Fortified Voriconazole

Voriconazole 0.05% · compounded ophthalmic solution

Antifungal

Approved uses

Invasive aspergillosis, candidemia and deep tissue candidiasis, esophageal candidiasis, scedosporiosis and fusariosis (intravenous, non-ocular)

Adults: 6 mg/kg IV every 12 hours for the first 24 hours, then 4 mg/kg IV every 12 hours (3 to 4 mg/kg for candidemia), or 200 mg orally every 12 hours

OFF-LABELNot in the FDA label for this product

Filamentous fungal keratitis

1% (10 mg/mL) topically, 1 drop every hour while awake until re-epithelialization, then 4 times daily for at least 3 weeks

RCT · n=323 · natamycin better

This regimen is the voriconazole arm of MUTT I, a phase 3 double-masked multicenter randomized trial of 323 smear-positive filamentous ulcers, and that trial found natamycin 5% superior: odds of corneal perforation or therapeutic penetrating keratoplasty were 0.42 with natamycin (95% CI 0.22 to 0.80, P = .009), with most of the difference from Fusarium cases while non-Fusarium cases fared similarly. The authors' own conclusion was that voriconazole should not be used as monotherapy in filamentous keratitis. A Cochrane review reached the same direction: reduced perforation or keratoplasty with natamycin (RR 0.61, 95% CI 0.40 to 0.94, 434 participants, high quality evidence), while its visual acuity estimate crossed no effect (mean difference -0.12 logMAR, 95% CI -0.31 to 0.06, low quality evidence).

Prajna NV, Krishnan T, Mascarenhas J, et al. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013;131(4):422-429 (phase 3 randomized controlled trial). FlorCruz NV, Evans JR. Medical interventions for fungal keratitis. Cochrane Database Syst Rev. 2015;2015(4):CD004241 (systematic review and meta-analysis, 12 trials).

Severe fungal keratitis, combined with topical natamycin

1% (10 mg/mL) topically alongside natamycin 5%, each 1 drop every hour while awake

Cohort · n=51 · nonrandomized

Prospective cohort of 51 fungal keratitis patients on empiric therapy: 88.9% of ulcers healed on natamycin plus voriconazole versus 39.1% on voriconazole alone (p = 0.018) and 52.6% on natamycin alone (p = 0.098, not significant). Interventions such as keratoplasty, anterior chamber wash, or a treatment change differed across arms (47.4% natamycin, 60.9% voriconazole, 11.1% combination, p = 0.034). The combination is not faster: median time to epithelialization was 65 days for the combination and 60 days for voriconazole alone versus 22 days for natamycin alone (log-rank p < 0.001). Arms were small (9, 23, and 19 patients), single-center, and not randomized. Application frequency comes from MUTT I, not from this cohort.

Nayel AA, Hamdy NA, Massoud TH, Mohamed NM. Graefes Arch Clin Exp Ophthalmol. 2024;262(6):1865-1882 (prospective cohort). Frequency from Prajna NV et al, JAMA Ophthalmol. 2013;131(4):422-429.

Recalcitrant deep fungal keratitis, intrastromal injection

50 mcg/0.1 mL intrastromal, given in cycles with amphotericin B 2.5 mcg/0.1 mL while topical antifungal therapy continues

Uncontrolled series · n=20

Uncontrolled case series of 20 consecutive culture-positive ulcers that had not responded to topical antifungals: best corrected acuity was worse than 20/400 in all 20 at presentation and improved to better than 20/400 in 11, while 7 required surgery. There is no control arm, so the effect cannot be separated from natural course or from the continued topical therapy. A Cochrane review found the single randomized comparison of topical 1% against intrastromal 50 mcg/0.1 mL (both on topical natamycin 5%) inconclusive because only one small trial was available. Listed here mainly because 50 mcg/0.1 mL equals 0.5 mg/mL and is easily confused with a drop concentration.

