Action

Inhibits fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, preventing fungal biosynthesis and inactivating fungal cell

Availability

Lyophilized powder for injection: 200 mg

Powder for oral suspension: 40 mg/ml

Tablets: 50 mg, 200 mg

Indications and dosages

➣ Invasive aspergillosis; serious fungal infections caused by Scedosporium apiospermum and Fusarium species

Adults and children ages 12 and older: Initially, 6 mg/kg I.V. q 12 hours for two doses (each dose infused over 1 to 2 hours), followed by a maintenance dose of 4 mg/kg I.V. q 12 hours given no faster than 3 mg/kg/hour. Change to oral dosing as described below when patient can tolerate it.

Adults and children ages 12 and older weighing more than 40 kg (88 lb): 200 mg P.O. q 12 hours 1 hour before or after a meal; may increase to 300 mg P.O. q 12 hours p.r.n.

Adults and children ages 12 and older weighing less than 40 kg (88 lb): 100 mg P.O. q 12 hours at least 1 hour before or after a meal; may increase to 150 mg P.O. q 12 hours p.r.n.

➣ Esophageal candidiasis

Adults and children ages 12 and older weighing 40 kg (88 lb) or more: 200 mg P.O. q 12 hours for at least 14 days, and for at least 7 days after symptoms resolve

Adults and children ages 12 and older weighing less than 40 kg (88 lb): 100 mg P.O. q 12 hours for at least 14 days, and for at least 7 days after symptoms resolve

➣ Candidemia (in nonneutropenic patients) and other deep-tissue Candida infections

Adults and children ages 12 and older: 6 mg/kg I.V. q 12 hours for first 24 hours, followed by maintenance dose of 3 mg/kg I.V. q 12 hours. Or 200 mg P.O. q 12 hours for candidemia and 4 mg/kg I.V. q 12 hours or 200 mg P.O. q 12 hours for other deep-tissue Candida infections. Patients should be treated for at least 14 days after resolution of symptoms or after last positive culture, whichever is longer.

Dosage adjustment

• Mild to moderate hepatic impairment

• Moderate to severe renal impairment (with I.V. use)

• Adult patients weighing less than 40 kg (88 lb)

• Concurrent use of phenytoin or efavirenz

Off-label uses

• Febrile neutropenia (as empiric therapy)

Contraindications

• Hypersensitivity to drug or its components

• Concurrent use of long-acting barbiturates, ergot alkaloids, rifabutin, rifampin, CYP450-3A4 substrates (such as astemizole, cisapride, pimozide, quinidine, terfenadine), sirolimus, high-dose ritonavir, St. John's wort, or carbamazepine

Precautions

Use cautiously in:

• hypersensitivity to other azoles

• renal disease, hepatic dysfunction, risk factors for pancreatitis (such as recent chemotherapy, hematopoietic stem cell transplant)

• hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption (avoid tablet use)

• concurrent use of low-dose ritonavir (avoid use unless benefit-risk to patient justifies use)

• pregnant or breastfeeding patients

• children younger than age 12 (safety and efficacy not established).

Administration

• Correct electrolyte disturbances before therapy starts.

Don't give concurrently with astemizole, cisapride, or terfenadine (no longer available in U.S.); carbamazepine; ergot alkaloids; long-acting barbiturates; pimozide; quinidine; rifabutin; rifampin; ritonavir; or sirolimus.

Don't give by I.V. bolus injection.

• Reconstitute powder with 19 ml of water for injection, to yield a volume of 20 ml. Shake vial until powder dissolves. Withdraw prescribed dose, then dilute further in compatible I.V. solution to a final concentration of 0.5 to 5 mg/ml. Give I.V. over 1 to 2 hours at a rate not exceeding 3 mg/kg/hour.

• Don't give through same I.V. line with other drugs, blood products, or electrolytes.

• To reconstitute powder for oral suspension, tap bottle to release powder. Add 46 ml of water, and shake vigorously for about 1 minute. Remove cap, push bottle adapter into neck of bottle, and replace cap. After reconstitution, suspension volume is 75 ml, providing usable volume of 70 ml (40 mg/ml). Shake bottle before each use. Use only 5-ml oral dispenser supplied. Don't mix with other drugs, and don't dilute further.

• Give oral suspension and tablets 1 hour before or after a meal.

Adverse reactions

CNS: dizziness, headache, hallucinations

CV: hypotension, hypertension, tachycardia, chest pain, vasodilation, peripheral edema

EENT: photophobia, blurred vision, visual disturbances, eye hemorrhage, chromatopsia

GI: nausea, vomiting, diarrhea, abdominal pain, dry mouth, pancreatitis

GU: renal dysfunction, acute renal failure

Hematologic: anemia, pancytopenia, leukopenia, thrombocytopenia

Hepatic: cholestatic jaundice, hepatic failure

Metabolic: hypomagnesemia, hypokalemia

Musculoskeletal: fluorosis, periostitis (with long-term use)

Respiratory: respiratory disorders

Skin: pruritus, maculopapular rash, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome

Other: chills, fever, sepsis, infusion-related reactions including anaphylaxis

Interactions

Drug-drug. Barbiturates (long-acting), carbamazepine, phenytoin, rifampin: decreased voriconazole blood level

Benzodiazepines: sedation

Calcium channel blockers, HMG-CoA reductase inhibitors: increased blood levels of these drugs

Cyclosporine, sirolimus, tacrolimus: increased blood levels of these drugs, greater risk of nephrotoxicity

CYP450-3A4 substrates: increased blood levels of these drugs, causing prolonged QT interval and risk of torsades de pointes

Ergot alkaloids: increased blood levels of these drugs, resulting in ergotism

Non-nucleoside reverse transcriptase inhibitors, protease inhibitors: inhibited voriconazole metabolism

Rifabutin: decreased voriconazole blood level, increased rifabutin blood level

Sulfonylureas: increased sulfonylurea blood level, greater risk of hypoglycemia

Vinca alkaloids: increased risk of neurotoxicity

Warfarin, other coumarin derivatives: increased partial thromboplastin time

Drug-diagnostic tests. Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, creatinine: increased levels

Drug-herbs. Gossypol: increased risk of nephrotoxicity

St. John's wort: significantly reduced voriconazole plasma exposure

Patient monitoring

• Monitor kidney and liver function tests. Watch for signs and symptoms of organ toxicity.

• Assess electrolyte levels and CBC, including platelet count.

Monitor ECG. Stay alert for prolonged QT interval.

During infusion, monitor patient for anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, and rash; consider stopping infusion should these reactions occur.

Be aware of postmarketing reports of pancreatitis, especially in children, and monitor appropriately.

Monitor patient receiving longterm therapy for skeletal pain. Discontinue drug if radiologic findings indicate fluorosis or periostitis.

• Check for vision problems in therapy exceeding 28 days.

Patient teaching

• Explain therapy to patient. Stress importance of follow-up laboratory tests.

• Tell patient using oral form to take doses 1 hour before or after a meal.

• Emphasize importance of taking drug exactly as directed for entire duration prescribed.

• Instruct patient to promptly report adverse reactions.

• Tell female of childbearing age to immediately report pregnancy.

• Caution patient to avoid driving and other hazardous activities, because drug may cause visual disturbances.

• Advise patient to minimize GI upset by eating small, frequent servings of food and drinking plenty of fluids.

• Advise patient not to use St. John's wort without consulting prescriber.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and herbs mentioned above.

w