Voriconazole

Pronunciation

Pronunciation: VOR-i-KON-a-zole
Class: Triazole antifungal

Trade Names

Vfend
- Tablets, oral 50 mg
- Tablets, oral 200 mg
- Injection, lyophilized powder for solution 200 mg
- Powder for suspension, oral 40 mg/mL (after reconstitution)

Pharmacology

Inhibition of fungal CYP-450–mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis.

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Pharmacokinetics

Absorption

Oral bioavailability is 96%. T max is 1 to 2 h. AUC decreases 24% (tablet) and 37% (oral suspension) and C max decreases 34% (tablet) and 58% (oral suspension) with a high-fat meal.

Distribution

Vd is 4.6 L/kg, suggesting extensive distribution into tissue. Approximately 58% is protein bound.

Metabolism

Metabolized by CYP-450 enzymes CYP2C19, CYP2C9, and CYP3A4, with CYP2C19 significantly involved; this enzyme also exhibits genetic polymorphism. Major metabolite, N-oxide, accounts for 72% of the circulating radiolabeled metabolites in the plasma but has minimal antifungal activity.

Elimination

Eliminated by hepatic metabolism, with less than 2% of the dose excreted unchanged in the urine. Terminal half-life is dose dependent and is not useful in predicting accumulation or elimination.

Special Populations

Renal Function Impairment

AUC and C max are not significantly affected by renal impairment. No dosage adjustment is necessary for oral dosing in patients with mild to severe renal impairment. Accumulation of the IV vehicle sulfobutyl ether beta-cyclodextrin sodium (SBECD) occurs in patients with moderate renal impairment (CrCl 30 to 50 mL/min). Avoid IV use in patients with CrCl less than 50 mL/min.

Hepatic Function Impairment

AUC is 3.2-fold higher in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). No pharmacokinetic data are available for patients with severe hepatic impairment.

Elderly

Plasma concentrations were approximately 80% to 90% higher than in younger patients.

Children

Pharmacokinetic data showed that steady-state plasma concentrations were similar at the maintenance dose in children and adults.

Gender

C max and AUC tau for women were 83% and 113% higher, respectively, than in men. No dosage adjustment is recommended.

Indications and Usage

Treatment of candidemia in nonneutropenic patients and Candida infections disseminated in skin and infections in abdomen, bladder wall, kidney, and wounds; treatment of esophageal candidiasis; treatment of invasive aspergillosis; treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium species, including Fusarium solani , in patients intolerant of or refractory to other therapy.

Contraindications

Coadministration with astemizole, carbamazepine, cisapride, ergot alkaloids (ergotamine and dihydroergotamine), long-acting barbiturates, pimozide, quinidine, rifabutin, rifampin, ritonavir (400 mg every 12 h), sirolimus, terfenadine, and St. John's wort; hypersensitivity to voriconazole or its excipients.

Dosage and Administration

Invasive Aspergillosis, Scedosporiosis, and Fusariosis
Adults and Children 12 y and older

IV Loading dose of 6 mg/kg every 12 h for the first 24 h, followed by a maintenance dose of 4 mg/kg every 12 h. If patients are unable to tolerate treatment, reduce IV maintenance dose to 3 mg/kg every 12 h.

PO Once an oral dose can be tolerated, patients weighing 40 kg or more should receive 200 mg every 12 h. If response is inadequate, the oral dose may be increased to 300 mg every 12 h. If patients are unable to tolerate 300 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 200 mg every 12 h. Patients weighing less than 40 kg should receive 100 mg every 12 h. If response is inadequate, the oral dose may be increased to 150 mg every 12 h. If patients weighing less than 40 kg are unable to tolerate 150 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 100 mg every 12 h.

Esophageal Candidiasis
Adults and Children 12 y and older

PO For patients weighing 40 kg or more, the recommended dosing regimen is 200 mg every 12 h. If the response is inadequate, the dose may be increased to 300 mg every 12 h. If patients are unable to tolerate 300 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 200 mg every 12 h. In patients weighing less than 40 kg, the recommended dose is 100 mg every 12 h. If the response is inadequate, the dose may be increased to 150 mg every 12 h. If patients weighing less than 40 kg are unable to tolerate 150 mg every 12 h, reduce the oral dose to 100 mg every 12 h. Treat for a minimum of 14 days and for at least 7 days after resolution of symptoms.

