Oteseconazole is an oral azole antifungal agent indicated to reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in persons with a history of RVVC who are not of reproductive potential. Persons who are not of reproductive potential are defined as biological females who are postmenopausal or have another reason for permanent infertility (e.g., tubal ligation, hysterectomy, salpingo-oophorectomy). Oteseconazole is contraindicated in persons of reproductive potential and during pregnancy and lactation based on animal data suggesting oteseconazole may cause fetal harm (i.e., ocular abnormalities). Unlike other azole antifungals which contain an imidazole or triazole moiety, oteseconazole has a tetrazole moiety with improved selectivity for fungal 14-alpha-demethylase (CYP51) and lower affinity for human cytochrome enzymes.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer with food.
-Swallow capsules whole. Do not chew, crush, dissolve, or open the capsules.
Transient serum creatinine phosphokinase (CPK) elevations 10 times or more the upper limit of normal were observed in 11 (1.9%) patients treated with oteseconazole vs. 2 (0.7%) patients in the comparator groups during the clinical trials.
Headache (7.4%), including migraine and sinus headache, was among the most frequently reported adverse events in oteseconazole-treated patients during clinical trials.
Nausea (3.6%) was among the most frequently reported adverse events in oteseconazole-treated patients during clinical trials. Dyspepsia occurred in less than 2% of patients receiving oteseconazole during clinical trials.
Hot flushing occurred in less than 2% of patients receiving oteseconazole during clinical trials. Of 580 patients treated with oteseconazole during clinical trials, 1 patient discontinued oteseconazole due to allergic dermatitis. Overall, similar percentages of serious adverse reactions and adverse reactions leading to drug discontinuation were reported across the oteseconazole and comparator patient dosing groups.
Menorrhagia (including genital hemorrhage, menometrorrhagia, uterine hemorrhage, and vaginal bleeding), metrorrhagia, and vulvovaginal irritation (including vulvovaginal burning sensation, vulvovaginal discomfort, and vulvovaginal pain) occurred in less than 2% of patients receiving oteseconazole during clinical trials.
Dysuria occurred in less than 2% of patients receiving oteseconazole during clinical trials.
The use of oteseconazole in persons with severe hepatic disease (Child-Pugh Class C) has not been studied.
The effect of end-stage renal failure (eGFR less than 15 mL/minute) on the pharmacokinetics of oteseconazole is unknown. Dialysis is not expected to alter oteseconazole exposures.
Oteseconazole is contraindicated for use during pregnancy based on animal data suggesting oteseconazole may cause fetal harm. In pre and postnatal animal studies, ocular abnormalities were observed in the offspring of rats administered oteseconazole 7.5 mg/kg/day (approximately 3.5-times the recommended human dose based on AUC comparisons) from gestation day 6 through lactation day 20. The observed ocular abnormalities included cataracts, opacities, exophthalmos/buphthalmos, optic nerve/retinal atrophy, lens degeneration, and hemorrhage. There are limited data in pregnant women who were exposed to oteseconazole during the clinical trials; these data are insufficient to exclude a potential risk of cataracts or other eye abnormalities in human infants. Additionally, the drug exposure window of approximately 690 days (based on 5-times the half-life of oteseconazole) precludes adequate mitigation of the embryofetal toxicity risks.
Oteseconazole is contraindicated for use during breast-feeding. There are no data on the presence of oteseconazole in human or animal milk or on the effects on milk production. There were no reported adverse effects in breast-fed infants after maternal exposure to oteseconazole during lactation; however, given the limited duration of follow-up of the oteseconazole-exposed infants during the post-natal period, no conclusions can be drawn from these data. Ocular abnormalities were observed in a pre and postnatal study in the offspring of rats administered oteseconazole from gestation day 6 through lactation day 20 at doses approximately 3.5 times the recommended human dose based on AUC comparisons. The relationship between the observed animal findings and breast-fed infants is unknown.
Oteseconazole may be associated with reproductive risk and is contraindicated for use in persons of reproductive potential. The drug exposure window of approximately 690 days (based on 5-times the half-life of oteseconazole) precludes adequate mitigation of the embryofetal toxicity risks. Persons who are not of reproductive potential are defined as biological females who are postmenopausal or have another reason for permanent infertility (e.g., tubal ligation, hysterectomy, salpingo-oophorectomy).
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Candida albicans, Candida dubliniensis, Candida glabrata, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of recurrent vulvovaginal candidiasis (RVVC) to reduce the incidence in persons with a history of RVVC who are not of reproductive potential:
Oral dosage (monotherapy regimen):
Adults: 600 mg PO as single dose on day 1, followed by 450 mg PO as a single dose on day 2, and then beginning on day 14, 150 mg PO once weekly for 11 weeks.
Children and Adolescents 10 to 17 years (post-menarchal): 600 mg PO as single dose on day 1, followed by 450 mg PO as a single dose on day 2, and then beginning on day 14, 150 mg PO once weekly for 11 weeks.
Oral dosage (fluconazole combination regimen):
Adults: 150 mg PO once daily for 7 days (days 14 to 20) beginning after initial fluconazole therapy (days 1, 4, and 7), followed by 150 mg PO once weekly for 11 weeks. The safety and effectiveness of oteseconazole have not been established in pre-menarchal persons.
Children and Adolescents 10 to 17 years (post-menarchal): 150 mg PO once daily for 7 days (days 14 to 20) beginning after initial fluconazole therapy (days 1, 4, and 7), followed by 150 mg PO once weekly for 11 weeks.
Maximum Dosage Limits:
-Adults
600 mg/day PO.
-Geriatric
600 mg/day PO.
-Adolescents
600 mg PO/day.
