Voriconazole

Antifungal Triazole

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 4-5 mg/kg q12h for first 2 days (loading dose), then 4-5 mg/kg q12h Duration: Variable; typically 2-6 months depending on infection
Notes: Therapeutic drug monitoring recommended; target trough concentrations 1-5 µg/mL. Administer on an empty stomach (1 hour before or 2 hours after feeding) to improve absorption.
Dog IV 4-5 mg/kg q12h Duration: Until oral therapy is tolerated
Notes: IV formulation should be infused over 1-2 hours; monitor for infusion-related reactions.
Cat PO 4-5 mg/kg q12h Duration: Variable; typically 2-6 months
Notes: Cats may require lower doses due to longer half-life; monitor for adverse effects. Administer on an empty stomach.
Horse PO 4-5 mg/kg q12h Duration: Variable; often 1-3 months
Notes: Oral bioavailability is variable; consider therapeutic drug monitoring. For keratitis, topical 1% solution may be used.
Horse Topical (ophthalmic) 1% solution q2-4h initially, then taper Duration: Until resolution of keratitis
Notes: Compounded voriconazole ophthalmic solution; use in conjunction with systemic therapy if needed.
Rabbit PO 10-20 mg/kg q12-24h Duration: Variable
Notes: Limited data; use with caution and monitor for hepatotoxicity.
Bird (Psittacines) PO 12-18 mg/kg q12h Duration: Variable; often 2-4 weeks
Notes: May be given via gavage; monitor for regurgitation.
Reptiles PO 10-20 mg/kg q24h Duration: Variable
Notes: Limited data; adjust based on species and temperature.

Clinical Indications & Species Uses

General Indications
  • Treatment of invasive aspergillosis
  • Treatment of candidiasis (including fluconazole-resistant strains)
  • Treatment of other serious fungal infections caused by susceptible organisms
Dog (Canine)
  • Treatment of systemic mycoses including aspergillosis (nasal, pulmonary, disseminated), blastomycosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and candidiasis
  • Treatment of fungal keratitis
  • Treatment of fungal osteomyelitis
Cat (Feline)
  • Treatment of systemic mycoses including cryptococcosis, histoplasmosis, blastomycosis, aspergillosis, and candidiasis
  • Treatment of fungal rhinosinusitis
  • Treatment of dermatophytosis (refractory cases)
Horse (Equine)
  • Treatment of fungal keratitis
  • Treatment of guttural pouch mycosis
  • Treatment of systemic mycoses (e.g., aspergillosis, histoplasmosis)
Rabbit & Small Mammals
  • Treatment of systemic mycoses (e.g., aspergillosis, candidiasis) - off-label use
Avian & Poultry
  • Treatment of aspergillosis in psittacines and raptors; off-label use in poultry (not approved)
Exotic & Other Species
  • Treatment of systemic mycoses in reptiles (e.g., snakes, lizards) and small mammals (e.g., ferrets, guinea pigs) - off-label use

Pharmacology & Mechanism of Action

Drug Class: Antifungal | Pharmacological Group: Triazole

Mechanism of Action: Voriconazole inhibits fungal cytochrome P450-dependent 14α-demethylase, which is essential for the conversion of lanosterol to ergosterol, a critical component of the fungal cell membrane. This leads to accumulation of toxic sterol precursors and depletion of ergosterol, resulting in increased membrane permeability and inhibition of fungal growth. Voriconazole is fungicidal against some species and fungistatic against others, depending on the organism and concentration.

Pharmacodynamics: Voriconazole exhibits broad-spectrum antifungal activity against Aspergillus spp., Candida spp., Cryptococcus neoformans, and various dimorphic fungi including Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis. It is also effective against some molds such as Scedosporium and Fusarium. The drug is generally more potent than fluconazole against Aspergillus and has activity against fluconazole-resistant Candida species. Voriconazole is primarily fungistatic, but may be fungicidal at high concentrations against susceptible organisms.