Candidemia in Nonneutropenic Patients and Other Deep Tissue Candida Infections
Adults and Children 12 y and older

IV Loading dose of 6 mg/kg every 12 h for the first 24 h, followed by a maintenance dose of 3 to 4 mg/kg every 12 h. If patients are unable to tolerate treatment, reduce IV maintenance dose to 3 mg/kg every 12 h.

PO Once an oral dose can be tolerated, patients weighing 40 kg or more should receive 200 mg every 12 h. If the response is inadequate, the oral dose may be increased to 300 mg every 12 h. If patients are unable to tolerate 300 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 200 mg every 12 h. Patients weighing less than 40 kg should receive 100 mg every 12 h. If the response is inadequate, the oral dose may be increased to 150 mg every 12 h. If patients weighing less than 40 kg are unable to tolerate 150 mg every 12 h, reduce the oral dose by 50 mg increments to a minimum of 100 mg every 12 h. Treat for a minimum of 14 days following resolution of symptoms or following last positive culture, whichever is longer.

Hepatic Function Impairment
Adults and Children 12 y and older

IV or PO It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh class A and B). Only use in patients with severe hepatic impairment if the benefit outweighs the potential risk.

Concomitant Therapy
Efavirenz

PO Maintenance dose of voriconazole should be increased to 400 mg every 12 h and the efavirenz dose should be decreased to 300 mg every 24 h. When treatment with voriconazole is stopped, use the initial dosage of efavirenz.

Phenytoin

IV Increase the IV maintenance dose of voriconazole to 5 mg/kg every 12 h.

PO Increase the oral maintenance dose from 200 to 400 mg every 12 h. In patients weighing less than 40 kg, increase the oral maintenance dose from 100 to 200 mg every 12 h.

General Advice

  • Injection
  • For IV infusion only; not for IV bolus administration. Infuse at a max rate of 3 mg/kg/h over 1 to 2 h.
  • Reconstitute powder for injection with 19 mL of water for injection. Discard vial if vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved. Reconstituted concentrate contains voriconazole 10 mg/mL.
  • Further dilute reconstituted concentrate in a compatible IV infusion solution to a final concentration of not less than 0.5 mg/mL or greater than 5 mg/mL.
  • The reconstituted injection solution can be diluted with the following: sodium chloride 0.9%, Ringer's lactate, dextrose 5% and Ringer's lactate, dextrose 5% and sodium chloride 0.45%, dextrose 5%, dextrose 5% and potassium chloride 20 mEq, sodium chloride 0.45%, or dextrose 5% and sodium chloride 0.9%.
  • Infusions of TPN and solutions containing nonconcentrated electrolytes can occur simultaneously with voriconazole but must be infused in a separate line. Use a different port for TPN and voriconazole injection.
  • Do not dilute injection solution with sodium bicarbonate 4.2% infusion.
  • For single use only. Discard any unused reconstituted concentrate. Do not save for future use.
  • Do not infuse concomitantly with any blood products or short-term infusion of concentrated electrolytes, even if the 2 infusions are running in separate IV lines.
  • Tablets and oral suspension
  • Tablets and oral suspension are bioequivalent and can be interchanged on a mg-to-mg basis.
  • Administer every 12 h, at least 1 h before or 1 h after a meal.
  • Shake reconstituted oral suspension for approximately 10 sec before measuring the dose. Administer using the supplied oral dispenser only.
  • Do not mix reconstituted oral suspension with any other medication or flavoring agent or further dilute the suspension with water or other vehicles.

Storage/Stability

Store powder for oral suspension in the refrigerator (36° to 46°F) before reconstitution. Store tablets and reconstituted oral suspension between 59° and 86°F. Do not refrigerate or freeze reconstituted oral suspension. Discard any remaining reconstituted oral suspension 14 days after reconstitution. Store injection vials between 59° and 86°F. Reconstituted injection should be used immediately. If not used immediately, reconstituted injection may be stored in the refrigerator (36° to 46°F) for up to 24 h. Discard any unused solution or solution stored for more than 24 h.

