ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most frequent adverse reactions (>= 2%) reported with BREXAFEMME in clinical trials of vulvovaginal candidiasis treatment were diarrhea, nausea, abdominal pain, dizziness, and vomiting. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact SCYNEXIS, Inc. at 1-888-982-7299 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of 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 545 patients were exposed to BREXAFEMME in two clinical trials of women with VVC (Trial and Trial 2). The women were treated with BREXAFEMME 300 mg (two 150 mg tablets) twice day, 12 hours apart, for one day. The women were 18 to 76 years of age (mean 34 years); 69% were White and 28% were Black or African American; 18% were of Hispanic or Latina ethnicity. The most frequently reported adverse reactions are presented in Table 1.There were no serious adverse reactions and out of 545 (0.4%) patients discontinued treatment with BREXAFEMME due to vomiting (1 patient) and dizziness (1 patient). Table 1. Adverse Reactions with Rates >=2% in BREXAFEMME-Treated PatientsAdverse ReactionBREXAFEMMEN 545 (%) PlaceboN 275 (%) Diarrhea Nausea Abdominal pain Dizziness Vomiting 91 (16.7%) 65 (11.9%) 62 (11.4%) 18 (3.3%) 11 (2.0%) (3.3%) 11 (4.0%) 14 (5.1%) (2.5%) (0.7%) Includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort Includes dizziness and postural dizziness Other Adverse ReactionsThe following adverse reactions occurred in 2% of patients receiving BREXAFEMME in Trial and Trial 2: dysmenorrhea, flatulence, back pain, elevated transaminases, vaginal bleeding, rash/hypersensitivity reaction.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ibrexafungerp is triterpenoid antifungal drug [see Microbiology 12.4 ]. 12.2 Pharmacodynamics. Ibrexafungerp exposure-response relationships and the time course of pharmacodynamic response are unknown. Cardiac ElectrophysiologyAt concentration of times or greater than that achieved after single day 300 mg twice daily dose, ibrexafungerp does not prolong the QTc interval to any clinically relevant extent.. 12.3 Pharmacokinetics. In healthy subjects, ibrexafungerp area under the curve (AUC) and maximal concentration (C max) increased approximately dose-proportionally following single dose administration from 10 to 1600 mg (0.02 to 2.67 times the approved recommended daily dose) and multiple-dose administration from 300-800 mg (0.50 to 1.33 times the approved recommended daily dose). Based on population pharmacokinetic analysis in patients with VVC, the model predicts that 300 mg twice day for doses achieves mean (%CV) AUC 0-24 exposure of 6832 (15%) ngohr/mL and max of 435 (15%) ng/mL under fasted conditions and mean AUC 0-24 exposure of 9867 (15%) ngoh/mL and max of 629 (15%) ng/mL under fed conditions. AbsorptionAfter oral administration of BREXAFEMME in healthy volunteers, ibrexafungerp generally reaches maximum plasma concentrations to hours after single and multiple dosing.Effect of FoodFollowing administration of BREXAFEMME to healthy volunteers, the ibrexafungerp max increased 32% and the AUC increased 38% with high fat meal (800-1000 calories; 50% fat), compared to fasted conditions. This exposure change is not considered clinically significant s ee Dosage and Administration 2.1 ]. DistributionThe mean steady state volume of distribution (Vss) of ibrexafungerp is approximately 600 L. Ibrexafungerp is highly protein bound (greater than 99%), predominantly to albumin. Animal studies demonstrate 9-fold higher exposure in vaginal tissue than in blood.EliminationIbrexafungerp is eliminated mainly via metabolism and biliary excretion. The elimination half-life is approximately 20 hours.MetabolismIn vitro studies show that ibrexafungerp undergoes hydroxylation