Voriconazole

Usage

Voriconazole is a broad-spectrum triazole antifungal agent primarily used for the treatment of invasive aspergillosis, candidemia in non-neutropenic patients, esophageal candidiasis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium species in patients intolerant of or refractory to other therapies. It is also used as prophylaxis against fungal infections in high-risk patients such as hematopoietic stem cell transplant (HSCT) recipients.

• Pharmacological Classification: Triazole antifungal agent.

• Mechanism of Action: Voriconazole inhibits the fungal cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase, which is essential for ergosterol biosynthesis. Ergosterol is a crucial component of the fungal cell membrane, and its depletion results in fungal cell death.

Alternate Names

Voriconazole is the generic name. Brand names include Vfend.

How It Works

• Pharmacodynamics: Voriconazole’s primary effect is fungistatic or fungicidal, depending on the fungal species and concentration. It disrupts fungal cell membrane integrity by inhibiting ergosterol synthesis.

• Pharmacokinetics:

  • Absorption: Oral bioavailability is high (approximately 96%). Food can delay but not significantly reduce absorption. Absorption is saturable, leading to non-linear pharmacokinetics.
  • Distribution: Voriconazole is widely distributed, including into the cerebrospinal fluid (CSF), reaching therapeutic concentrations.
  • Metabolism: Primarily metabolized by hepatic cytochrome P450 enzymes, mainly CYP2C19, CYP3A4, and CYP2C9, with significant genetic polymorphism influencing metabolism (especially CYP2C19).
  • Elimination: Primarily eliminated via hepatic metabolism with minimal renal excretion.

• Mode of Action: Voriconazole specifically targets the fungal cytochrome P450 enzyme lanosterol 14-alpha-demethylase. This enzyme is crucial for the conversion of lanosterol to ergosterol, an essential component of the fungal cell membrane. By inhibiting this enzyme, voriconazole disrupts ergosterol biosynthesis, leading to fungal cell death.

• Receptor binding, enzyme inhibition, or neurotransmitter modulation: The primary mechanism of action is the inhibition of the fungal cytochrome P450 enzyme lanosterol 14-alpha-demethylase. There is no significant receptor binding or neurotransmitter modulation.

• Elimination pathways: Primarily hepatic metabolism, with minimal renal excretion (less than 2% unchanged drug).

Dosage

Standard Dosage

Adults:

• IV: Loading dose: 6 mg/kg every 12 hours for the first 24 hours. Maintenance dose: 4 mg/kg every 12 hours. Patients less than 40 kg: 3 mg/kg every 12 hours.
• Oral: Loading dose: 400 mg every 12 hours for the first 24 hours. Maintenance dose: 200 mg every 12 hours. Patients less than 40 kg: 100-150 mg every 12 hours.

Children:

• 2 to <12 years: IV: Loading dose: Not recommended. Maintenance dose: 7 mg/kg twice daily. Oral: 200mg twice daily.
• 12 to 14 years (<50 kg): Follow pediatric dosing based on weight.
• 12 to 14 years (≥50 kg) and ≥15 years: Follow adult dosing.
• <2 years: Use is not recommended.

Special Cases:

• Elderly Patients: No dose adjustment is typically necessary but consider lower doses in frail elderly.
• Patients with Renal Impairment: No dose adjustment needed. Prefer oral administration in moderate-severe renal insufficiency.
• Patients with Hepatic Dysfunction: Reduce maintenance dose by 50% in mild to moderate hepatic impairment. Use with caution in severe hepatic impairment only if benefit outweighs risk.
• Patients with Comorbid Conditions: Monitor closely for adverse effects and drug interactions. Adjust dose based on drug interaction potential and patient tolerance.

Clinical Use Cases

The dosing in clinical use cases generally follows the standard dosage recommendations with potential adjustments based on patient-specific factors and clinical response. Monitor voriconazole levels to ensure therapeutic concentrations are achieved while minimizing toxicity.

• Intubation, Surgical Procedures, Mechanical Ventilation, ICU Use, Emergency Situations: Standard dosages are recommended initially, with careful monitoring and adjustments based on patient response, organ function, and concomitant medications.

Dosage Adjustments

Dosage adjustments are crucial due to voriconazole’s non-linear pharmacokinetics and susceptibility to drug interactions. Therapeutic drug monitoring (TDM) is recommended.

• Renal/Hepatic Dysfunction: Adjust dosage as described above.
• Metabolic Disorders: Monitor for potential drug interactions.
• Genetic Polymorphisms: CYP2C19 genotype significantly influences metabolism. Consider lower doses in poor metabolizers and higher doses in ultra-rapid metabolizers.

Side Effects

Common Side Effects:

Visual disturbances (blurred vision, photophobia, altered color perception), nausea, vomiting, diarrhea, headache, rash, fever, chills, elevated liver enzymes.

Rare but Serious Side Effects:

Hepatotoxicity (jaundice, hepatic failure), Stevens-Johnson syndrome, toxic epidermal necrolysis, hallucinations, seizures, QT prolongation, torsades de pointes, renal dysfunction, pancreatitis, peripheral neuropathy, infusion site reactions.