⚡ Pharmacokinetics Summary

Absorption: Voriconazole is well absorbed after oral administration in most species, with a bioavailability of approximately 96% in humans. In dogs, oral bioavailability is reported to be around 50-60% due to first-pass metabolism. Absorption is reduced when taken with food, especially high-fat meals. In horses, oral bioavailability is variable and may be lower. In cats, oral absorption is also variable.
Distribution: Voriconazole has a large volume of distribution, penetrating well into tissues including the central nervous system, vitreous humor, and prostate. It is widely distributed in body fluids and tissues. Protein binding is approximately 58% in humans, but may vary in animals.
Metabolism: Voriconazole is extensively metabolized in the liver, primarily by the cytochrome P450 enzymes CYP2C19, CYP3A4, and to a lesser extent CYP2C9. It exhibits non-linear pharmacokinetics due to saturation of its metabolism, leading to disproportionate increases in plasma concentrations with dose escalation. In animals, metabolism may vary by species; dogs and cats have similar pathways but with different enzyme activities.
Excretion: Voriconazole is eliminated primarily via hepatic metabolism, with less than 2% of the parent drug excreted unchanged in the urine. Metabolites are excreted in urine (about 80%) and feces (about 20%). The elimination half-life is dose-dependent and ranges from 6 to 24 hours in humans; in dogs, it is approximately 4-6 hours, and in cats, it may be longer.
Half-Life: Dogs: 4-6 hours; Cats: 8-12 hours; Horses: 4-8 hours; Humans: 6-24 hours (non-linear)
Bioavailability: Oral: ~96% in humans; ~50-60% in dogs; variable in cats and horses
Protein Binding: Approximately 58% in humans; may vary in animals (e.g., dogs ~50%)

Available Formulations & Strengths

Oral Tablet 50 mg, 200 mg (PO)
Oral Suspension (powder for reconstitution) 40 mg/mL after reconstitution (PO)
Injectable Solution (IV) 200 mg/vial (lyophilized powder for reconstitution to 10 mg/mL) (IV)
Ophthalmic Solution (compounded) 1% (10 mg/mL) (Topical (ophthalmic))

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to voriconazole or other azole antifungals
  • Concurrent use with drugs that are strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenobarbital) due to significant reduction in voriconazole efficacy
  • Concurrent use with sirolimus, as voriconazole significantly increases sirolimus concentrations
  • Use in pregnant animals unless benefits outweigh risks (teratogenic in some species)
  • Use in lactating animals unless benefits outweigh risks (excreted in milk)
Warnings & Clinical Precautions:
  • Hepatotoxicity: Monitor liver enzymes (ALT, AST, ALP) and bilirubin periodically; discontinue if signs of hepatic injury occur.
  • Visual disturbances: Transient visual changes (photopsia, blurred vision) may occur; monitor for behavioral changes in animals.
  • Photosensitivity: Avoid excessive sunlight exposure; may cause severe sunburn-like reactions.
  • Cardiac effects: Prolongation of QT interval may occur; use with caution in animals with cardiac disease or those receiving other QT-prolonging drugs.
  • Pancreatitis: Rare cases reported; monitor for signs such as vomiting and abdominal pain.
  • Renal impairment: Dose adjustment may be necessary in animals with significant renal dysfunction (especially with IV formulation due to cyclodextrin vehicle).
  • Drug interactions: Voriconazole inhibits CYP3A4, CYP2C9, and CYP2C19; adjust doses of concomitant drugs metabolized by these enzymes.
  • Use in young animals: Safety not established; potential for skeletal abnormalities in growing animals.
  • Compounded ophthalmic solutions should be used within 30 days of preparation and stored appropriately.

