VORICONAZOLE
(vor-i-con'a-zole)
Vfend
Classifications: antiinfective; antibiotic; azole antifungal
Prototype: Fluconazole
Pregnancy Category: D

Availability

50 mg, 200 mg tablets; 200 mg injection

Actions

Inhibits fungal cytochrome P-450 enzymes used for an essential step in fungal ergosterol biosynthesis. The subsequent loss of ergosterol in the fungal cell wall may be responsible for the antifungal activity of voriconazole.

Therapeutic Effects

Voriconazole is active against Aspergillus fumigatus as well as A. flavus, A. niger, and A. terreus. Variable activity against Scedosporium apiospermum and Fusarium sp., including Fusarium solani, has been seen.

Uses

Treatment of invasive Aspergillosis, esophageal candidiasis, candidemia in nonneutropenic patients and disseminated skin infections, and abdomen, kidney, bladder wall, and wound infections due to Candida.

Contraindications

Known hypersensitivity to voriconazole; intravenous voriconazole should be avoided in moderate or severe renal impairment (Cl_cr <50 mL/min); severe hepatic impairment; children <2 y; history of galactose intolerance; Lapp lactase deficiency or glucose-galactose malabsorption; concurrent use of sirolimus; coadministration of the CYP3A4 substrates pimozide or quinidine; concurrent use of rifampin, rifabutin, carbamazepine and long-acting barbiturates, ergot alkaloids; sunlight (UV) exposure; pregnancy (category D); lactation.

Cautious Use

Mild to moderate hepatic cirrhosis, hepatitis, hepatic disease; renal disease, renal impairment; ocular disease; hypersensitivity to other azole antifungal agents such as fluconazole; children >2 y and <12 y.

Route & Dosage

Aspergillosis
Adult/Geriatric: IV 6 mg/kg q12h day 1, then 4 mg/kg q12h. May reduce to 3 mg/kg q12h if not tolerated PO >40 kg, 400 mg q12h day 1, then 200 mg q12h. May increase to 300 mg q12h if inadequate response. <40 kg, 400 mg q12h day 1, then 100 mg q12h. May increase to 150 mg q12h if inadequate response.

Esophageal Candidiasis
Adult/Geriatric: PO >40 kg, 200 mg q12h for a minimum of 14 d and for at least 7 d after resolution of symptoms; <40 kg, 100 mg q12h for a minimum of 14 d and for at least 7 d after resolution of symptoms.

Dose Adjustment for Concomitant Fosphenytoin or Phenytoin
Adult/Geriatric: IV 6 mg/kg q12h day 1, then 5 mg/kg q12h. PO >40 kg, 400 mg q12h day 1, then 400 mg q12h. <40 kg, 400 mg q12h day 1, then 200 mg q12h

Administration

Oral

Give at least 1 h before or 1 h following a meal.
Manufacturer recommendation: maintenance dose to be halved in patients with mild to moderate hepatic cirrhosis. Consult physician.
Store tablets at 15°–30° C (59°–86° F).

Intravenous

IV voriconazole should be avoided in patients with moderate or severe renal impairment.

PREPARE: Intermittent: Use a 20 mL syringe to reconstitute powder with exactly 19 mL of sterile water for injection to yield 10 mg/mL. Discard vial if a vacuum does not pull the diluent into vial. Shake until completely dissolved. From an IV infusion bag of NS, D5W, D5/NS, D5/.45NS, RL or other suitable diluent withdraw and discard a volume of IV solution adequate to produce final voriconazole concentration within the range of 0.5–5 mg/mL. Inject the calculated dose of voriconazole into the IV bag. Discard unused voriconazole. Infuse IV solution immediately.

ADMINISTER: Intermittent: Infuse over 1–2 h at a maximum rate of 3 mg/kg per h. DO NOT give a bolus dose.

INCOMPATIBILITIES Solution/additive: Do not dilute with sodium bicarbonate; do not mix with any other drugs. Y-site: Do not infuse with other drugs.

Store unreconstituted vials at 15°–30° C (59°–86° F).

Adverse Effects (1%)

Body as a Whole: Peripheral edema, fever, chills. CNS: Headache, hallucinations, dizziness. CV: Tachycardia, hypotension, hypertension, vasodilation. GI: Nausea, vomiting, abdominal pain, abnormal LFTs, diarrhea, cholestatic jaundice, dry mouth. Metabolic: Increased alkaline phosphatase, AST, ALT, hypokalemia, hypomagnesemia. Skin: Rash, pruritus. Special Senses: Abnormal vision (enhanced brightness, blurred vision, or color vision changes), photophobia.

Interactions

Drug: Due to significant increased toxicity or decreased activity, the following drugs are contraindicated with voriconazole: barbiturates, carbamazepine, efavirenz, ergot alkaloids, pimozide, quinidine, rifabutin, sirolimus; fosphenytoin, phenytoin, rifampin, ritonavir may significantly decrease voriconazole levels. protease inhibitors (except indinavir) may increase voriconazole toxicity; voriconazole may increase the toxicity of benzodiazepines, cyclosporine, protease inhibitors (except indinavir), nonnucleoside reverse transcriptase inhibitors, omeprazole, tacrolimus, vinblastine, vincristine, warfarin; nonnucleoside reverse transcriptase inhibitors may increase or decrease voriconazole levels. Food: Absorption reduced with high-fat meals.

Pharmacokinetics

Absorption: 96% absorbed PO. Has a non-linear pharmacokinetic profile, a small change in dose may cause a large change in serum levels. Steady state not achieved until day 5–6 if no loading dose is given. Peak: 1–2 h. Metabolism: Metabolized in liver by (and is an inhibitor of) CYP3A4, 2C9 and 2C19. Elimination: Primarily excreted in urine. Half-Life: 6 h–6 d depending on dose.

Nursing Implications

Assessment & Drug Effects

Monitor visual acuity, visual field, and color perception if treatment continues beyond 28 d.
Withhold drug and notify physician if skin rash develops.
Monitor cardiovascular status especially with preexisting CV disease.
Lab tests: Monitor baseline and periodic LFTs including bilirubin; patients who develop abnormal liver function tests during therapy should be monitored for the development of more severe hepatic injury. Monitor frequently renal function tests, especially serum creatinine. Monitor periodic CBC with platelet count, Hct & Hgb, serum electrolytes, alkaline phosphatase, blood glucose, and lipid profile.
Concurrent drugs: Monitor PT/INR closely with warfarin as dose adjustments of warfarin may be needed. Monitor frequently blood glucose levels with sulfonylurea drugs as reduction in the sulfonylurea dosage may be needed. Monitor for and report any of the following: S&S of rhabdomyolysis in patient receiving a statin drug; prolonged sedation in patient receiving a benzodiazepine; S&S of heart block, bradycardia, or CHF in patient receiving a calcium channel blocker.

Patient & Family Education

Use reliable means of birth control to prevent pregnancy. If you suspect you are pregnant, contact physician immediately.
Do not drive at night while taking voriconazole as the drug may cause blurred vision and photophobia.
Do not drive or engage in other potentially hazardous activities until reaction to drug is known.
Avoid strong, direct sunlight while taking voriconazole.
Do not breast feed while taking this drug.

Common adverse effects in italic, life-threatening effects underlined; generic names in bold; classifications in SMALL CAPS; Canadian drug name; Prototype drug