Long-Term Effects:

Skin cancer (squamous cell carcinoma) with prolonged use, especially in immunosuppressed patients, cataracts, peripheral neuropathy.

Adverse Drug Reactions (ADR):

Severe skin reactions, hepatotoxicity, cardiac arrhythmias, visual disturbances requiring immediate intervention.

Contraindications

• Hypersensitivity to voriconazole or any of the excipients.
• Coadministration with CYP3A4 substrates such as terfenadine, astemizole, cisapride, pimozide, quinidine, or ivabradine.
• Coadministration with sirolimus.
• Coadministration with rifampin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids.

Drug Interactions

Voriconazole is a major substrate and inhibitor of CYP2C19, CYP3A4, and CYP2C9, leading to numerous drug interactions.

• CYP450 interactions: Inhibits CYP2C19, CYP3A4, and CYP2C9.
• Commonly Prescribed Medications: Many interactions, including increased levels of immunosuppressants (ciclosporin, tacrolimus), warfarin, statins, benzodiazepines, some opioids.
• OTC drugs and supplements: St. John’s Wort significantly reduces voriconazole levels.
• Food and lifestyle factors: Avoid grapefruit juice.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D. Voriconazole is teratogenic and should be avoided during pregnancy. Effective contraception is essential.
• Breastfeeding: Voriconazole is present in breast milk. Breastfeeding should generally be avoided while on voriconazole.

Drug Profile Summary

• Mechanism of Action: Inhibits fungal ergosterol biosynthesis by targeting lanosterol 14-alpha-demethylase.
• Side Effects: Visual disturbances, nausea, hepatotoxicity, skin reactions.
• Contraindications: Hypersensitivity, coadministration with specific CYP3A4 substrates and sirolimus.
• Drug Interactions: Numerous, mainly through CYP2C19, CYP3A4, and CYP2C9 inhibition.
• Pregnancy & Breastfeeding: Avoid in pregnancy; not recommended while breastfeeding.
• Dosage: IV/Oral loading and maintenance doses as described above, with adjustments for specific populations.
• Monitoring Parameters: Voriconazole trough levels, liver function tests, renal function, electrocardiogram (ECG) for QT prolongation, and visual acuity.

Popular Combinations

Often used in combination with other antifungals or antibacterial agents, depending on the specific infection. Closely monitor for drug interactions.

Precautions

• General Precautions: Monitor liver and renal function, assess for visual disturbances, screen for CYP2C19 genotype.
• Specific Populations: Follow specific dosage adjustments for hepatic impairment, renal impairment, elderly patients. Avoid in pregnancy and use with caution when breastfeeding. Pediatric dosing requires careful monitoring.
• Lifestyle Considerations: Avoid excessive sun exposure due to photosensitivity risk. Caution with driving due to potential visual side effects.

FAQs

Q1: What is the recommended dosage for Voriconazole?

A: See detailed dosage guidelines above for IV and oral administration in adults, children, and special populations.

Q2: What are the most common side effects of Voriconazole?

A: Visual disturbances (blurred vision, photophobia, altered color perception), nausea, vomiting, diarrhea, headache, and rash.

Q3: What are the serious side effects of Voriconazole?

A: Hepatotoxicity, Stevens-Johnson syndrome, toxic epidermal necrolysis, visual hallucinations, seizures, QT prolongation, and cardiac arrhythmias.

Q4: What are the contraindications for Voriconazole?

A: Hypersensitivity to voriconazole, coadministration with specific CYP3A4 substrates (e.g., terfenadine, astemizole, cisapride) and sirolimus, concomitant use of strong CYP3A4 inducers.

Q5: What are the key drug interactions with Voriconazole?

A: Numerous interactions due to its inhibition of CYP2C19, CYP3A4, and CYP2C9. It can increase levels of many drugs, including immunosuppressants, warfarin, statins, and benzodiazepines.

Q6: Can Voriconazole be used in pregnant or breastfeeding women?

A: It should be avoided during pregnancy due to teratogenic effects. Use with caution during breastfeeding; consider alternative antifungals.

Q7: What monitoring is recommended for patients on Voriconazole?

A: Voriconazole trough levels, liver function tests, ECG for QT interval, visual acuity, renal function.

Q8: How should Voriconazole be administered?

A: Available as intravenous and oral formulations. Oral tablets should be taken on an empty stomach at least one hour before or two hours after a meal. Intravenous infusions should be administered over 1-2 hours.

Q9: What is the role of CYP2C19 polymorphism in Voriconazole dosing?

A: CYP2C19 genotype influences voriconazole metabolism. Poor metabolizers are at risk of toxicity with standard doses, while ultra-rapid metabolizers may require higher doses.

Q10: What are the long-term risks associated with Voriconazole use?

A: Increased risk of squamous cell carcinoma of the skin, especially in immunosuppressed individuals and with prolonged use, Cataracts, peripheral neuropathy.