Adverse Effects & Reactions

Common:

  • Gastrointestinal upset (vomiting, diarrhea, anorexia)
  • Elevated liver enzymes (ALT, AST, ALP)
  • Visual disturbances (photopsia, blurred vision) - more common in humans but may occur in animals
  • Skin reactions (erythema, pruritus)

Serious / Severe:

  • Hepatotoxicity (hepatic necrosis, jaundice)
  • Pancreatitis
  • Cardiac arrhythmias (QT prolongation, torsades de pointes)
  • Severe photosensitivity reactions
  • Stevens-Johnson syndrome (rare)
  • Anaphylaxis (rare)

Rare:

  • Peripheral neuropathy
  • Hypokalemia
  • Adrenal insufficiency
  • Bone marrow suppression
  • Renal toxicity (especially with IV formulation)

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Rifampin Significant reduction in voriconazole plasma concentrations (CYP3A4 induction); avoid concurrent use. High
Phenobarbital Reduces voriconazole concentrations; monitor efficacy or avoid. High
Carbamazepine Reduces voriconazole concentrations; avoid concurrent use. High
Sirolimus Voriconazole increases sirolimus concentrations significantly; avoid concurrent use. High
Cyclosporine Voriconazole increases cyclosporine concentrations; reduce cyclosporine dose and monitor levels. Moderate
Tacrolimus Voriconazole increases tacrolimus concentrations; reduce dose and monitor levels. Moderate
Warfarin Voriconazole increases warfarin concentrations and PT/INR; monitor coagulation parameters. Moderate
Benzodiazepines (e.g., midazolam) Voriconazole increases benzodiazepine concentrations; reduce dose and monitor for sedation. Moderate
Omeprazole Voriconazole increases omeprazole concentrations; monitor for adverse effects. Mild
Fluoroquinolones (e.g., enrofloxacin) Potential additive QT prolongation; use with caution. Moderate

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe gastrointestinal signs (vomiting, diarrhea)
  • Hepatotoxicity (jaundice, elevated liver enzymes)
  • Visual disturbances (photophobia, blindness)
  • Neurological signs (ataxia, seizures, depression)
  • Cardiac arrhythmias (QT prolongation)

Emergency Treatment Protocol: There is no specific antidote. Treatment is symptomatic and supportive. Induce emesis if recent ingestion and animal is conscious. Administer activated charcoal to reduce absorption. Provide intravenous fluids, monitor liver and renal function, and manage arrhythmias if they occur. In severe cases, consider hemodialysis (though voriconazole is highly protein-bound, so efficacy is limited). Supportive care and monitoring are essential.

Food Animal Withdrawal Times

Voriconazole is not approved for use in food-producing animals. Extra-label use in food animals is prohibited in many countries due to lack of withdrawal information and potential for residues. Do not use in animals intended for human consumption.

Storage, Handling & Regulatory Information

Storage Temperature: Store tablets and powder for oral suspension at 15-30°C (59-86°F). Reconstituted oral suspension should be stored at 2-8°C (refrigerated) and used within 14 days. IV solution should be used immediately after reconstitution and diluted; protect from light.

Light Sensitivity: Light-sensitive — protect from direct exposure.

Handling & Special Conditions: Protect from light. Do not freeze. Compounded ophthalmic solutions should be stored in the refrigerator and used within 30 days.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Not approved for veterinary use in the US. Approved for human use (VFEND).

Extra-Label (Off-Label) Use: Voriconazole is not FDA-approved for veterinary use in most species. Use in animals is extra-label and must comply with AMDUCA (Animal Medicinal Drug Use Clarification Act) in the US. Extra-label use is permitted only by or on the order of a licensed veterinarian within a valid veterinarian-client-patient relationship. It is prohibited in food-producing animals due to lack of withdrawal times and potential for residues.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Voriconazole is a potent triazole antifungal with excellent activity against Aspergillus and other molds. It is often used as a first-line treatment for aspergillosis in dogs and cats, and for fungal keratitis in horses. Due to its variable oral bioavailability and non-linear pharmacokinetics, therapeutic drug monitoring is recommended, especially in dogs and horses. The drug is generally well tolerated, but hepatotoxicity and visual disturbances are the most significant adverse effects. It is important to monitor liver enzymes and adjust doses accordingly. Voriconazole has numerous drug interactions due to its inhibition of CYP450 enzymes; a thorough medication review is essential. In food animals, its use is prohibited due to lack of withdrawal data. Compounded formulations should be used with caution, ensuring proper sterility and stability. Overall, voriconazole is a valuable antifungal in veterinary medicine, but requires careful monitoring and individualized dosing.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)