Vivjoa

DESCRIPTION

VIVJOA (oteseconazole capsules) contains oteseconazole which is an oral azoleantifungal 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, α-(2,4- difluorophenyl)-β β-difluoro- α-(1H-tetrazol-1-ylmethyl)-5-(4-(2,2,2-trifluoroethoxy)phenyl)-,(αR)-. The empirical formula is C₂₃H₁₆F₇N₅O₂. 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).

INDICATIONS

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警告AND PRECAUTIONS,Use In Specific Populations, andClinical Studies].

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.

DOSAGE AND ADMINISTRATION

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 [seeVIVJOA-only Dosage Regimen]
• Fluconazole/VIVJOA dosage regimen [seeFluconazole/VIVJOA Dosage Regimen].

Administer VIVJOA orally with food [seeCLINICAL PHARMACOLOGY]. Swallow the capsules whole. Do not chew, crush, dissolve, or open the capsules.

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).

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).

HOW SUPPLIED

Dosage Forms And Strengths

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.

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 (NDC74695-823-18) 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.

Storage And Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [SeeUSP Controlled Room Temperature]. Protect from light when removed from the outer carton.

Manufactured for and distributed by: Mycovia Pharmaceuticals, Inc., Durham, NC 27703. Revised: Apr 2022

SIDE EFFECTS

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) [seeClinical Studies]. 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 [seeCONTRAINDICATIONS,警告AND PRECAUTIONS, andUse In Specific Populations].

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 [seeClinical Studies].

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.

DRUG INTERACTIONS

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 [seeCLINICAL PHARMACOLOGY].

警告

Included as part of thePRECAUTIONSsection.

PRECAUTIONS

Embryo-Fetal Toxicity

VIVJOA reproducti女性的禁忌ve 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 [seeUse In Specific Populations].

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 [seeCONTRAINDICATIONS,警告AND PRECAUTIONSandUse In Specific Populations].

Lactation

Advise patients that VIVJOA is contraindicated in lactating women because it may cause harm to the breastfed infant [seeCONTRAINDICATIONS,警告AND PRECAUTIONSandUse In Specific Populations].

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 [seeDOSAGE AND ADMINISTRATION].

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 [seeDRUG INTERACTIONS].

Nonclinical Toxicology

Carcinogenesis, 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.

在口服致癌性研究中,雄性sd r中ats 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).

Use In Specific Populations

Pregnancy

Risk Summary

VIVJOA reproducti女性的禁忌ve 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警告AND PRECAUTIONSandCLINICAL PHARMACOLOGY].

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 (seeData). 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

老鼠和兔子embryofetal发展阿塞斯d 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.

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警告AND PRECAUTIONS].

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 [seeUse In Specific Populations]. The relationship between the observed animal findings and breastfed infants is unknown.

Females Of Reproductive Potential

VIVJOA reproducti女性的禁忌ve 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警告AND PRECAUTIONS,Use In Specific PopulationsandCLINICAL PHARMACOLOGY].

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).

Pediatric Use

VIVJOA reproducti女性的禁忌ve 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 [seeCONTRAINDICATIONS,警告AND PRECAUTIONSandUse In SpecificPopulationsandCLINICAL PHARMACOLOGY].

The safety and effectiveness of VIVJOA have not been established in pre-menarchal pediatric females.

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.

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) [seeCLINICAL PHARMACOLOGY].

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 [seeCLINICAL PHARMACOLOGY].

OVERDOSE

No Information provided

CONTRAINDICATIONS

VIVJOA is contraindicated in:

• Females of reproductive potential [see警告AND PRECAUTIONSandUse In Specific Populations]
• Pregnant and lactating women [see警告AND PRECAUTIONS, andUse In Specific Populations]

Patients with known hypersensitivity to oteseconazole.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Oteseconazole is an antifungal drug [seeMicrobiology].

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.

Pharmacokinetics

的AUC oteseconazole增加大约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•g/mL)	64.2 (29.4)
Cmin (μg/mL)	2.5 (1.19)
aFollowing 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-caloriemeal (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 significantmetabolism.

Excretion

Following oral administration of radiolabeled oteseconazole, approximately 56% of the radiolabeled dose was recovered in feces primarily throughbiliaryexcretion 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.

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).

