Oteseconazole

VIVJOA™ is an azole antifungal indicated to reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are NOT of reproductive potential. ( 1 )

1.1 Vulvovaginal Candidiasis VIVJOA is indicated to reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are NOT of reproductive potential [see Warnings and Precautions (5.1) , Use in Specific Populations (8.3) , and Clinical Studies (14) ] .

1.2 Usage If specimens for fungal culture are obtained prior to therapy, antifungal therapy may be instituted before the results of the cultures are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

VIVJOA Capsules: 150 mg of oteseconazole in lavender hard gelatin capsules imprinted with OTE 150 in black ink. Fluconazole is not supplied in the carton. Capsules: 150 mg of oteseconazole (fluconazole is not supplied in the carton). ( 3 )

VIVJOA is contraindicated in: Females of reproductive potential [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3) ] Pregnant and lactating women [see Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.2) ] Patients with known hypersensitivity to oteseconazole. Females of Reproductive Potential ( 4 ), ( 5.1 ), ( 8.3 ) Pregnant and Lactating women ( 4 ), ( 8.1 ), ( 8.2 ) Hypersensitivity to oteseconazole ( 4 )

Embryo-Fetal Toxicity : Based on animal studies, VIVJOA may cause fetal harm. The drug exposure window of approximately 690 days (based on 5 times the half-life of oteseconazole) precludes adequate mitigation of the embryo-fetal toxicity risks. Advise patients that VIVJOA is contraindicated in females of reproductive potential, and in pregnant and lactating women because of potential risks to a fetus or breastfed infant. ( 5.1 , 8.1 , 8.2 , 8.3 )

5.1 Embryo-Fetal Toxicity VIVJOA is contraindicated in females of reproductive potential, and in pregnant and lactating women. Based on animal studies, VIVJOA may cause fetal harm. The drug exposure window of approximately 690 days (based on 5 times the half-life of oteseconazole) precludes adequate mitigation of the embryo-fetal toxicity risks. Ocular abnormalities were observed in the offspring of pregnant rats dosed at 7.5-mg/kg/day during organogenesis through lactation in pre and postnatal developmental studies. The observed ocular abnormalities included cataracts, opacities, exophthalmos/buphthalmos, optic nerve/retinal atrophy, lens degeneration and hemorrhage. Ocular abnormalities occurred at doses about 3.5 times the steady state clinical exposure seen with patients being treated for RVVC. Advise patients that VIVJOA is contraindicated in females of reproductive potential, and in pregnant and lactating women because of potential risks to a fetus or breastfed infant [see Use in Specific Populations (8.1 , 8.2 , 8.3) ].

The most frequently reported adverse reactions (incidence > 2%) were headache and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mycovia Pharmaceuticals, Inc. at 1-855-299-0637 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 580 patients were treated with VIVJOA in three clinical trials (Trial 1, Trial 2, and Trial 3) [see Clinical Studies (14) ] . Patients in the clinical trials were women with RVVC who received VIVJOA treatment for 12 weeks. The mean age of the patient population was 34 years (range:16-78 years), with 84% of patients aged 18-44 years and 16% of patients aged 45 years and older. Although females of reproductive potential were included in the clinical safety data, VIVJOA is contraindicated in females of reproductive potential due to the risk of embryo-fetal toxicity [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3 , 8.4) ] . The clinical trials population was 75% (435/580) White, 17% (96/580) Black or African American, 6% (36/580) Asian, and 2% (13/580) Other women. Fifteen percent (86/580) of all women were Hispanic/Latino. Patients enrolled in the induction and maintenance phases of the clinical trials were treated with different VIVJOA dosage regimens versus comparators [see Clinical Studies (14) ] . The adverse reaction that led to discontinuation in 1 of 580 (0.2 %) VIVJOA-treated patients was allergic dermatitis. Overall, similar percentages of serious adverse reactions and adverse reactions leading to drug discontinuation were reported across the VIVJOA and comparator patient dosing groups. The most frequently reported adverse reactions (incidence >2%) among VIVJOA-treated patients in Trial 1, Trial 2 and Trial 3 were headache (includes headache, migraines, sinus headaches) (7.4%) and nausea (3.6%). Other Adverse Reactions The following selected adverse reactions occurred in <2% of patients receiving VIVJOA in Trial 1, Trial 2 and Trial 3: Laboratory investigations: Increased blood creatine phosphokinase Gastrointestinal disorders: Dyspepsia Vascular disorders: Hot flush Renal and urinary disorders: Dysuria Reproductive system and breast disorders: Menorrhagia (includes genital hemorrhage, menorrhagia; menometrorrhagia; uterine hemorrhage, vaginal hemorrhage) metrorrhagia; vulvovaginal irritation (includes vulvovaginal burning sensation, vulvovaginal discomfort, and vulvovaginal pain) Laboratory Findings Elevations in Creatine Phosphokinase Serum creatine phosphokinase (CPK) (an indirect marker of muscle injury/necrosis) elevations greater than or equal to 10 times the upper limit of normal were observed in 11 (1.9%) patients treated with VIVJOA versus 2 (0.7%) patients in the comparator groups during the VIVJOA clinical trials. The elevations were transient.