-Children
10 to 12 years: 600 mg/day PO.
1 to 9 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is recommended for mild or moderate hepatic impairment (Child-Pugh Class A or B). Oteseconazole use has not been studied in persons with severe hepatic impairment (Child-Pugh Class C).
Patients with Renal Impairment Dosing
CrCl 15 to 89 mL/minute: No dosage adjustment is recommended.
CrCl 14 mL/minute or less: The effect of end-stage renal disease on the pharmacokinetics of oteseconazole.
Intermittent hemodialysis
Dialysis is not expected to alter oteseconazole exposures.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with oteseconazole. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Alpelisib: (Major) Avoid coadministration of alpelisib with oteseconazole due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with oteseconazole is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP substrate; oteseconazole is a BCRP inhibitor.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with oteseconazole is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP substrate; oteseconazole is a BCRP inhibitor.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with oteseconazole may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with oteseconazole may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with oteseconazole. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with oteseconazole. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with oteseconazole. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with oteseconazole may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with oteseconazole may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with oteseconazole may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with oteseconazole may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with oteseconazole may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with oteseconazole may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with oteseconazole may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with oteseconazole may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with oteseconazole may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and oteseconazole as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a substrate of BCRP and oteseconazole is a BCRP inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of oteseconazole is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of BCRP and oteseconazole is a BCRP inhibitor.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with oteseconazole may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Pazopanib: (Major) Avoid coadministration of pazopanib and oteseconazole due to the potential for increased pazopanib exposure. Pazopanib is a BCRP substrate; oteseconazole is a BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit BCRP.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with oteseconazole. Oteseconazole increased rosuvastatin exposure by 114%. Rosuvastatin is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with oteseconazole. Oteseconazole increased rosuvastatin exposure by 114%. Rosuvastatin is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of oteseconazole is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with oteseconazole may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with oteseconazole may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with oteseconazole may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Topotecan: (Major) Avoid coadministration of oteseconazole with oral topotecan due to increased topotecan exposure; oteseconazole may be administered with intravenous topotecan. Oral topotecan is a substrate of the BCRP and oteseconazole is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with oteseconazole. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of BCRP; oteseconazole is a BCRP inhibitor.
Oteseconazole is an azole metalloenzyme inhibitor. It exerts its antifungal activity by targeting fungal 14-alpha-demethylase (CYP51), an enzyme that catalyzes the demethylation of lanosterol at the 14-alpha position. By inhibiting CYP51, oteseconazole prevents the conversion of lanosterol to ergosterol, a sterol essential for fungal cell membrane formation and integrity, and causes an accumulation of 14-methylated sterols, some of which are toxic to fungi. Unlike other azole antifungals which contain an imidazole or triazole moiety, oteseconazole has a tetrazole moiety with improved selectivity for fungal CYP51 and lower affinity for human cytochrome enzymes. In an in vitro study, oteseconazole was found to bind at least 2,200-fold more tightly to fungal than to human CYP51 while itraconazole and voriconazole were shown to bind 2- and 92-fold greater, respectively, to fungal than to human CYP51.
The potential for increases in minimum inhibitory concentrations (MIC) to oteseconazole has been evaluated in vitro including specific mechanisms of resistance. Increases in oteseconazole MIC were associated with upregulation of the efflux pumps CDR1, MDR1, and lanosterol 14- alpha-demethylase (CYP51). Against certain Candida sp., oteseconazole maintained meaningful in vitro activity against clinical isolates that were resistant to fluconazole.
Oteseconazole is administered orally. Oteseconazole is more than 99% bound to plasma proteins and has a central Vd of approximately 423 L. Animal data indicate that drug exposures in vaginal tissue are comparable to plasma exposures. Oteseconazole does not undergo significant metabolism. After oral administration of radiolabeled oteseconazole, approximately 56% of the radiolabeled dose was recovered in feces primarily through biliary excretion and 26% was recovered in urine. The median terminal half-life of oteseconazole is approximately 138 days.
Affected cytochrome P450 isoenzymes and drug transporters: Breast Cancer Resistance Protein (BCRP)
Oteseconazole is a BCRP inhibitor. Concomitant use with BCRP substrates may increase the exposure of BCRP substrates.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration of oteseconazole, the time to peak plasma concentration (Tmax) is approximately 5 to 10 hours. The recommended oteseconazole dosing regimen produces a maximum plasma concentration (Cmax) of 2.8 mcg/mL, systemic exposure (AUC) of 64.2 mcg x hour/mL, and trough (Cmin) of 2.5 mcg/mL. Over a range of 20 mg to 320 mg, the oteseconazole AUC increases approximately dose proportionally while the Cmax increases less than dose proportionally. Administration of oteseconazole with a high-fat, high-calorie meal (800 to 1,000 calories; 50% fat) increases the Cmax and AUC by 45% and 36%, respectively, but no significant differences are observed with a low-fat, low-calorie meal.
-Special Populations
Hepatic Impairment
The pharmacokinetics of oteseconazole were not altered in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) when exposure estimates were compared to healthy subjects. The impact of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of oteseconazole is unknown.
Renal Impairment
No clinically significant differences in the pharmacokinetics of oteseconazole were observed in subjects with mild, moderate, or several renal impairment when exposure estimates were compared to subjects with normal renal function. Oteseconazole has not been studied in subjects with end-stage renal disease not on dialysis. Due to protein binding of more than 99%, dialysis is not expected to alter oteseconazole exposures.
Gender Differences
There are no clinically significant differences in the pharmacokinetics of oteseconazole based on gender.
Ethnic Differences
There are no clinically significant differences in the pharmacokinetics of oteseconazole based on ethnicity.