Voriconazole

(BAN, USAN, rINN)
Voriconazole Chemical formula
Synonyms: UK-109496; Voriconazol; Voriconazolum; Vorikonazol. (2R,3S)2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol.
Cyrillic synonym: Вориконазол.

💊 Chemical information

Chemical formula: C16H14N5F3O = 349.3.
CAS — 137234-62-9.
ATC — J02AC03.
ATC Vet — QJ0 2AC0 3.

💊 Adverse Effects

The most commonly reported adverse effects with voriconazole are visual disturbances, fever, rashes, nausea, vomiting, diarrhoea, abdominal pain, headache, sepsis, respiratory disorders, and peripheral oedema. There have been some serious hepatic reactions including fatalities. Skin reactions have included rare cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Photosensitivity reactions may occur and are more likely during long-term treatment. Other adverse effects reported as being common during treatment with voriconazole include: chills, flu-like syndrome, asthenia, back pain, chest pain, injection site reactions, facial oedema, hypotension, sinusitis, altered liver function tests, jaundice, cheilitis, blood disorders, hypokalaemia, hypoglycaemia, dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paraesthesia, pruritus, alopecia, exfoliative dermatitis, acute renal failure, and haematuria. Hypersensitivity reactions, including anaphylaxis, have occurred rarely.

Effects on the blood.

Fever and leucocytosis with eosinophilia in one patient has been attributed to voriconazole treatment.1
1. Vishnubhotla P, et al. Fever and eosinophilia associated with voriconazole. Ann Pharmacother 2004; 38: 900–901.

Effects on the heart.

Bradycardia with a prolonged QT interval and asymptomatic episodes of torsade de pointes occurred in a 15-year-old patient, after 3 weeks of voriconazole therapy at usual doses.1 All drug treatment was stopped but the effects recurred on rechallenge with a small dose of voriconazole.
1. Alkan Y, et al. Voriconazole-induced QT interval prolongation and ventricular tachycardia: a non-concentration-dependent adverse effect. Clin Infect Dis 2004; 39: e49–e52.

Effects on mental function.

There have been reports1,2 of patients experiencing hallucinations (auditory or visual) during treatment with voriconazole. In one study 18 of 415 patients (4.3%) given voriconazole had visual hallucinations compared with 2 of 422 (0.5%) given amphotericin B.1
1. Walsh TJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346: 225–34
2. Agrawal AK, Sherman LK. Voriconazole-induced musical hallucinations. Infection 2004; 32: 293–5.

💊 Precautions

Acute renal failure may occur with voriconazole and renal function should be monitored during treatment. Liver function should also be monitored before and during treatment with voriconazole. It should be used with caution in patients with hepatic impairment and doses may need to be adjusted (see under Uses and Administration, below). Patients should avoid sunlight during treatment as photosensitivity reactions have been reported. Visual disturbances may occur and patients affected should not drive or operate hazardous machinery. In addition, all patients, whether affected by visual disturbances or not, should not drive at night, and should have their visual function monitored if they are receiving voriconazole for more than 28 days. Voriconazole has been associated with QT interval prolongation and should therefore be given with caution to patients with potentially pro-arrhythmic conditions. Voriconazole has been shown to be teratogenic and embryotoxic in animal studies and its use is generally not recommended during pregnancy. For a discussion of the caution needed when using azole antifungals during pregnancy, see under Pregnancy in Precautions of Fluconazole. Licensed product information recommends that women of child-bearing potential should use effective contraception during treatment with voriconazole.

