FDA Rationale for Recognition Decision: Voriconazole
FDA has completed their review of the rationale document titled, “Voriconazole Breakpoints for Aspergillus fumigatus” (FR01, May 2024), submitted by the Clinical and Laboratory Standards Institute (CLSI) to the public docket, FDA-2017-N-5925-0035, in May 2024.1
Voriconazole is an azole antifungal drug indicated for the treatment of invasive aspergillosis, candidemia in non-neutropenics and other deep tissue Candida infections, esophageal candidiasis, serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy.
For invasive aspergillosis, in adult patients voriconazole is administered intravenously at 6 mg/kg every 12 hours for the first 24 hours, then intravenously at 4 mg/kg every 12 hours or orally at 200 mg every 12 hours. If a patient’s response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours to 300 mg every 12 hours.2
FDA has recognized CLSI susceptibility test interpretive criteria, also known as breakpoints, for voriconazole against Candida species.3 No other voriconazole breakpoints have been recognized by FDA. CLSI published minimum inhibitory concentration (MIC) breakpoints for voriconazole A. fumigatus sensu stricto in June 2020, Table 1.4 These breakpoints are supported by voriconazole dosages listed above and remain current.
Table 1. Current CLSI Voriconazole Breakpoints against A. fumigatus sensu strictoa
Minimum Inhibitory Concentrations (mcg/mL) | ||
|---|---|---|
S | I | R |
≤ 0.5 | 1 | ≥ 2 |
S= susceptible; I=intermediate; R=resistant
a Breakpoints were derived from a collection of sequence-confirmed isolates of A. fumigatus sensu stricto and are not applicable to other members of the A. fumigatus species complex.
In evaluating voriconazole breakpoints for A. fumigatus, FDA has considered MIC distribution data, correlation between MIC and Cyp51 gene mutations (Cyp51 is an enzyme needed for ergosterol synthesis and is the target of azoles), the epidemiological cutoff value (ECV), pharmacokinetic-pharmacodynamic (PK/PD) data, and clinical outcome data.
The CLSI ECV for voriconazole against A. fumigatus is 1 mcg/mL. In general, breakpoints should be set above the ECV to enhance reproducibility of susceptibility testing results. However, as was clarified by CLSI, one limitation of the A. fumigatus voriconazole ECV is that there was no post hoc confirmation of resistance mechanisms for isolates that fell into the non-wild-type category, and there is uncertainty whether isolates with a voriconazole MIC of 1 mcg/ml that were used to calculate the voriconazole ECV may have harbored Cyp51 mutations.
Nonclinical PK/PD data for voriconazole against A. fumigatus included a study in non-neutropenic mice and two in vitro studies. While there are uncertainties around the predictive value of the studies, the proposed susceptible breakpoint of 0.5 mcg/mL was comparable. Clinical PK/PD studies also suggest a susceptible breakpoint of 0.5 mcg/mL, although interpretation of these studies is limited by heterogeneity of infection types and clinical outcome assessments.
Analysis of clinical outcomes by MIC in the provided studies are limited by various definitions of clinical success, non-speciation of Aspergillus species in some studies, a small number of patients in others, or not specifying MIC values for isolates with MIC ≤ 2 mcg/mL. 5,6,7,8 Considering all limitations, clinical data suggest that for Aspergillus spp. mortality rates are higher for isolates with voriconazole MIC > 1 mcg/mL.
FDA concludes that the available microbiological, PK/PD, and clinical data support the recognition of the current CLSI MIC breakpoints for voriconazole against A. fumigatus sensu stricto, i.e., a susceptible breakpoint of ≤ 0.5 µg/mL, an intermediate breakpoint of 1 mcg/ml, and a resistant breakpoint of ≥ 2 mcg/mL. FDA agrees with CLSI that having an intermediate category is important to mitigate the inherent variability of testing methods.
1 https://www.regulations.gov/comment/FDA-2017-N-5925-0035
2 Vfend (voriconazole) prescribing information, revised 10/2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021266s053,021267s063,021630s042lbl.pdf
3 https://www.fda.gov/drugs/development-resources/voriconazole-tablets-powder-oral-suspension-injection
4 CLSI. Performance Standards for Antifungal Susceptibility Testing of Filamentous Fungi. 2nd ed. CLSI supplement M61. Clinical and Laboratory Standards Institute; 2020.
5 Lestrade PP, Bentvelsen RG, Schauwvlieghe A, et al. Voriconazole resistance and mortality in invasive aspergillosis: a multicenter retrospective cohort study. Clin Infect Dis. 2019;68(9):1463-1471.
6 Resendiz-Sharpe A, Mercier T, Lestrade PPA, et al. Prevalence of voriconazole-resistant invasive aspergillosis and its impact on mortality in haematology patients. J Antimicrob Chemother. 2019;74(9):2759-2766.
7 Troke PF, Hockey HP, and Hope WW (2011) Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients AAC 55(10):4782-88.
8 Andes DR, Ghannoum MA, Mukherjee PK, et al. Outcomes by MIC values for patients treated with isavuconazole or voriconazole for invasive aspergillosis in the phase 3 SECURE and VITAL trials. Antimicrob Agents Chemother. 2019;63(1):e01634-18.