Vanazole

Voriconazole.

Each tablet contains voriconazole 50 mg and 200 mg.

Pharmacology: Pharmacodynamics: Voriconazole is a triazole antifungal that in sensitive fungi inhibits cytochrome P450-dependent enzymes resulting in the impairment of ergosterol synthesis in fungal cell membranes. Voriconazole has a broad spectrum of activity against all Candida species, including fluconazole-resistant strains, as well as Aspergillus spp., Scedosporium spp., and Fusarium spp.
Pharmacokinetics: Voriconazole has non-linear pharmacokinetics due to saturable metabolism. It is rapidly and almost completely absorbed from the gastrointestinal tract. The oral bioavailability of voriconazole is estimated to be 96%. Peak plasma concentrations occur about 1 to 2 hours after an oral dose. Plasma protein binding of voriconazole is about 58%. The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg. Voriconazole diffuses into CSF. Voriconazole is metabolized by hepatic cytochrome P450 isoenzyme CYP2C19; the major metabolite is the inactive N-oxide. Metabolism via isoenzymes CYP2C9 and CYP3A4 has also been shown in vitro. Half-life elimination is variable and dose-dependent. About 80% of voriconazole is excreted in the urine as inactive metabolites and with less than 2% as unchanged drug.

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.

The following oral loading doses of voriconazole are given every 12 hours for the first 24 hours: Adults and adolescents weighing more than 40 kg: 400 mg.
Under 40 kg: 200 mg.
Subsequent oral maintenance doses are: Adults and adolescents over 40 kg: 200 mg twice daily, increased to 300 mg twice daily if the response is inadequate.
Under 40 kg: 100 mg twice daily, increased to 150 mg twice daily if the response is inadequate.
US licensed product information does not suggest a loading dose for oesophageal candidiasis; oral maintenance doses are as above and treatment should be given for a minimum of 14 days and continued for at least 7 days after resolution of symptoms.
Dosage adjustment in patients receiving concomitant CYP450 enzyme inducer or substrates: Cyclosporine: Reduce cyclosporine dose by one-half and monitor closely; upon discontinuation of voriconazole, monitor cyclosporine concentrations and escalate the cyclosporine dose as needed.
Efavirenz: Increase maintenance dose of voriconazole to 400 mg every 12 hours and reduce efavirenz dose to 300 mg once daily; upon discontinuation of voriconazole, return to the initial dose of efavirenz.
Omeprazole: Reduce omeprazole dose by one-half in patients maintained on ≥40 mg/day of omeprazole.
Phenytoin: Increase voriconazole dose to 400 mg every 12 hours in patients ≥40 kg (200 mg every 12 hours in patients <40 kg).
Tacrolimus: Reduce tacrolimus dose by one-third and monitor closely; upon discontinuation of voriconazole, monitor tacrolimus concentrations and escalate the tacrolimus dose as needed.
Dosage adjustment in renal impairment: No dose adjustment is needed for oral voriconazole in patients with renal impairment. Patients with a creatinine clearance less than 50 ml/minute should receive oral voriconazole instead of intravenous voriconazole as accumulation of intravenous vehicle may occur.
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.
Method of Administration: Voriconazole should be taken at least 1 hour before, or 1 hour after a meal.

Toxicity in overdose is rare and not expected. The majority of toxic effects are related to drug interactions because these agents competitively inhibit CYP3A4. Overdose and inadvertent exposures are uncommon and serious toxicity from acute ingestion has not been reported. Overdose effects would be expected to be similar to adverse effects reported after therapeutic use. Adverse effects include nausea. vomiting, diarrhea, abdominal pain, hypokalemia, and visual changes (abnormal vision, color vision changes, photophobia). There are reports of dizziness, hepatotoxicity, congestive heart failure, thrombocytopenia, neutropenia, seizures, and delirium. Azole antifungals have been implicated in case reports to cause toxic epidermal necrolysis and less serious rashes.
Treatment: Management of mild to moderate toxicity: Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Antiemetic medications and IV fluids can be used for gastrointestinal distress.
Management of severe toxicity: Treatment is symptomatic and supportive. Severe toxicity is not expected after fluconazole (or related agents) overdose. Most overdoses do not lead to toxicity. Prehospital gastrointestinal decontamination is generally not required and activated charcoal is typically not recommended. There is no antidote.

Hypersensitivity to voriconazole or any component of the formulation (cross-reaction with other azole antifungal agents may occur but has not been established, use with caution); coadministration of CYP3A4 substrates which may lead to QT_c 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.