Moramarco A, Grendele A, Iannetta D, et al. Microorganisms. 2024;12(5):922 (case series, n = 20). FlorCruz NV, Evans JR. Cochrane Database Syst Rev. 2015;2015(4):CD004241.

Contraindications

Known hypersensitivity to voriconazole or its excipients.
Coadministration contraindications on the systemic label (pimozide, quinidine, ivabradine, sirolimus, rifampin, carbamazepine, long-acting barbiturates, St. John's Wort, efavirenz 400 mg every 24 hours or higher, ritonavir 400 mg every 12 hours, rifabutin, ergot alkaloids, naloxegol, tolvaptan, lurasidone, and venetoclax during CLL or SLL ramp-up) apply to intravenous and oral dosing.

Available Forms

Ophthalmic solution, compounded, no fixed ophthalmic package size, source single-dose vial 200 mg lyophilized powder, yields 20 mL of 10 mg/mL (1%) after reconstitution

Mechanism of Action

Triazole; inhibits fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, an essential step in ergosterol biosynthesis, and the resulting sterol accumulation and ergosterol loss drive the antifungal effect. Active against Aspergillus, Candida, Fusarium, and Scedosporium apiospermum, although Fusarium isolates from corneal ulcers are the least susceptible filamentous genus.

Warnings & Precautions

Off-label ocular route: No FDA-approved ophthalmic voriconazole exists; the linked label covers intravenous use, so every ocular application on this card is off-label.
Monotherapy failure in filamentous keratitis: Natamycin 5% outperformed topical 1% on perforation and therapeutic keratoplasty in a 323-patient randomized trial (odds ratio 0.42, 95% CI 0.22 to 0.80), most of the difference coming from Fusarium cases, and the investigators concluded against using it as monotherapy in filamentous disease.
Unpreserved single-dose vial: The 200 mg vial is reconstituted with 19 mL sterile water for injection to 20 mL of 10 mg/mL concentrate, used undiluted as the drop; the reconstituted concentrate carries no preservative and the label limits in-use storage to 24 hours at 2 to 8 C, so drop sterility and beyond-use dating fall to the compounder.
Optic neuritis and papilledema: Post-marketing reports with systemic therapy; the effect on visual function beyond 28 days of treatment is unknown, so monitor acuity, visual field, and color perception when systemic dosing continues past 28 days.
Systemic toxicity profile: Hepatic failure, QT prolongation and torsade de pointes, severe cutaneous reactions, photosensitivity with reported squamous cell carcinoma and melanoma, adrenal dysfunction, and skeletal fluorosis or periostitis are labeled for intravenous and oral exposure and are not established for topical drops.

Common Side Effects

Ocular surface: Burning and irritation with topical drops; 2 of 9 patients in a refractory fungal keratitis case series stopped the drops for ocular burning, at 1 day and 4 weeks.
Visual disturbances: Systemic dosing only, abnormal vision 18.7%, photophobia 2.2%, chromatopsia 1.2%, with roughly 21% reporting abnormal vision, color vision change, and/or photophobia; 28 days of dosing in healthy subjects reduced ERG amplitude, constricted visual fields, and altered color perception, all back to normal 14 days after stopping.
Systemic: Fever 5.7%, nausea 5.4%, rash 5.3%, vomiting 4.4%, chills 3.7%, headache 3%, abnormal liver function tests 2.7%, tachycardia 2.4%, hallucinations 2.4%; transaminases above 3 times the upper limit of normal in 17.7%.

Pregnancy & Lactation

Pregnancy: Can cause fetal harm; no human data. Rat pups exposed during organogenesis showed hydroureter and hydronephrosis at and above 10 mg/kg (0.3 times the recommended human dose by body surface area) and cleft palate at 60 mg/kg (about 2 times), and rabbits dosed at 100 mg/kg (6 times) had embryomortality, reduced fetal weight, and skeletal variations. Effective contraception is advised during systemic treatment.

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

Pediatric Use

Systemic use is established at 2 years and older and not recommended below age 2; no ophthalmic data.