VORICONAZOLE
Clinical safety rating: avoid
Contraindicated (not allowed)
Inhibits fungal CYP450-dependent 14α-lanosterol demethylase, disrupting ergosterol synthesis and increasing membrane permeability.
| Metabolism | Extensively metabolized by hepatic CYP2C19, CYP3A4, and CYP2C9. CYP2C19 polymorphism significantly affects exposure. |
| Excretion | Voriconazole is primarily metabolized in the liver via CYP2C19, CYP3A4, and to a lesser extent CYP2C9. Less than 2% of the dose is excreted unchanged in urine. Fecal excretion accounts for approximately 20% of the dose, with the remainder as metabolites in urine. Overall, renal elimination of unchanged drug is negligible, but metabolites are excreted renally. |
| Half-life | The terminal elimination half-life is approximately 6 hours for CYP2C19 extensive metabolizers. In poor metabolizers (which occur in 15-20% of Asian populations), the half-life can be prolonged to up to 24 hours. Clinical context: Dosing adjustments may be necessary based on CYP2C19 genotype; the short half-life necessitates twice-daily dosing for most patients. |
| Protein binding | Approximately 58% bound to serum albumin. |
| Volume of Distribution | Volume of distribution is about 4.6 L/kg, indicating extensive tissue penetration, including into the central nervous system and vitreous humor. |
| Bioavailability | Oral bioavailability is approximately 96% under fasting conditions. When taken with a high-fat meal, absorption may be reduced by up to 24%; thus, voriconazole should be taken on an empty stomach. |
| Onset of Action | Intravenous: Clinical effect (e.g., reduction in fungal burden) typically observed within 24-48 hours after loading dose. Oral: Onset of measurable plasma concentrations occurs within 1-2 hours (Tmax 1-2 hours); however, clinical response may take 24-48 hours following loading doses. |
| Duration of Action | Duration is approximately 12 hours consistent with dosing interval of 12 hours. Clinical notes: Trough levels should be monitored to ensure efficacy (1-5.5 mg/L) and avoid toxicity (>5.5 mg/L). |
| Molecular Weight | 349.33 |
Loading dose: 6 mg/kg IV every 12 hours for 2 doses, then maintenance 4 mg/kg IV every 12 hours; or 200–300 mg PO every 12 hours (400 mg PO every 12 hours for first 24 hours as loading dose if no IV).
| Dosage form | POWDER |
| Renal impairment | IV formulation: Avoid if CrCl < 50 mL/min due to SBECD accumulation; use oral if CrCl < 50 mL/min. Oral: No adjustment needed. |
| Liver impairment | Child-Pugh A or B: Standard loading dose, then reduce maintenance to 50% (e.g., 200 mg PO every 12 hours or 3 mg/kg IV every 12 hours). Child-Pugh C: Not recommended (insufficient data). |
| Pediatric use | Age 2–12 years: Loading dose 9 mg/kg IV every 12 hours for 2 doses, then maintenance 8 mg/kg IV every 12 hours; oral 9 mg/kg every 12 hours (max 350 mg/dose). Age 12–14 years (weight <50 kg): same as pediatric; weight ≥50 kg: adult dosing. |
| Geriatric use | No specific dose adjustment required based on age alone; monitor renal function and adjust according to creatinine clearance (see renal adjustment). |
| 1st trimester | Avoid. Animal studies show teratogenic effects (cleft palate, renal defects). Human data limited but risk cannot be excluded. Contraception recommended during treatment. |
| 2nd trimester | Avoid. Potential for fetal toxicity. Only use if benefit clearly outweighs risk. |
| 3rd trimester | Avoid. May cause fetal harm; use only if no alternatives. |
Clinical note
Inhibits CYP3A4 increasing levels of many drugs (eg statins) Can cause visual disturbances hepatotoxicity and photosensitivity.
| Placental transfer | Significant. Voriconazole crosses the placenta in animal models; human data limited but likely substantial based on molecular weight and lipophilicity. |
| Breastfeeding | Excreted into breast milk in animal studies; unknown in humans. Because of potential for serious adverse reactions (e.g., hepatotoxicity, visual disturbances), breast-feeding is not recommended during therapy and for 5 half-lives after last dose. |
■ FDA Black Box Warning
Voriconazole is contraindicated with CYP3A4 substrates that prolong QTc interval (e.g., terfenadine, astemizole, cisapride, pimozide, quinidine) due to risk of serious cardiovascular events.
| Common Effects | Visual disturbances |
| Serious Effects |
Hypersensitivity to voriconazole or any excipientConcomitant use with CYP3A4 substrates that prolong QTc interval (e.g., terfenadine, astemizole, cisapride, pimozide, quinidine)Concomitant use with sirolimus, rifampin, rifabutin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir (high dose), ergot alkaloids
| Precautions | Hepatotoxicity: Monitor hepatic function; discontinue if signs of liver injury., Visual disturbances: Photophobia, blurred vision; monitor for optic neuritis., QT prolongation: Monitor ECG in patients with risk factors., Photosensitivity: Avoid sunlight, photosensitivity reactions including SCC., Renal impairment: Injection formulation contains cyclodextrin; monitor renal function., Pancreatitis: Monitor amylase/lipase with risk factors., Infusion-related reactions: Consider premedication., Teratogenicity: Avoid in pregnancy unless benefit outweighs risk. |
Loading safety data…
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | Voriconazole is teratogenic in animal studies (cleft palate, hydronephrosis) and is classified as FDA Pregnancy Category D. First trimester exposure is associated with increased risk of congenital malformations. Second and third trimester exposure may cause fetal toxicity including growth restriction. Use is contraindicated in pregnancy unless no alternative. |
| Fetal Monitoring | Monitor liver function tests (ALT, AST, alkaline phosphatase, bilirubin) every 2-4 weeks. Monitor renal function and serum electrolytes (potassium, magnesium, calcium). Assess visual function (visual acuity, color vision, fundoscopic exam) monthly. Monitor voriconazole trough concentrations (target 1-5.5 mg/L). Fetal ultrasound for anomaly detection if exposed during pregnancy. |
| Fertility Effects | Animal studies show reversible decreases in fertility in male and female rats at doses similar to human exposures. Human data insufficient; potential for transient impairment of spermatogenesis or ovarian function. |
| Food/Dietary | Avoid grapefruit and grapefruit juice; may increase voriconazole levels. High-fat meals decrease absorption; take at least 1 hour before or after a meal. Avoid alcohol due to hepatotoxicity risk. |
| Clinical Pearls | Monitor liver function tests (LFTs) at baseline and regularly; voriconazole induces CYP450 enzymes and has nonlinear pharmacokinetics. Avoid coadministration with rifampin, carbamazepine, and high-dose ritonavir due to significant interaction. Correct hypokalemia before initiation. Visual disturbances (photopsia) are common and usually reversible; advise patients to avoid driving at night. Therapeutic drug monitoring recommended for trough levels between 1-5.5 mg/L. |
| Patient Advice | Take exactly as prescribed, with or without food, but avoid high-fat meals as they reduce absorption. · Do not take with grapefruit or grapefruit juice. · Report any vision changes, especially sensitivity to light or blurred vision. · Avoid prolonged sun exposure; use sunscreen and protective clothing due to photosensitivity. · Complete the full course; do not stop without consulting your doctor. |