Voriconazole (Dosage)

Voriconazole is an antifungal drug of the triazole derivatives group, used in the treatment of fungal infections such as Candida, Aspergillus and Scedosporium. Identifying genetic polymorphisms of genes involved in the metabolism of voriconazole, such as the CYP2C19 gene, may allow better adjustment of treatment dosage.

Voriconazole is an antifungal agent against species of Candida, Aspergillus, Scedosporium or Fusarium.

Its mechanism of action consists in the inhibition of the fungal enzyme 14-alpha-sterol demethylase, an essential enzyme in the biosynthesis of ergosterol, an essential compound for fungi.

CONTRAINDICATIONS

Hypersensitivity.

Voriconazole is contraindicated in concomitance with: terfenadine, astemizole, cisapride, pimozide and quinidine due to the risk of prolongation of the QTc interval. Voriconazole is contraindicated in concomitance with rifampicin, carbamazepine and phenobarbital, high doses of ritonavir (≥ 400 mg 2 times/day), high doses of efavirenz (≥ 400 mg/day), ergot alkaloids due to risk of ergotism, sirolimus and hypericum.

CAUTIONS

Previous hypersensitivity to azole compounds.

Precautions should be taken when prescribing voriconazole in patients with acquired or congenital prolongation of the cardiac QT interval, cardiomyopathy (in particular with associated heart failure), sinus bradycardia, symptomatic arrhythmia, precautions in concomitance with QT prolongation. It is recommended before and during treatment to monitor and correct electrolyte alterations (hypokalemia, hypomagnesemia and hypocalcemia).

During treatment with voriconazole it is recommended to monitor liver function at the beginning and at least once a week during the first month of treatment and in case of alteration of the liver function tests during the entire duration of the treatment. If the treatment is prolonged, perform liver function tests once a month and consider suspension of treatment if there are signs of liver disease.

In patients with severe hepatic impairment, the risk/benefit should be assessed before prescribing voriconazole.

Avoid exposure to sunlight, voriconazol has been associated with photoxicity, pseudoporphyria and in prolonged treatments has been reported squamous cell carcinoma of the skin, with increased risk in children.

In cases of concomitance of treatment with other drugs, a risk/benefit assessment is recommended before prescribing voriconazole:

Ritonavir, phenytoin, rifabutin, methadone, short-acting opioids (alfentanil, fentanyl, sulfentanil) or long-acting opioids (oxycodone, hydrocodone), CYP3A4 substrates. Intensive and frequent adverse effects associated with opiates should be monitored and dosage adjustment considered. One should monitor adverse effects of voriconazole if used sequentially after fluconazole. On concomitant treatment with efavirenz, increase the maintenance dose of voriconazole to 400 mg/12 h and reduce the dose of efavirenz to 300 mg/24 h. Treatment with voriconazole produces a risk of increasing the levels of everolimus, thus concomitant intake is not recommended.

In children under 2 years old there are insufficient data on efficacy and safety in intravenous treatments.

SIDE EFFECTS

Gastroenteritis, sinusitis, gingivitis.

Squamous cell carcinoma, agranulocytosis, pancytopenia, thrombocytopenia, anemia, hypersensitivity, peripheral edema, hypoglycemia, hypokalemia, hyponatremia, depression, hallucinations, anxiety, insomnia, agitation, confusional state, headache, convulsion, tremors, paresthesia, hypertonia, somnolence, syncope , dizziness and visual disturbance (blurred vision, chromatopsia, photophobia).

Retinal hemorrhage, supraventricular arrhythmia, tachycardia, bradycardia, hypotension, phlebitis, respiratory distress, acute respiratory distress syndrome, pulmonary edema, abdominal pain, nausea, vomiting, diarrhea, dyspepsia, constipation, cheilitis. Elevated liver function tests, jaundice, cholestatic jaundice, hepatitis. Eruption/rash, exfoliative dermatitis, maculopapular rash, pruritus, alopecia, erythema, back pain, acute renal failure, hematuria, pyrexia, chest pain, facial edema, asthenia, flu-like illness, chills and increases in creatinine levels.

PHARMACOLOGIC INTERACTIONS

Monitor the concentration of ciclosporin (it is recommended to reduce the dose by half) and tacrolimus (it is recommended to reduce the dose to one third).

Consider a dose adjustment of: statins metabolized by CYP3A4, benzodiazepines, omeprazole (it is recommended to reduce the dose by half).

Nausea and menstrual disorders in concomitance with oral contraceptives.

Control toxicity and/or loss of efficacy with non-nucleoside reverse transcriptase inhibitors (antiretrovirals)

Voriconazole increases the Cmin. and AUC (""Area Under the Curve"") of NSAIDs, monitor adverse effects and toxicity.

Voriconazole is incompatible with simultaneous administration of blood products and perfusion of concentrated electrolyte solutions, simultaneous perfusion in the same cannula with other intravenous drugs.

BRAND NAME

  • Vfend ®

Genes analyzed

CYP2C19

Bibliography

Dean L. Voriconazole Therapy and CYP2C19 Genotype. 2019 Dec 27. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. PMID: 31886997.

Hamadeh IS, Klinker KP, Borgert SJ, et al. Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections. Pharmacogenet Genomics. 2017 May;27(5):190-196.

Moriyama B, Obeng AO, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther. 2017 Jul;102(1):45-51.

Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther. 2011 May;89(5):662-73.

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