Drug Interactions

Aripiprazole, benzodiazepines (eg, alprazolam, midazolam, triazolam), calcium channel blockers (eg, felodipine, nifedipine), cyclosporine, erlotinib, HMG-CoA reductase inhibitors (eg, lovastatin), imatinib, NSAIDs (eg, diclofenac, ibuprofen), opioid analgesics (alfentanil, fentanyl, methadone, oxycodone), prednisolone, sulfonylurea hypoglycemic agents (eg, glipizide), tacrolimus, vinca alkaloids (eg, vinblastine), warfarin, zolpidem

Plasma exposure to these agents may be increased by voriconazole, increasing the pharmacologic and adverse effects. Close clinical monitoring and dosage adjustments are warranted. When initiating therapy in patients already receiving cyclosporine or tacrolimus, reduce the dose by 50% and 33%, respectively, of the original dose.

Axitinib, brentuximab, budesonide, cabazitaxel, crizotinib, direct factor Xa inhibitors (eg, rivaroxaban), erythromycin, everolimus, ixabepilone, lurasidone, nilotinib, romidepsin, temsirolimus, ticagrelor, toremifene, tyrosine kinase receptor inhibitors (eg, dasatinib, lapatinib, pazopanib, sunitinib)

Plasma concentrations of these agents may be elevated by voriconazole, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration.

Carbamazepine, cisapride, dronedarone, ergot derivatives (eg, dihydroergotamine, ergotamine), long-acting barbiturates (eg, mephobarbital, phenobarbital), pimozide, quinidine, rifabutin, rifampin, ritonavir (400 mg every 12 h), sirolimus, St. John's wort

Coadministration of these agents with voriconazole is contraindicated.

Cilostazol, ivacaftor, mifepristone, ruxolitinib, saxagliptin, vilazodone

Plasma concentrations of these agents may be elevated, increasing the pharmacologic effects and risk of toxicity. When coadministered with voriconazole, a cilostazol dose of 50 mg twice daily should be considered; an ivacaftor dose of 150 mg twice weekly should be considered; the mifepristone dose should be limited to 300 mg daily; a starting dose of ruxolitinib 10 mg twice daily is recommended and further dose reductions may be needed; the saxagliptin dose should be limited to 2.5 mg daily; and the vilazodone dose should be reduced to 20 mg daily.

Cimetidine

Voriconazole C max and AUC are increased by an average of 18% and 23%, respectively, with coadministration. No dosage adjustment appears to be needed.

Contraceptives, hormonal (eg, ethinyl estradiol/norethindrone)

Ethinyl estradiol C max and AUC, as well as norethindrone C max and AUC, may be increased. In addition, voriconazole C max and AUC may be increased. Monitor for adverse reactions related to the contraceptive agent as well as voriconazole.

Docetaxel

Docetaxel plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. If coadministration cannot be avoided, consider reducing the docetaxel dose by 50% with close clinical and laboratory monitoring.

Dofetilide

Pharmacologic effects and plasma concentrations of dofetilide may be increased. CV toxicity, including torsades de pointes, may occur. Coadminister with caution and monitor for QT prolongation and signs or symptoms of torsades-like arrhythmias.

Fluconazole

Voriconazole C max and AUC may be increased. Coadministration is not recommended. Close clinical monitoring is recommended if voriconazole is given sequentially after fluconazole, especially within 24 h of the last fluconazole dose.

Maraviroc

Maraviroc plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. A maraviroc dose reduction may be needed. Coadministration is contraindicated in patients with severe renal impairment (CrCl 30 mL/min or less).

NNRTIs (eg, delavirdine, efavirenz, nevirapine)

May increase or decrease voriconazole concentrations. Monitor for voriconazole toxicity or decrease in efficacy. Voriconazole may also increase NNRTI concentrations. Monitor for NNRTI toxicity. When coadministered with efavirenz, the voriconazole maintenance dosage should be increased to 400 mg every 12 h and the efavirenz dosage should be decreased to 300 mg every 24 h. When voriconazole is discontinued, the initial dosage of efavirenz should be restored.

