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.

There are two recommended VIVJOA dosage regimens: a VIVJOA-only regimen and a Fluconazole/VIVJOA regimen. Use one of these two dosage regimens. ( 2.1 ) Administer VIVJOA orally with food. ( 2.1 ) For the VIVJOA-only Dosage Regimen : ( 2.2 ) On Day 1: Administer VIVJOA 600 mg (as a single dose), then On Day 2: Administer VIVJOA 450 mg (as a single dose), then Beginning on Day 14 : Administer VIVJOA 150 mg once a week (every 7 days) for 11 weeks (Weeks 2 through 12). For the Fluconazole/VIVJOA Dosage Regimen , prescribe fluconazole and: ( 2.3 ) On Day 1 , Day 4 , and Day 7 : Administer fluconazole 150 mg orally, then On Days 14 through 20 : Administer VIVJOA 150 mg once daily for 7 days, then Beginning on Day 28 : Administer VIVJOA 150 mg once a week (every 7 days) for 11 weeks (Weeks 4 through 14).

2.1 Dosage Overview and Important Administration Instructions There are two recommended VIVJOA dosage regimens: a VIVJOA-only regimen and a Fluconazole/ VIVJOA regimen. Use one of the following two dosage regimens: VIVJOA-only dosage regimen [see Dosage and Administration (2.2) ] Fluconazole/VIVJOA dosage regimen [see Dosage and Administration (2.3) ] . Administer VIVJOA orally with food [see Clinical Pharmacology (12.3) ]. Swallow the capsules whole. Do not chew, crush, dissolve, or open the capsules.

2.2 VIVJOA-only Dosage Regimen For the VIVJOA-only dosage regimen: On Day 1: Administer VIVJOA 600 mg (as a single dose), then On Day 2: Administer VIVJOA 450 mg (as a single dose), then Beginning on Day 14: Administer VIVJOA 150 mg once a week (every 7 days) for 11 weeks (Weeks 2 through 12).

2.3 Fluconazole/VIVJOA Dosage Regimen For the Fluconazole/VIVJOA dosage regimen, prescribe fluconazole and: On Day 1, Day 4, and Day 7: Administer fluconazole 150 mg orally, then On Days 14 through 20: Administer VIVJOA 150 mg once daily for 7 days, then Beginning on Day 28: Administer VIVJOA 150 mg once a week (every 7 days) for 11 weeks (Weeks 4 through 14).

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 )

5 WARNINGS AND PRECAUTIONS 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) ].

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) ] .

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.

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.

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.

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.

VIVJOA (oteseconazole capsules) contains oteseconazole which is an oral azole antifungal agent. The chemical name of oteseconazole is ( R )-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1 H -tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol or 2-Pyridineethanol, α-(2,4-difluorophenyl)-β β-difluoro- α-(1 H -tetrazol-1-ylmethyl)-5-(4-(2,2,2-trifluoroethoxy)phenyl)-,(α R )-. The empirical formula is C 23 H 16 F 7 N 5 O 2 . The molecular weight is 527.39 g/mol. The structural formula is Oteseconazole is a white to off-white crystalline powder and is practically insoluble in water within a pH range of 1 to 9 but is soluble in a variety of organic solvents. Each oteseconazole capsule, for oral use, contains 150 mg oteseconazole and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose, magnesium stearate, silicified microcrystalline cellulose, and sodium lauryl sulfate. Capsule shell and print constituents: FD&C Blue #1, FD&C Red #3, gelatin, Opacode SW-9008/SW-9009 and titanium dioxide. Contains no ingredient made from a gluten-containing grain (wheat, barley, or rye). Chemical Structure