Visual changes, including blurred vision, changes in visual acuity, color perception, and photophobia, are commonly associated with treatment; postmarketing cases of optic neuritis and papilledema (lasting > 1 month) have also been reported. 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).
Serious hepatic reactions (including hepatitis, cholestasis, and fulminant hepatic failure) have occurred during treatment, primarily in patients with serious concomitant medical conditions. However, hepatotoxicity has occurred in patients with no identifiable risk factors. Use caution in patients with pre-existing hepatic impairment (dose adjustment or discontinuation may be required). Voriconazole tablets contain lactose; avoid administration in hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. Acute renal failure has been observed in severely ill patients; use with caution in patients receiving concomitant nephrotoxic medications.
Use caution in patients taking strong cytochrome P450 inducers, CYP2C9 inhibitors, and major 3A4 substrates; consider alternative agents that avoid or lessen the potential for CYP-mediated interactions. 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 QT_c- prolonging drugs). Use with caution in these patient populations; correct electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia) prior to initiating therapy.
Rare cases of malignancy (melanoma, squamous cell carcinoma) have been reported in patients (mostly immunocompromised) with prior onset of severe photosensitivity reactions and exposure to long-term voriconazole therapy. Other serious exfoliative cutaneous reactions, including Stevens-Johnson syndrome, have also been reported. Patient should avoid strong, direct exposure to sunlight; may cause photosensitivity, especially with long-term use. Discontinue use in patients who develop an exfoliative cutaneous reaction or a skin lesion consistent with squamous cell carcinoma or melanoma. Periodic total body skin examinations should be performed, particularly with prolonged use.
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.

Pregnancy: category D.
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. Woman 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.

Nausea, vomiting, abdominal pain, diarrhea, jaundice, oedema, hypotension, chest pain, respiratory distress syndrome, sinusitis, headache, dizziness, asthenia, anxiety, depression, confusion, agitation, hallucinations, paraesthesia, tremor, influenza-like symptoms, hypoglycemia, hematuria, blood disorders (including anemia, thrombocytopenia, leucopenia, pancytopenia), acute renal failure, hypokalemia, visual disturbances (including altered perception, blurred vision, and photophobia), rash, pruritus, photosensitivity, alopecia, cheilitis.
Less commonly, dyspepsia, duodenitis, cholecystitis, pancreatitis, hepatitis, constipation, arrhythmias (including QT interval prolongation), syncope, raised serum cholesterol, hypersensitivity reactions (including flushing), ataxia, nystagmus, hypoesthesia, adrenocortical insufficiency, arthritis, blepharitis, optic neuritis, scleritis, glossitis, gingivitis, psoriasis, Stevens-Johnson syndrome.
Rarely, pseudomembranous colitis, taste disturbances (more common with oral suspension), convulsions, insomnia, tinnitus, hearing disturbances, extrapyramidal effects, hypertonia, hypothyroidism, hyperthyroidism, discoid lupus erythematosus, toxic epidermal necrolysis, pseudoporphyria, retinal hemorrhage, optic atrophy; also reported squamous cell carcinoma of skin (particularly in presence of phototoxicity or in the immunosuppressed).

Voriconazole is metabolized by CYP2C19, CYP2C9, and CYP3A4. The affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhbitors or inducers of these 3 enzymes may increase or decrease voriconazole systemic exposure (plasma concentrations), respectively.
Voriconazole inhibits the metabolic activity of CYP2C19, CYP2C9, and CYP3A4. The inhibition potency of voriconazole for CYP3A4 was significantly less than that of 2 other azoles, ketoconazole and itraconazole. The major metabolite of voriconazole, the voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. There is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentration) of other drugs metabolized by these CYP450 enzymes.
Drugs that affect voriconazole include the following: barbiturates (long acting), cimetidine, fluconazole, hormonal contraceptives, nonnucleoside reverse transcriptase inhibitors (NNRIs), phenytoin, protease inhibitors, proton pump inhibitors, rifampin, rifabutin and St. John's wort.
Drugs affected by voriconazole include the following: aripiprazole, benzodiazepines, cabazitaxel, calcium channel blockers, cisapride, clopidogrel, coumarin anticoagulants, cyclosporine, docetaxel, dronedarone, ergot alkaloids, erlotinib, erythromycin, hormonal contraceptives, HMG-CoA reductase inhibitors, ixabepilone, maraviroc, mammalian target of rapamycin inhibitors (eg, everolimus, temsirolimus), nilotinib, NNRTIs, nonsteroidal anti-inflammatory drugs, opioid analgesics, phenytoin, prednisolone, protease inhibitors, pimozide, proton pump inhibitors, quinidine, rifabutin, romidepsin, sirolimus, sulfonylureas, tacrolimus, tyrosine kinase receptor inhibitors, vinca alkaloids, zolpidem.

Store below 30°C.

Antifungals

J02AC03 - voriconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.

D