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 loweraffinityfor 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 withupregulationof 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 [seeINDICATIONS AND USAGE]:

• Candida albicans
• Candida glabrata
• Candida krusei
• Candida parapsilosis
• Candida tropicalis
• Candida lusitaniae
• Candida dubliniensis

Animal Toxicology And/Or Pharmacology

在口服致癌性研究中,雄性sd r中ats 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 in males due to excess mortality. Incidences ofhemorrhagewere increased in the adrenals, brain, coagulatinggland, ears, epididymides, head, heart, lung, nose, pancreas,pharynx,prostate, seminalvesicles,spinal cord, testes,thymus, andbladderof male Crl:CD®(SD) rats (after 77 weeks of dosing at about 5 times the MRHD based on AUC comparisons). There were no increases in the incidence of hemorrhage in rats after 26 weeks at 5 mg/kg. The clinical relevance of these findings after very high doses (5 to 7 times the MRHD) for the lifetime of the rat remains unclear.

Clinical Studies

Overview Of The Clinical Studies

A total of 656 adults and post-menarchal pediatric females with RVVC (defined as ≥3 episodes of vulvovaginalcandidiasis)阴道假丝(致病菌种及12个月)在两个随机multicenter, multinational, double-blind, placebo-controlled trials: Trial 1 (NCT#03562156) and Trial 2 (NCT#03561701). A total of 219 adults and post-menarchal pediatric females with RVVC were randomized in a multicenter, double-blind trial [Trial 3 (NCT#03840616)]. Although females of reproductive potential were included in the clinical efficacy data, VIVJOA is contraindicated in females of reproductive potential due to the risk of embryo-fetal toxicity [seeCONTRAINDICATIONS,警告AND PRECAUTIONSandUse In Specific Populations].

Trial 1 And Trial 2

试验试验1和2都是随机,安慰剂-controlled trials evaluating the efficacy and safety of VIVJOA in the reduction of RVVC. Both trials consisted of two phases: an open-label induction phase and an 11-week maintenance phase. Patients received three sequential doses of 150 mg of fluconazole (every 72 hours) on Days, 1, 4 and 7 during the induction phase. Patients returned 14 days after the first dose of fluconazole and if the acute VVC episode was resolved (vulvovaginal signs and symptoms score < 3) they were randomized (2:1) to receive either 150 mg of VIVJOA or placebo for 7 days followed by 11 weekly doses in the maintenance phase.

In Trial 1, a total of 483 patients were enrolled in the induction phase with 326 patients entering the maintenance phase with 217 patients randomized to VIVJOA and 109 patients randomized to placebo. A total of 182 patients (84%) in the VIVJOA group and 91 patients (83%) in the placebo group completed the trial. The mean age of patients was 34 years old (range 17-78 years old) with 85% of patients aged 18-44 years and 15% of patients aged 45 years and older. Patients were 72% White, 13% Black orAfrican American亚洲,14%,8%的西班牙裔或拉丁裔乙nicity.

In Trial 2, a total of 425 patients were enrolled into the induction phase with 330 patients entering the maintenance phase with 220 subjects randomized to VIVJOA and 110 patients randomized to placebo. A total of 191 patients (87%) in the VIVJOA group and 91 patients (83%) in the placebo group completed the trial. The mean age of patients was 34 years old (range 18-73 years old) with 85% of patients aged 18-44 years and 15% of patients aged 45 years and older. Patients were 89% White, 10% Black or African American and 15% were of Hispanic or Latino ethnicity.

For both Trial 1 and Trial 2, efficacy was assessed by the proportion of patients with ≥1 culture-verified acute VVC episode (positive fungal culture for Candida species associated with a clinical signs and symptoms score of ≥3) during the Maintenance Phase through Week 48. Evaluation of clinical signs and symptoms includederythema(redness), edema (swelling), excoriation (skin picking), itching, burning and irritation. Since treatment for acute VVC was allowed to be provided to a patient if it was deemed to be clinically needed when the patient had a signs and symptoms score ≥ 3 and a positive KOH test, the proportion of patients with ≥1 culture-verified acute VVC episode or who took medication known to treat VVC during the Maintenance Phase through Week 48 is also presented.

VIVJOA was superior to placebo with reference to the proportion of patients with ≥1 culture-verified acute VVC episode through Week 48 (Table 2) or the proportion of patients with ≥1 culture-verified acute VVC episode or who took medication known to treat VVC during the Maintenance Phase through Week 48. For both Trial 1 and Trial 2, the average percentage of patients was lower in the VIVJOA groups compared with the placebo group (Table 2).

