Voriconazole

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Contents

[edit] BRAND NAMES

[edit] STRUCTURE

Voriconazole.jpg

[edit] MECHANISM OF ACTION

Voriconazole is an triazole antifungal. It inhibits lanosterol 14α-demethylase, a cytochrome P-450 enzyme that converts lanosterol to ergosterol.

Ergosterol is an essential component of the fungal cell membrane. The inhibition of its synthesis results in accumulation of toxic 14α-methylated sterols and the production of a defective cell membrane with altered permeability and leakage of cellular contents.

Voriconazole is one of the azoles that has the widest spectrum. It has a very good absorption.

Voriconazole is metabolized by the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and to a lesser extent by CYP3A4.

[edit] INDICATIONS

Voriconazole crosses the BBB and is the preferred antifungal agent for invasive Aspergillus infections.

Voriconazole is also used for GI candidiasis, especially when Candida doesn’t respond (or is resistant) to Fluconazole.

Candidemia (nonneutropenics) and disseminated candidiasis in skin, abdomen, kidney, bladder wall, and wounds

Serious infections caused by Scedosporium apiospermum and Fusarium species. including Fusarium solani, in patients intolerant of, or refractory to, other therapy

[edit] DOSAGE

Infection Loading dose Maintenance Dose

IV IV Oral
Invasive Aspergillosis 6 mg/Kg every 12 hours for the first 24 hours  4 mg/Kg every 12 hours  200 mg every 12 hours 
Candidemia in nonneutropenics and other deep tissue Candida infections 3-4 mg/Kg every 12 hours  200 mg every 12 hours 
Scedosporiosis and Fusariosis 4 mg/Kg every 12 hours  200 mg every 12 hours 
Esophageal Candidiasis Not Evaluated Not Evaluated 200 mg every 12 hours 

Adult patients weighing less than 40 kg: oral maintenance dose 100 or 150 mg every 12 hours

[edit] CONTRAINDICATIONS

  • Hypersensitivity to voriconazole.
  • Coadministration of terfenadine, astemizole, cisapride, pimozide or quinidine with Voriconazole is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes
  • Coadministration of Voriconazole with sirolimus is contraindicated because Voriconazole significantly increases sirolimus concentrations
  • Coadministration of Voriconazole with rifampin, carbamazepine and long-acting barbiturates is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly.
  • Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24h or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations
  • Coadministration of Voriconazole with high-dose ritonavir (400 mg every 12h) is contraindicated because ritonavir (400 mg q12h) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
  • Coadministration of Voriconazole with rifabutin is contraindicated since Voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations.
  • Coadministration of Voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because Voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism
  • Coadministration of Voriconazole with St. John's Wort is contraindicated because this herbal supplement may decrease voriconazole plasma concentration.

[edit] WARNINGS AND PRECAUTIONS

  • Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver function tests at start of and during voriconazole therapy.
  • Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days.
  • Embryo-Fetal Toxicity: Do not administer to pregnant women unless the benefit to the mother outweighs the risk to the fetus. Inform pregnant patient of hazard.
  • Arrhythmias and QT Prolongation: Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions.
  • Infusion Related Reactions (including anaphylaxis): Stop the infusion.
  • Dermatological Reactions: Discontinue for exfoliative cutaneous reactions. Avoid sunlight due to risk of photosensitivity.
  • Skeletal Events: Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these events occur .

[edit] INTERACTIONS

[edit] PREGNANCY AND LACTATION

  • Pregnancy Category D (US) Do not administer to pregnant women unless the benefit to the mother outweighs the risk to the fetus. Inform pregnant woman of risk.
  • Nursing women: Discontinue Voriconazole or discontinue nursing

[edit] SIDE EFFECTS

Voriconazole is generally well-tolerated, but also has the potential to modify the liver function causing hepatotoxicity. It has also been charged for prolongation of the QT interval, thus, increasing the risk of development of arrhythmias. Lastly, it can cause photosensitivity.

Most common adverse reactions (incidence ≥2%) are visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, and hallucinations.

[edit] RELATED LINKS

Azoles mechanism of action

[edit] BIBLIOGRAPHY

[edit] REFERENCES

Antifungals
Ergosterol target : Cell membrane target Azoles (lanosterol 14 alpha-demethylase inhibitors) : Ergosterol inhibitors Imidazoles Topical: Bifonazole   Clotrimazole   Econazole   Fenticonazole   Ketoconazole   Isoconazole   Miconazole   Sertaconazole   Tioconazole
Triazoles Topical: Fluconazole   Terconazole
Systemic: Fluconazole   Itraconazole   Posaconazole   Voriconazole
Polyene antimycotics (ergosterol binding; they form pores in the membrane) Topical: Nystatin
Systemic: Amphotericin B
Allylamines (squalene epoxidase inhibitors) : Ergosterol inhibitors Topical: Amorolfine   Naftifine   Terbinafine
Systemic: Terbinafine
Echinocandins (β-glucan synthase inhibitors) : Cell wall target Anidulafungin   Caspofungin   Micafungin
Pyrimidine analogues / Thymidylate synthase inhibitors : Nucleic acid inhibitors Flucytosine
Mitotic inhibitors Griseofulvin
Others Ciclopirox