PG, Kauffman CA, Andes D, et al, "Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America," Clin Infect Dis, 2009, 48(5):503-35.
Walsh TJ, Anaissie EJ, Denning DW, et al, “Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America,” Clin Infect Dis, 2008, 46(3):327-60.
Walsh TJ, Pappas P, Winston DJ et al, "Voriconazole Compared with Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Neutropenia and Persistent Fever," N Engl J Med, 2002, 346(4):225-34.
Zonios DI, Gea-Banacloche J, Childs R et al, "Hallucinations During Voriconazole Use," Abstract M-1172; 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Illinois, September, 2007.
International Brand Names
Lexi-Comp.com
Last full review/revision September 2009
Content last modified September 2009
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