Phenytoin

Voriconazole C max and AUC may be decreased, while phenytoin C max and AUC may be increased. Monitor phenytoin concentrations and for phenytoin adverse effects. Adjust the voriconazole dose accordingly.

Protease inhibitors (eg, fosamprenavir, nelfinavir, ritonavir, saquinavir)

Voriconazole may inhibit the metabolism of certain protease inhibitors, and the metabolism of voriconazole may be inhibited or induced by certain protease inhibitors. Monitor closely for toxicity. Coadministration with ritonavir (400 mg every 12 h) is contraindicated. Coadministration with ritonavir 100 mg every 12 h should be avoided unless assessment of benefit/risk justifies the use of voriconazole.

Proton pump inhibitors (eg, omeprazole)

Omeprazole may increase the C max and AUC of voriconazole. Voriconazole may increase the C max and AUC of omeprazole. When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or more, reduce the dose of omeprazole by 50%. Voriconazole also may inhibit the metabolism of other proton pump inhibitors that are CYP2C19 substrates (eg, esomeprazole).

Vemurafenib

Vemurafenib plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Coadminister with caution.

Adverse Reactions

Cardiovascular

Tachycardia (2%); atrial arrhythmia, atrial fibrillation, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, CHF, complete AV block, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, MI, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolongation, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsades de pointes) (less than 2%).

CNS

Hallucinations, headache (3%); abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, asthenia, ataxia, brain edema, coma, confusion, convulsion, decreased libido, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, extrapyramidal syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo (less than 2%).

Dermatologic

Rash (5%); alopecia, angioedema, contact dermatitis, discoid lupus erythematosus, dry skin, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, squamous cell carcinoma, Stevens-Johnson syndrome, sweating, TEN, urticaria (less than 2%).

EENT

Abnormal vision, color vision change, photophobia (21%); abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, dry eyes, ear pain, epistaxis, eye hemorrhage, eye pain, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, pharyngitis, retinal hemorrhage, retinitis, rhinitis, scleritis, tinnitus, uveitis, visual field defect (less than 2%); chromatopsia (1%); optic neuritis (postmarketing).

Endocrine

Adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism (less than 2%).

GI

Nausea (5%); vomiting (4%); abdominal pain, anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, dry mouth, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, elevated GGT/LDH, enlarged abdomen, esophageal ulcer, esophagitis, flatulence, gastroenteritis, GI hemorrhage, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, intestinal perforation, intestinal ulcer, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, peritonitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, taste loss, taste perversion, tongue edema (less than 2%).

Genitourinary

Abnormal kidney function, anuria, blighted ovum, decreased CrCl, dysmenorrhea, dysuria, epididymitis, glycosuria, hematuria, hemorrhagic cystitis, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, uterine hemorrhage, UTI, vaginal hemorrhage (less than 2%).

Hematologic-Lymphatic

Agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, cyanosis, DIC, ecchymosis, enlarged spleen, eosinophilia, hemolytic anemia, hypervolemia, increased bleeding time, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechiae, purpura, thrombocytopenia, thrombotic thrombocytopenic purpura, uremia (less than 2%).

Hepatic

Increased AST (20%); increased ALT, increased total bilirubin (19%); abnormal LFTs (3%); cholestatic jaundice, increased hepatic enzymes (2%); ascites, enlarged liver, hepatic coma, hepatic failure, hepatitis, jaundice (less than 2%).

Local

Injection-site infection/inflammation, injection-site pain (less than 2%).

Metabolic-Nutritional

Increased alkaline phosphatase (23%); increased creatinine (21%); decreased potassium (17%); bilirubinemia (1%); albuminuria, decreased glucose tolerance, edema, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, increased BUN and CPK, peripheral edema (less than 2%).

Musculoskeletal

Arthralgia, arthritis, back pain, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis (less than 2%); fluorosis, periostitis (postmarketing).

Respiratory

Dyspnea, hemoptysis, hypoxia, increased cough, lung edema, pleural effusion, pneumonia, RDS, respiratory disorder, respiratory tract infection, sinusitis, voice alteration (less than 2%).

