Vfend®

Voriconazole 200 mg · oral tablet

Antifungal

Approved uses

Systemic fungal infection, this label's only approved use: invasive aspergillosis, candidemia in non-neutropenic patients and other deep tissue Candida infections, esophageal candidiasis, and serious Scedosporium apiospermum or Fusarium infection in patients intolerant of or refractory to other therapy

Adults, 200 mg orally every 12 hours as maintenance (100 mg to 150 mg every 12 hours below 40 kg); aspergillosis, candidemia and scedosporiosis or fusariosis start with intravenous loading 6 mg/kg every 12 hours for the first 24 hours.

OFF-LABELNot in the FDA label for this product

Severe filamentous fungal keratitis, oral adjunct to topical antifungals

400 mg orally every 12 hours for 24 hours, then 200 mg orally every 12 hours for 20 days, alongside topical antifungal therapy

RCT · n=240 · no benefit

MUTT II, a multicenter double-masked placebo-controlled randomized trial of 240 patients with smear-positive filamentous ulcers and vision 20/400 or worse, found no difference in corneal perforation or therapeutic penetrating keratoplasty when this oral regimen was added to topical therapy (hazard ratio 0.82, 95% CI 0.57 to 1.18, P=0.29), with 58 adverse events (48.7%) versus 28 (23.1%) on placebo, P<0.001; the authors concluded there appears to be no benefit. In the earlier phase 3 MUTT I trial of 323 patients, compounded topical voriconazole 1% was inferior to topical natamycin 5% on 3-month best corrected acuity (regression coefficient 0.18 logMAR favoring natamycin, P=0.006) and on perforation or keratoplasty (odds ratio 0.42 favoring natamycin, 95% CI 0.22 to 0.80, P=0.009), with the difference driven by Fusarium cases.

Prajna NV, et al. Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II). JAMA Ophthalmol. 2016;134(12):1365-1372; Prajna NV, et al. The Mycotic Ulcer Treatment Trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131(4):422-429 (10.1001/jamaophthalmol.2013.1497)

Contraindications

Hypersensitivity to voriconazole or its excipients
Concomitant drugs highly dependent on CYP3A4 clearance whose raised levels cause serious or life-threatening reactions (eplerenone, ergot alkaloids, finerenone, ivabradine, lurasidone, naloxegol, pimozide, quinidine, rifabutin, sirolimus, tolvaptan, venetoclax at CLL or SLL initiation and ramp-up, voclosporin)
Concomitant CYP2C19, CYP2C9 or CYP3A4 inducers that cut plasma levels and cost efficacy (carbamazepine, long-acting barbiturates, rifampin, rifabutin, efavirenz 400 mg or more every 24 hours, high-dose ritonavir 400 mg every 12 hours, St. John's Wort)

Available Forms

50 mg and 200 mg tablets

Mechanism of Action

Azole antifungal that inhibits fungal cytochrome P-450 mediated 14 alpha-lanosterol demethylation, an essential step in ergosterol biosynthesis. Accumulation of 14 alpha-methyl sterols with subsequent loss of ergosterol may account for the antifungal activity, and isolates with reduced susceptibility to fluconazole or itraconazole can show cross-resistance.

Warnings & Precautions

Visual disturbances: Effect on visual function past 28 days of treatment is unknown, and postmarketing reports include prolonged reactions such as optic neuritis and papilledema. Monitor visual acuity, visual field and color perception if treatment continues beyond 28 days.
Hepatic toxicity: Clinical hepatitis, cholestasis and fulminant hepatic failure including fatalities, some in patients with no other identifiable risk factor. Measure transaminases and bilirubin at initiation and at least weekly for the first month, then monthly.
QT prolongation and arrhythmias: Rare torsades de pointes, cardiac arrest and sudden death, usually in seriously ill patients with confounding risks. Correct potassium, magnesium and calcium before and during therapy.
Severe cutaneous adverse reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS, which can be life threatening or fatal; discontinue if one develops.
Photosensitivity and skin cancer: Squamous cell carcinoma, Bowen disease and melanoma reported during long-term therapy in patients with photosensitivity reactions; phototoxicity is more frequent in pediatric patients.
Renal toxicity: Acute renal failure observed; monitor serum creatinine, particularly alongside nephrotoxic drugs.
Adrenal dysfunction: Adrenal insufficiency reported with and without concomitant corticosteroids, and Cushing syndrome reported with corticosteroids; monitor during and after treatment.
Pancreatitis: Observed during treatment; watch patients with recent chemotherapy or hematopoietic stem cell transplantation.
Skeletal adverse reactions: Fluorosis and periostitis with long-term therapy; discontinue if skeletal pain with compatible radiologic findings appears.

Common Side Effects

Ocular: Abnormal vision 18.7%, photophobia 2.2%, chromatopsia 1.2%; about 21% of patients in therapeutic trials had abnormal vision, color vision change and/or photophobia, more often at higher plasma concentrations or doses.
Retinal function: 28 days of dosing in healthy subjects lowered ERG waveform amplitude, narrowed the visual field and altered color perception, all back to normal 14 days after dosing ended.
Ocular, under 2%: Optic neuritis, papilledema, optic atrophy, keratitis, keratoconjunctivitis, uveitis, scleritis, retinitis, retinal hemorrhage, visual field defect, night blindness, corneal opacity, dry eyes, mydriasis, blepharitis.
Systemic: Fever 5.7%, nausea 5.4%, rash 5.3%, vomiting 4.4%, chills 3.7%, headache 3.0%, abnormal liver function tests 2.7%, tachycardia 2.4%, hallucinations 2.4%.
Transaminase elevation: Rises above 3 times the upper limit of normal in 17.7% (268 of 1514) of adults across pooled therapeutic trials.
Discontinuation drivers: Elevated liver function tests, rash and visual disturbances were the reactions that most often ended therapy.

Pregnancy & Lactation

Pregnancy: Can cause fetal harm and there are no human data. Cleft palate and hydronephrosis or hydroureter occurred in rats at and above 0.3 times the recommended maintenance dose by body surface area, and embryomortality with reduced fetal weight occurred in rabbits at 6 times that dose.

Lactation: No data on presence in human milk, on effects in the breastfed infant, or on milk production.

Embryo-fetal toxicity: Fetal malformations in rats and fetal toxicity in rabbits; effective contraception is advised in females of reproductive potential.

Drug interactions: Extensive contraindicated and dose-altering interactions across CYP2C19, CYP2C9 and CYP3A4; review every concomitant medication, and raise the maintenance dose with phenytoin or efavirenz.

Galactose intolerance: Tablets contain lactose and are not for patients with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Pediatric Use

Established from 2 years of age; not recommended below 2 years.