DRUG INTERACTIONS--(summary)

 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.

DRUG INTERACTIONS-(summary)

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)].

BRIEF SUMMARY

OTESECONAZOLE-(Apr 2022)

Indn- To reduce the incidence of  recrrent vuvvoluar

candidiasis (RVVC) who are not reproductive potential

Dosage- Capsules: 150 mg of oteseconazole (fluconazole is not supplied in the carton).

o On Day 1: Administer VIVJOA 600 mg (as a single dose), then o On Day 2: Administer VIVJOA 450 mg (as a single dose), then o Beginning on Day 14: Administer VIVJOA 150 mg once a week (every 7 days) for 11 weeks (Weeks 2 through 12).

ADR-  The most frequently reported adverse reactions (incidence > 2%) were headache and nausea

CI- WARNINGS AND PRECAUTIONS-

 Embryo-Fetal Toxicity: Based on animal studies, VIVJOA may cause fetal harm

arm. 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. 

Pat inform-

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)].

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U.S. FDA APPROVED DRUGS SURING 2022                                        

Serial No 11.

Name of the Drug-    VIVJOA

Active Ingredient -   Oteseconazole

Pharmacological Classification- To reduce the incidence of  recrrent vuvvoluar

candidiasis (RVVC) who are not reproductive potential                                                                                                                                                                                               

  Date of Approval- 4/26/2022         

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use VIVJOA™ safely and effectively. See full prescribing information for VIVJOA™. VIVJOA™ (oteseconazole) capsules, for oral use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE-

 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. 

DOSAGE AND ADMINISTRATION-

 • There are two recommended VIVJOA dosage regimens: a VIVJOAonly regimen and a Fluconazole/VIVJOA regimen. Use one of these two dosage regimens.

 o Administer VIVJOA orally with food.

 • For the VIVJOA-only Dosage Regimen: 

o On Day 1: Administer VIVJOA 600 mg (as a single dose), then o On Day 2: Administer VIVJOA 450 mg (as a single dose), then o 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:

 o On Day 1, Day 4, and Day 7: Administer fluconazole 150 mg orally, then

o On Days 14 through 20: Administer VIVJOA 150 mg once daily for 7 days, then

o Beginning on Day 28: Administer VIVJOA 150 mg once a week (every 7 days) for 11 weeks (Weeks 4 through 14).

DOSAGE FORMS AND STRENGTHS-

 Capsules: 150 mg of oteseconazole (fluconazole is not supplied in the carton). 

ADVERSE REACTIONS-

 The most frequently reported adverse reactions (incidence > 2%) were headache and nausea.

WARNINGS AND PRECAUTIONS-

 Embryo-Fetal Toxicity: Based on animal studies, VIVJOA may cause fetal harm

arm. 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. 

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)]. Reference ID: 4974238 13

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)].

Manufactured for and distributed by: Mycovia Pharmaceuticals, Inc. Durham, NC 27703 Patent numbers: 8,236,962, 8,754,227,10,173,998,10,464,921,10,836,740, 9,840,492,10,414,75

CLINICAL PHARMACOLOGY

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. Reference ID: 4974238 7

Cardiac Electrophysiology At 5 times the maximum exposures for the recommended dose, VIVJOA does not prolong the QT interval to any clinically relevant extent.

12.3Pharmacokinetics The AUC of oteseconazole increased approximately dose proportionally while the Cmax 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 Parametera Mean (± SD) Cmax (µg/mL) 2.8 (1.25) AUC24h (h·µg/mL) 64.2 (29.4) Cmin (µg/mL) 2.5 (1.19) a Following repeat dose administration of VIVJOA at the approved recommended dosage for RVVC at the end of treatment. 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 Cmax and AUC0-72h by 45% and 36%, but no significant differences were observed with a low-fat, lowcalorie 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 Cmax and AUC0-24h of rosuvastatin, a BCRP substrate, by 118% and 114%, respectively. Reference ID: 4974238 8

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, 14a 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

DRUG INTERACTIONS

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)].

8 USE IN SPECIFIC POPULATIONS 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. Reference ID: 4974238 5 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. Reference ID: 4974238 6 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 (ChildPugh 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)].

11 DESCRIPTION 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-(1H-tetrazol-1-yl)-1- (5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol or 2-Pyridineethanol, a-(2,4- difluorophenyl)-ß ß-difluoro- a-(1H-tetrazol-1-ylmethyl)-5-(4-(2,2,2-trifluoroethoxy)phenyl)-,(aR)-. The empirical formula