Table 2: Trial 1 and 2 Efficacy Endpoints: ITT Population

	Trial 1		Trial 2
	VIVJOA (N=217)	Placebo (N=109)	VIVJOA (N=218)	Placebo (N=108)
Proportion of Patients with ≥1 Culture-verified Acute VVC Episode (Day 1 through Week 48)a	6.7%	42.8%	3.9%	39.4%
Treatment Difference p-valueb	<0.001		<0.001
Proportion of Patients with ≥1 Culture-verified Acute VVC Episode or received VVC medication (Day 1 through Week 48)a	27.3%	50.8%	21.3%	49.7%
Treatment Difference p-valueb	<0.001		<0.001
Abbreviations: ITT=Intent-to-Treat (Population); VVC=vulvovaginal candidiasis. aAverage %. Missing values were imputed with multiple imputation using the following auxiliary information: region, treatment, Baseline body mass index, Baseline age, ethnicity, and visit. bThe p-value was obtained using a Chi-square test comparing VIVJOA with placebo.

Trial 3

Trial 3 was a randomized, double-blind trial evaluating the efficacy and safety of VIVJOA versus fluconazole and placebo in adults and post-menarchal pediatric females with RVVC. The trial consisted of two phases: induction and maintenance.

During the induction phase, patients received 1050 mg of VIVJOA over two days (600 mg [4x150mg] on Day 1 and 450 mg [3x150mg] on Day 2) or three sequential doses of 150 mg of fluconazole (every 72 hours) on Days, 1, 4 and 7. Patients returned 14 days after the first dose and moved to the maintenance phase if the acute VVC episode was resolved. During the maintenance phase, patients received 150 mg VIVJOA weekly or placebo weekly for 11 weeks.

A total of 219 patients were randomized (2:1) into the induction phase: 147 to VIVJOA and 72 to fluconazole/placebo. One patient in the VIVJOA group did not receive drug therefore 146 patients received VIVJOA. A total of 112 patients (76%) in the VIVJOA group and 55 patients (76%) in the fluconazole/placebo group completed the trial.

The mean age of patients was 35 years (range 16-78) with 80% of patients aged 18-44 years and 19% of patients aged 45 years and older. Patients were 59% White, 34% Black or African American, 1% Asian and 26% were of Hispanic or Latino ethnicity. The trial was conducted completely in the United States.

Efficacy was assessed by the proportion of patients with ≥1 culture verified acute VVC episode during the maintenance phase (post-randomization through Week 50) or who failed clearing their infection during the induction phase. A recurring acute VVC episode was defined as a positive culture for Candida species and a clinical signs and symptoms score of ≥3. Evaluation of clinical signs and symptoms included erythema(redness), edema (swelling), excoriation (skin picking), itching, burning and irritation. Additionally, the proportion of patients with ≥1 culture verified acute VVC episode or who took medication known to treat VVC during the maintenance phase (post-randomization through Week 50) or who failed clearing their infection during the induction phase is presented.

VIVJOA was superior to fluconazole/placebo in the proportion of patients with ≥1 culture-verified recurring acute VVC episode during the maintenance phase (post randomization through Week 50) or failed clearing their infection during the induction phase and the proportion of patients with ≥1 culture-verified recurring acute VVC episode or took VVC medication known to treat VVC during the maintenance phase (post randomization through Week 50) or who failed clearing their infection during the induction phase. The average percentage of patients was lower in the VIVJOA group compared with the fluconazole/placebo group (Table 3).

Table 3: Trial 3 Efficacy Endpoints ITT population

	VIVJOA (N = 147)	Fluconazole /Placebo (N=72)	Treatment Difference p-valueb
Proportion of Patients with ≥1 Culture-verified Acute VVC Episode through Week 50 or Unresolved VVC Episode During the Induction Phasea	10.3%	42.9%	<0.001
Proportion of Patients with ≥1 Culture-verified Acute VVC Episode or took VVC medication through Week 50 or Unresolved VVC Episode During the Induction Phasea	43.5%	59.0%	0.039
Abbreviations: ITT=Intent-to-Treat (Population); VVC=vulvovaginal candidiasis aAverage %, Missing values were imputed with multiple imputation using the following auxiliary information: treatment, baseline body mass index, baseline age, ethnicity, and visit. bThe p-value was obtained using a Chi-square test comparing VIVJOA with fluconazole/placebo.

PATIENT INFORMATION

No information provided. Please refer to the警告AND PRECAUTIONSsection.