By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first drug to reduce recurrent vulvovaginal candidiasis (RVVC) in women. Oteseconazole is an orally active azole antifungal agent with high affinity for a key yeast cytochrome (CYP) isoenzyme (CYP51) and lower affinity for a range of human CYP isoenzymes.1 It received priority review and orphan designation. It is distributed by as Vivjoa.
INDICATIONS
Oteseconazole can be prescribed to reduce the incidence of RVVC in women with a history of RVVC who are not of reproductive potential.1
DOSAGE
There are two recommended regimens: oteseconazole 600 mg starting on day 1, 450 mg on day 2; beginning on day 14, 150 mg once a week (every seven days) for 11 weeks (weeks 2-12). Second, fluconazole 150 mg orally on days 1, 4, and 7; oteseconazole 150 mg once daily days 14-20; on Day 28, oteseconazole 150 mg once a week for 11 weeks (weeks 4-14). Oteseconazole should be taken with food. It is available as 150 mg capsules.
POTENTIAL ADVANTAGES
The long median elimination half-life of 138 days results in a long drug exposure window of 690 days (i.e., five half-lives). It is potent against a range of Candida species, including isolates with reduced susceptibility to fluconazole.2 It does not appear to interact meaningfully with human CYP isoenzymes. Conversely, fluconazole is a potent inhibitor of CYP isoenzyme 2C9 and 2C19, and a moderate inhibitor of 3A4.
POTENTIAL DISADVANTAGES
Oteseconazole may cause fetal harm. It is contraindicated in women of reproductive potential, and in pregnant and lactating women.1 Because of its long drug exposure window, it is impractical to mitigate embryo-fetal risk.1
Oteseconazole is an inhibitor of the breast cancer-resistant protein (BCRP) transporter. Concomitant use with substrates of BCRP may increase the systemic exposure, possibly leading to higher risk of adverse reactions (e.g., rosuvastatin). The most frequently reported adverse reactions were headache (7.4%), nausea (3.6%), and increase in blood creatine phosphokinase (1.9% for 10 times upper limit of normal).1
COMMENTS
Oteseconazole targets the fungal sterol, 14alpha demethylase (CYP51), disrupting fungal cell membrane formation and integrity.1 The efficacy of oteseconazole was evaluated in two randomized, placebo-controlled trials and one vs. fluconazole in subjects with RVVC (≥ 3 episodes of vulvovaginal candidiasis in a 12-month period).1
The first two studies consisted of two phases. The open-label induction phase was three sequential doses of 150 mg of fluconazole every 72 hours on days 1, 4, and 7. If acute VVC episodes were resolved (based on severity of sign and symptoms), this was followed by either 150 mg of oteseconazole or placebo for seven days, followed by 11 weekly doses (oteseconazole or placebo) in the maintenance phase. The intention-to-treat population (ITT) was 326 in study 1 and 326 in study 2. The primary efficacy endpoint was the proportion of patients with ≥ 1 culture-verified acute VVC episode during the maintenance phase through week 48. An acute VVC episode is defined as a positive fungal culture for Candida species associated with a clinical signs and symptoms score of ≥ 3 (based on a 4-point severity scale, 0-3). The results were 6.7% for oteseconazole vs. 42.8% for placebo and 3.9% vs. 39.4% in studies 1 and 2, respectively.
In the third study, the induction phase consisted of oteseconazole 600 mg on day 1 and 450 mg on day 2, or three sequential doses of fluconazole 150 mg on days 1, 4, and 7. The maintenance phase began 14 days after the first dose (if acute VVC episode resolved) and consisted of oteseconazole 150 mg weekly or placebo for 11 weeks. In the ITT population (n = 219), outcomes (percent with verified acute VVC through week 50 or unresolved VVC during the induction phase) were 10.3% for oteseconazole vs. 42.9% for fluconazole/placebo.
CLINICAL IMPLICATIONS
Vaginal candidiasis, usually caused by Candida albicans, is the second most common cause of vaginal infection.3 It is most common in women age 25 to 34 years (12%). RVVC is a chronic, debilitating vaginal infection defined as ≥ 3 cases of vaginal candidiasis within one year.3 It is estimated 5% to 8% of women meet the criteria for RVVC.4 The FDA orphan designation suggests < 200,000 persons in the U.S. are affected. For this condition, maintenance fluconazole is the first-line treatment (i.e., a 100-mg, 150-mg, or 200-mg dose) weekly for six months.5 However, relapse is common after an initial course of maintenance (55% in one study, and 63% in another).6,7 The cost for oteseconazole was unavailable at the time of this review.
REFERENCES
- Mycovia Pharmaceuticals, Inc. Vivjoa prescribing information. April 2022.
- Sobel JD, Nyirjesy P. Oteseconazole: An advance in treatment of recurrent vulvovaginal candidiasis. Future Microbiol 2021;16:1453-1461.
- Nyirjesy P, Brookhart C, Lazenby G, et al. Vulvovaginal candidiasis: A review of the evidence for the 2021 Centers for Disease Control and Prevention of Sexually Transmitted Infections Treatment Guidelines. Clin Infect Dis 2022;74:S162-S168.
- Center for Drug Research and Evaluation. Integrated review. Vivjoa (oteseconazole).
- Centers for Disease Control and Prevention. Sexually Transmitted Infections Treatment Guidelines, 2021. Vulvovaginal candidiasis.
- Collins LM, Moore R, Sobel JD. Prognosis and long-term outcome of women with idiopathic recurrent vulvovaginal candidiasis caused by Candida albicans. J Low Genit Tract Dis 2020;24:48-52.
- Crouss T, Sobel JD, Smith K, Nyirjesy P. Long-term outcomes of women with recurrent vulvovaginal candidiasis after a course of maintenance antifungal therapy. J Low Genit Tract Dis 2018;22:382-386.
The FDA has approved the first drug to reduce recurrent vulvovaginal candidiasis.
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