BCRP (Breast Cancer Resistance Protein) Substrates: Concomitant use of VIVJOA with BCRP substrates may increase the exposure of drugs that are BCRP substrates, which may increase the risk of adverse reactions associated with these drugs. Use the lowest possible starting dose of the BCRP substrate or consider reducing the dose of the substrate drugs and monitor for adverse reactions. ( 7.1 )

7.1 Effect of VIVJOA on Other Drugs BCRP (Breast Cancer Resistance Protein) Transporter Substrates Oteseconazole is a BCRP inhibitor. Concomitant use of VIVJOA with BCRP substrates (e.g., rosuvastatin) may increase the exposure of BCRP substrates (e.g., rosuvastatin), which may increase the risk of adverse reactions associated with these drugs. Use the lowest possible starting dose of the BCRP substrate or consider reducing the dose of the substrate drug and monitor for adverse reactions [see Clinical Pharmacology (12.3) ] .

Renal Impairment: Not recommended in severe renal impairment or ESRD (with or without dialysis). ( 8.6 ) Hepatic Impairment: Not recommended in moderate or severe hepatic impairment. ( 8.7 )

8.1 Pregnancy Risk Summary VIVJOA is contraindicated in females of reproductive potential and in pregnant women. Based on animal studies, VIVJOA may cause fetal harm when administered to pregnant women. In addition, the drug exposure window of approximately 690 days (based on 5 times the half-life of oteseconazole) precludes adequate mitigation of the embryo-fetal toxicity risks [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. Ocular abnormalities were observed in a pre and postnatal animal study in the offspring of rats administered oteseconazole from Gestation Day 6 through Lactation Day 20 at doses about 3.5 times the recommended human dose based on AUC comparisons (see Data ). The observed ocular abnormalities included cataracts, opacities, exophthalmos/buphthalmos, optic nerve/retinal atrophy, lens degeneration and hemorrhage. There are limited human data in pregnant women who were exposed to VIVJOA during the clinical trials; these data are insufficient to exclude a potential risk of cataracts or other eye abnormalities in human infants. Data Animal Data Rat and rabbit embryofetal development was assessed after oral administration of oteseconazole. There was no embryofetal toxicity or malformations at 40 mg/kg/day following administration of oteseconazole during organogenesis in pregnant rats at doses about 10 times the maximum human exposure for RVVC based on AUC comparisons. Abortions occurred in rabbits in the presence of maternal toxicity (reduced bodyweight gain with reduced food consumption) but there were no malformations at 15 mg/kg/day following administration of oteseconazole during organogenesis in pregnant rabbits about 6 times the maximum human exposure for RVVC based on AUC comparisons. Ocular abnormalities including cataracts, opacities, exophthalmos/buphthalmos, optic nerve/retinal atrophy, lens degeneration and hemorrhage were observed in the offspring of rats administered oteseconazole from Gestation Day 6 through Lactation Day 20 at 7.5 mg/kg day (about 3.5 times the recommended human dose based on AUC comparisons). There were no effects on pregnancy or parturition in these pre and postnatal studies at any dose.

8.2 Lactation Risk Summary VIVJOA is contraindicated in lactating women and females of reproductive potential. There are no data on the presence of oteseconazole in human or animal milk or data on the effects of oteseconazole on milk production. There were no reported adverse effects in breastfed infants following 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 [see Warnings and Precautions (5.1) ] . 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 [see Use in Specific Populations (8.1) ]. The relationship between the observed animal findings and breastfed infants is unknown.

8.3 Females of Reproductive Potential VIVJOA is contraindicated in females of reproductive potential based on animal findings. The drug exposure window of approximately 690 days (based on 5 times the half-life of oteseconazole) precludes adequate mitigation of the embryo-fetal toxicity risks [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ]. Females who are NOT of reproductive potential are defined as: persons who are biological females who are postmenopausal or have another reason for permanent infertility (e.g., tubal ligation, hysterectomy, salpingo-oophorectomy).

8.4 Pediatric Use VIVJOA is contraindicated in females of reproductive potential. Based on animal studies, VIVJOA may cause fetal harm when administered to a pregnant woman or potential harm to the breastfed infant. The drug exposure window of approximately 690 days (based on 5 times the half-life of oteseconazole) precludes adequate mitigation of the embryo-fetal toxicity risks associated with VIVJOA use [see Contraindications (4) , Warnings and Precautions (5.1) and Use in Specific Populations (8.1 , 8.2 , 8.3) and Clinical Pharmacology (12.3) ] . The safety and effectiveness of VIVJOA have not been established in pre-menarchal pediatric females.

8.5 Geriatric Use Clinical studies of VIVJOA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.6 Renal Impairment No dosage adjustment of VIVJOA is recommended in patients with mild to moderate renal impairment (i.e., estimated glomerular filtration rate (eGFR) by the modification of diet in renal disease (MDRD) equation 30-89 mL/min). Clinical studies of VIVJOA did not include sufficient numbers of patients with severe renal impairment (eGFR 15-29 mL/min) or end-stage renal disease (ESRD), defined as eGFR <15 mL/min, to determine the safety of VIVJOA in this population. Therefore, VIVJOA is not recommended for use in patients with severe renal impairment or ESRD (with or without dialysis) [see Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment No dosage adjustment of VIVJOA is recommended in patients with mild hepatic impairment (Child-Pugh A). There is insufficient information to determine the safety of VIVJOA in patients with moderate or severe hepatic impairment (Child-Pugh B-C). Therefore, VIVJOA is not recommended for use in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) ].

Oteseconazole is an antifungal drug [see Microbiology (12.4) ] .