💊 Interactions

Voriconazole is metabolised by cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. Use of drugs that either inhibit or induce these isoenzymes may increase or decrease plasma concentrations of voriconazole, respectively. Rifampicin has been shown to decrease voriconazole plasma concentrations and a similar effect may be expected with carbamazepine or phenobarbital; use of voriconazole with these drugs is therefore not recommended. Concentrations of other drugs that are metabolised by CYP2C19, CYP2C9, or CYP3A4 may be increased by voriconazole. Increased plasma concentrations of astemizole, cisapride, pimozide, quinidine, and terfenadine could be expected and concomitant use is contra-indicated because of the risk of cardiac arrhythmias including torsade de pointes. Use with ergot alkaloids such as ergotamine and dihydroergotamine is also contra-indicated because of the possible risk of ergotism. Increased plasma concentrations of sirolimus and tacrolimus have been noted; use with sirolimus is contra-indicated, although tacrolimus may be used providing its dose is reduced and concentrations monitored. Similarly, reduced dose with monitoring is recommended for ciclosporin. Likewise, monitoring and possible dose reductions of methadone are recommended during concomitant use. Concentrations of oral anticoagulants may be affected and increased prothrombin time has occurred with warfarin; monitoring should therefore be carried out. Close monitoring of blood glucose is necessary if voriconazole is used with oral hypoglycaemics such as the sulfonylureas. Dose reductions may be needed for some statins, calciumchannel blockers, vinca alkaloids, and some benzodiazepines (such as midazolam and triazolam) if their plasma concentrations are increased. Interactions may occur where both voriconazole and the other drug are affected. Examples are phenytoin and rifabutin (where concentrations of voriconazole are reduced but those of phenytoin or rifabutin are increased). If it is essential to give either drug with voriconazole, then an increase in the dose of voriconazole is recommended. With omeprazole, the plasma concentration of both drugs may be increased and a reduced dose of omeprazole is recommended. Voriconazole may inhibit metabolism of non-nucleoside reverse transcriptase inhibitors and they in turn may either inhibit the metabolism of voriconazole (e.g. delavirdine and efavirenz) or induce the metabolism of voriconazole (e.g. efavirenz and nevirapine). Co-administration of voriconazole and efavirenz is contra-indicated. Similarly, voriconazole may inhibit metabolism of HIV-protease inhibitors (e.g. saquinavir, amprenavir, and nelfinavir) while they may in turn inhibit the metabolism of voriconazole. High doses of ritonavir (400 mg twice daily) significantly decrease plasma concentrations of voriconazole and co-administration is contra-indicated. Similar effects have been seen with low doses of ritonavir (100 mg twice daily) and use with voriconazole should be avoided where possible. Indinavir, however, does not appear to interact with voriconazole. For further information on interactions between drugs metabolised by the cytochrome P450 isoenzyme CYP3A and azoles, see under Itraconazole.

💊 Antimicrobial Action

Voriconazole is a triazole antifungal that in sensitive fungi inhibits cytochrome P450-dependent enzymes resulting in the impairment of ergosterol synthesis in fungal cell membranes. Voriconazole has a broad spec-
trum of activity against all Candida species, including fluconazole-resistant strains, as well as Aspergillus spp., Scedosporium spp., and Fusarium spp.
1. Marty FM, et al. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 2004; 350: 950–2
2. Siwek GT, et al. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. Clin Infect Dis 2004; 39: 584–7
3. Imhof A, et al. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis 2004; 39: 743–6
4. Oren I. Breakthrough zygomycosis during empirical voriconazole therapy in febrile patients with neutropenia. Clin Infect Dis 2005; 40: 770–1
5. Vigouroux S, et al. Zygomycosis after prolonged use of voriconazole in immunocompromised patients with hematologic disease: attention required. Clin Infect Dis 2005; 40: e35-e37.

💊 Pharmacokinetics

Voriconazole exhibits non-linear pharmacokinetics due to saturable metabolism. It is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations occur about 1 to 2 hours after an oral dose. Plasma protein binding of voriconazole is about 58%. Voriconazole diffuses into CSF. Voriconazole is metabolised by hepatic cytochrome P450 isoenzyme CYP2C19; the major metabolite is the inactive N-oxide. Metabolism via isoenzymes CYP2C9 and CYP3A4 has also been demonstrated in vitro. About 80% of voriconazole is excreted in the urine.
1. Purkins L, et al. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 2002; 46: 2546–53
2. Johnston A. The pharmacokinetics of voriconazole. Br J Clin Pharmacol 2003; 56 (suppl 1): 1
3. Walsh TJ, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother 2004; 48: 2166–72
4. Theuretzbacher U, et al. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet 2006; 45: 649–63.

💊 Uses and Administration

Voriconazole is a triazole antifungal used mainly in immunocompromised patients for the treatment of invasive aspergillosis, candidaemia in non-neutropenic patients, fluconazole-resistant serious invasive candidiasis, oesophageal candidiasis, and serious fungal infections due to Scedosporium and Fusarium spp. Voriconazole may be given orally or intravenously. Oral doses as film-coated tablets should be taken at least 1 hour before, or 1 hour after, a meal; oral suspensions should be taken at least 1 hour before, or 1 to 2 hours after, a meal. The oral suspension may be preferred in children.
Published December 26, 2018.