12.1 Mechanism of Action Oteseconazole is an antifungal drug [see Microbiology (12.4) ] .

12.2 Pharmacodynamics Oteseconazole exposure-response relationships and the time course of pharmacodynamic response are unknown. Cardiac Electrophysiology At 5 times the maximum exposures for the recommended dose, VIVJOA does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics The AUC of oteseconazole increased approximately dose proportionally while the C max increased less than dose proportionally over a dose range of 20 mg (0.13 times the lowest recommended dose) to 320 mg (0.53 times the highest recommended dose). The pharmacokinetic parameters of oteseconazole associated with the administration of the recommended dosing regimen of VIVJOA are presented in Table 1. Table 1: Pharmacokinetic (PK) Parameters of Oteseconazole PK Parameter Following repeat dose administration of VIVJOA at the approved recommended dosage for RVVC at the end of treatment. Mean (± SD) C max (µg/mL) 2.8 (1.25) AUC 24h (h∙µg/mL) 64.2 (29.4) C min (µg/mL) 2.5 (1.19) Absorption The time to peak plasma concentrations of oteseconazole was approximately 5 to 10 hours. Effect of Food Administration of VIVJOA with a high-fat, high-calorie meal (800-1000 Calories; 50% fat) increased C max and AUC 0-72h by 45% and 36%, but no significant differences were observed with a low-fat, low-calorie meal. Distribution The central volume of distribution of oteseconazole is approximately 423 L. Oteseconazole is 99.5-99.7% bound to plasma proteins. Animal studies indicated that oteseconazole exposures in vaginal tissue are comparable to plasma exposures. Elimination The median terminal half-life of oteseconazole is approximately 138 days. Metabolism Oteseconazole does not undergo significant metabolism. Excretion Following 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. Specific Populations There were no clinically significant differences in the pharmacokinetics of oteseconazole based on sex, race/ethnicity or mild to moderate renal impairment. Drug Interaction Studies BCRP substrates: Oteseconazole increased the C max and AUC 0-24h of rosuvastatin, a BCRP substrate, by 118% and 114%, respectively . Other Drugs: No clinically significant differences in the pharmacokinetics of the following drugs were observed when co-administered with oteseconazole: Midazolam (sensitive CYP3A4 substrate), ethinyl estradiol (CYP3A4 substrate), norethindrone (CYP3A4 substrate), or digoxin (P-gp substrate).

12.4 Microbiology Mechanism of Action: Oteseconazole is an azole metalloenzyme inhibitor targeting the fungal sterol, 14α demethylase (CYP51), an enzyme that catalyzes an early step in the biosynthetic pathway of ergosterol, a sterol required for fungal cell membrane formation and integrity. Inhibition of CYP51 results in the accumulation of 14-methylated sterols, some of which are toxic to fungi. Through the inclusion of a tetrazole metal-binding group, oteseconazole has a lower affinity for human CYP enzymes. Resistance: 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 the azole target, lanosterol 14-alpha-demethylase (CYP51). Against certain Candida spp. oteseconazole maintained meaningful in vitro activity against clinical isolates that were resistant to fluconazole. Antimicrobial Activity: The following in vitro data is available, but their clinical significance is unknown. Oteseconazole has been shown to be active against most isolates of the following microorganisms associated with RVVC [see Indications and Usage (1.1) ] : Candida albicans Candida glabrata Candida krusei Candida parapsilosis Candida tropicalis Candida lusitaniae Candida dubliniensis

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

Oteseconazole exposure-response relationships and the time course of pharmacodynamic response are unknown. Cardiac Electrophysiology At 5 times the maximum exposures for the recommended dose, VIVJOA does not prolong the QT interval to any clinically relevant extent.

The AUC of oteseconazole increased approximately dose proportionally while the C max increased less than dose proportionally over a dose range of 20 mg (0.13 times the lowest recommended dose) to 320 mg (0.53 times the highest recommended dose). The pharmacokinetic parameters of oteseconazole associated with the administration of the recommended dosing regimen of VIVJOA are presented in Table 1. Table 1: Pharmacokinetic (PK) Parameters of Oteseconazole PK Parameter Following repeat dose administration of VIVJOA at the approved recommended dosage for RVVC at the end of treatment. Mean (± SD) C max (µg/mL) 2.8 (1.25) AUC 24h (h∙µg/mL) 64.2 (29.4) C min (µg/mL) 2.5 (1.19) Absorption The time to peak plasma concentrations of oteseconazole was approximately 5 to 10 hours. Effect of Food Administration of VIVJOA with a high-fat, high-calorie meal (800-1000 Calories; 50% fat) increased C max and AUC 0-72h by 45% and 36%, but no significant differences were observed with a low-fat, low-calorie meal. Distribution The central volume of distribution of oteseconazole is approximately 423 L. Oteseconazole is 99.5-99.7% bound to plasma proteins. Animal studies indicated that oteseconazole exposures in vaginal tissue are comparable to plasma exposures. Elimination The median terminal half-life of oteseconazole is approximately 138 days. Metabolism Oteseconazole does not undergo significant metabolism. Excretion Following 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. Specific Populations There were no clinically significant differences in the pharmacokinetics of oteseconazole based on sex, race/ethnicity or mild to moderate renal impairment. Drug Interaction Studies BCRP substrates: Oteseconazole increased the C max and AUC 0-24h of rosuvastatin, a BCRP substrate, by 118% and 114%, respectively . Other Drugs: No clinically significant differences in the pharmacokinetics of the following drugs were observed when co-administered with oteseconazole: Midazolam (sensitive CYP3A4 substrate), ethinyl estradiol (CYP3A4 substrate), norethindrone (CYP3A4 substrate), or digoxin (P-gp substrate).