Miscellaneous

Fever (6%); chills (4%); allergic reaction, anaphylactoid reaction, bacterial infection, chest pain, cellulitis, facial edema, flank pain, flu syndrome, fungal infection, graft versus host reaction, granuloma, infection, mucous membrane disorder, multiorgan failure, pain, pelvic pain, sepsis, substernal chest pain (less than 2%).

Precautions

Monitor

Monitor visual function (eg, color perception, visual acuity, visual field) if treatment continues beyond 28 days. Evaluate liver (particularly bilirubin and LFTs) and kidney function tests at start of and during the course of therapy. Monitor patients with risk factors for pancreatitis (eg, recent chemotherapy, hematopoietic stem cell transplantation) for the development of pancreatitis during therapy.


Pregnancy

Category D . May cause fetal harm. Women of childbearing potential should use effective contraception during treatment.

Lactation

Undetermined.

Children

Safety and efficacy have not been established in children younger than 12 y. There have been postmarketing reports of pancreatitis in children.

Hypersensitivity

Use caution when prescribing voriconazole to patients with hypersensitivity to other azoles.

Renal Function

Use oral voriconazole in patients with moderate to severe renal impairment (CrCl less than 50 mL/min) unless an assessment of benefit/risk to patient justifies the use of IV voriconazole and accumulation of the IV vehicle SBECD. Monitor serum creatinine closely and, if increases occur, consider changing to oral voriconazole.

Hepatic Function

Reduce maintenance dose by 50% in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). Use in patients with severe hepatic impairment (Child-Pugh class C) only if benefit outweighs risk and monitor patients carefully for drug toxicity.

Photosensitivity

Has occurred, especially during long-term therapy.

CV effects

Voriconazole has been associated with prolongation of the QT interval and rare cases of arrhythmias (including ventricular arrhythmias such as torsades de pointes), cardiac arrests, and sudden deaths. Use with caution in patients with proarrhythmic conditions. Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating therapy.

Dermatologic reactions

Serious exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have occurred. Closely monitor patients who develop a rash; consider discontinuing therapy.

Galactose intolerance

The tablets may contain lactose and should not be given to patients with hereditary galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption.

Hepatic toxicity

Cases of serious hepatic reactions (clinical hepatitis, cholestasis, and fulminant hepatic failure, including fatalities) have been reported. Consider discontinuing therapy if clinical signs and symptoms consistent with liver disease develop.

Infusion-related reactions

Anaphylactoid reactions (chest tightness, dyspnea, faintness, fever, flushing, nausea, pruritus, rash, sweating, tachycardia) have appeared immediately upon initiating infusion. Consider stopping the infusion if these reactions occur.

Ophthalmic effects

Effect of voriconazole on visual function is not known if treatment continues beyond 28 days. There have been postmarketing reports of prolonged visual adverse reactions, including optic neuritis and papilledema.

Renal toxicity

Acute renal failure has been observed.

Skeletal effects

Fluorosis and periostitis have been reported during long-term therapy.

Overdosage

Symptoms

Photophobia.

Patient Information

  • Advise patients or caregivers that the injectable form of the drug will be prepared and administered by a health care provider in a medical facility.
  • Explain the need for prolonged therapy and for close monitoring during course of therapy.
  • Advise patients to take tablets or oral suspension at least 1 h before or 1 h after a meal.
  • Advise patients or caregivers using oral suspension to shake the suspension for approximately 10 sec before measuring a dose and to only use the oral dispenser supplied with the medication.
  • Advise patients to report any of the following to their health care provider: chills; dark urine; fever; injection-site reaction; persistent diarrhea, nausea, or vomiting; persistent headache; rash; swelling of the feet, ankles, or calves; visual disturbances; yellowing of the skin or eyes.
  • Advise patients that medication may cause photosensitivity (sensitivity to sunlight), and to avoid unnecessary exposure to sunlight or tanning lamps, use sunscreens, and wear protective clothing to avoid photosensitivity reactions.
  • Caution patients not to drive at night while taking this medication because it may cause changes in vision, including blurring and sensitivity to bright light.
  • Advise patients that voriconazole may cause visual changes and to avoid driving or operating machinery if they perceive any change in vision.
  • Instruct women of childbearing potential to use effective contraception while taking voriconazole.

Copyright © 2009 Wolters Kluwer Health.

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