, Mutagenesis, Impairment of Fertility Carcinogenesis There was no increase in the incidence of tumors following daily oral administration of oteseconazole to Tg.rasH2 mice for 6 months at doses of 5 mg/kg/day (males) and 15 mg/kg/day (females), which are up to 3 and 10 times, respectively, the maximum human exposure for RVVC based on AUC comparisons. In an oral carcinogenicity study, Sprague Dawley rats were administered doses of 0.5, 1.5, or 5 mg/kg/day oteseconazole once daily for up to 90 weeks. The high dose was initially reduced from 5 to 3 mg/kg/day due to excess mortality in males and reduced body weight in females. In males, an increase in the incidence in Leydig cell adenomas of the testes and thyroid follicular cell adenomas/carcinomas (combined) were increased at ≥1.5 mg/kg/day (similar to the maximum human exposure for RVVC based on AUC comparisons). In females, thyroid follicular cell adenomas and carcinomas (combined) were increased at ≥1.5 mg/kg/day (similar to the maximum human exposure for RVVC based on AUC comparisons) and thyroid carcinomas were increased at 5 to 3 mg/kg/day (5 times the maximum human exposure for RVVC based on AUC comparisons). The Leydig and thyroid findings are of uncertain relevance to humans. Mutagenesis Oteseconazole was negative in the bacterial reverse mutation assay, in vitro chromosomal aberration assay and micronucleus assay in rats. Impairment of Fertility Male rats were administered daily oral doses of 0, 0.5, 3, or 10 mg/kg/day oteseconazole beginning 42 days prior to pairing with untreated females, through the mating and post-mating period until euthanasia on Day 76 of treatment followed by a 12-week recovery period. There were no effects on reproductive and/or fertility parameters at the time of mating at 10 mg/kg/day (7 times the maximum human exposure for RVVC based on AUC comparisons). Increased incidences of abnormal sperm were observed at 3 mg/kg/day and sperm counts were reduced at 10 mg/kg/day. Although fertility was unaffected, sperm concentration remained reduced at the end of the recovery period. Female rats were administered daily oral doses of 0, 1.5, 5, or 25 mg/kg/day oteseconazole beginning 28 days prior to cohabitation with untreated males, continuing throughout mating and through gestational day 7. Although there were no effects on estrous cyclicity, effects on reproductive and fertility parameters were observed at 25 mg/kg/day in the presence of maternal toxicity (11 times the maximum human exposure for RVVC based on AUC comparisons).

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Embryo-Fetal Toxicity Advise patients that VIVJOA is contraindicated in females of reproductive potential and in pregnant women because it may cause fetal harm [see Contraindications (4) , Warnings and Precautions (5.1) and Use in Specific Populations (8.1 , 8.3) ] . Lactation Advise patients that VIVJOA is contraindicated in lactating women because it may cause harm to the breastfed infant [see Contraindications (4) , Warnings and Precautions (5.1) and Use in Specific Populations (8.2) ]. Important Administration Instructions Advise patients that VIVJOA must be taken with food, and that capsules must be swallowed whole and not chewed, crushed, dissolved, or opened [see Dosage and Administration (2.1) ]. Concomitant Administration with BCRP Transporter Substrates Advise patients to inform their health care provider if they are taking a BCRP substrate (e.g., rosuvastatin). Concomitant use with VIVJOA may increase the exposure of drugs that are BCRP substrates, which may increase the risk of adverse reactions associated with these drugs [see Drug Interactions (7.1) ] .

16.1 How Supplied VIVJOA (oteseconazole capsules) are supplied as lavender hard gelatin capsules. Printed black "OTE 150" on the capsule and contain 150 mg oteseconazole. They are available in an 18-count (NDC 74695-823-18) blister package within a child resistant wallet. There will be one blister pack per wallet and one wallet per outer carton. The fluconazole/VIVJOA dosage regimen is in an 18-count (NDC 74695-945-18) blister package within a child resistant wallet. There is one blister pack of VIVJOA (oteseconazole capsules) per wallet and one wallet per outer carton. The outer carton and wallet contain the following: "fluconazole/VIVJOA dosage regimen" and "fluconazole is prescribed separately". Fluconazole is not supplied in the carton.