by CYP3A4, followed by glucuronidation and sulfation of hydroxylated inactive metabolite. ExcretionFollowing oral administration of radio-labeled ibrexafungerp to healthy volunteers, mean of 90% of the radioactive dose (51% as unchanged ibrexafungerp) was recovered in feces and 1% was recovered in urine.Specific PopulationsGeriatric PatientsA comparison of elderly healthy males and females (range of 65 to 76 years) with young healthy males (range of 20 to 45 years) showed that the geometric means ratio (GMR) of pooled elderly males and females young males for the AUC 0- inf (90% CI) was 1.39 (1.19, 1.62). Dose adjustment for age is not required. Drug Interaction StudiesIbrexafungerp is substrate of CYP3A4 and P-gp. In vitro, ibrexafungerp is an inhibitor of CYP2C8, CYP3A4, P-gp transporter, and OATP1B3 transporter. Ibrexafungerp is not an inducer of CYP3A4.The effect of coadministration of drugs on the pharmacokinetics of ibrexafungerp and the effect of ibrexafungerp on the pharmacokinetics of coadministered drugs were studied in healthy subjects.Effect of Coadministered Drugs on Ibrexafungerp PharmacokineticsStrong CYP 3A4 nhibitor: Ketoconazole (400 mg once daily for 15 days), strong CYP3A4 and P-gp inhibitor, increased the ibrexafungerp AUC by 5.8-fold and max by 2.5-fold s ee Drug Interactions 7 ] Moderate CYP3A4 Inhibitor: Diltiazem (240 mg once daily for 15 days) increased the ibrexafungerp AUC by 2.5-fold and max by 2.2-fold. This exposure change is not considered clinically significant at the approved recommended dosage for VVC. Proton Pump Inhibitor: Pantoprazole (40 mg once daily for days) decreased ibrexafungerp AUC by approximately 25% and max by 22%. This exposure change is not considered clinically significant at the approved recommended dosage for VVC. Effect of Ibrexafungerp on the Pharmacokinetics of Coadministered Drugs The effects of ibrexafungerp on substrates of CYP2C8, CYP3A4, P-gp, and OATP1B3 transporters were evaluated in studies that included loading doses of ibrexafungerp of 1250 to 1500 mg (2.1 to 2.5 times the approved recommended daily dose) for two days followed by 750 mg (1.25 times the approved recommended daily dose) once daily for 3-7 days.CYP2C8 substrates: Ibrexafungerp did not increase the AUC 0-inf or max of rosiglitazone, moderate sensitive CYP2C8 substrate. CYP3A4 substrates: Ibrexafungerp resulted in 1.4-fold increase in the AUC 0-inf and no effect on the max of the sensitive CYP3A4 and P-gp substrate tacrolimus. P-gp substrates: Ibrexafungerp resulted in 1.4-fold increase in the AUC 0-48 and 1.25-fold increase in the max of the P-gp substrate dabigatran. OATP1B3 transporters: Ibrexafungerp resulted in 2.8-fold increase in the AUC 0-24 and 3.5 fold increase in the max of the OATP1B3 transporter substrate pravastatin. 12.4 Microbiology. Mechanism of ActionIbrexafungerp, triterpenoid antifungal agent, inhibits glucan synthase, an enzyme involved in the formation of 1,3--D-glucan, an essential component of the fungal cell wall.Ibrexafungerp has concentration-dependent fungicidal activity against Candida species as measured by time kill studies. Ibrexafungerp retains in vitro antifungal activity when tested at pH 4.5 (the normal vaginal pH). ResistanceThe potential for resistance to ibrexafungerp has been evaluated in vitro and is associated with mutations of the fks-2 gene; the clinical relevance of these findings is unknown. Ibrexafungerp retains activity against most fluconazole resistant Candida spp. Interaction with Other AntifungalsIn vitro studies have not demonstrated antagonism between ibrexafungerp and azoles or echinocandins. Antimicrobial ActivityIbrexafungerp has been shown to be active against most isolates of the following microorganism both in vitro and in clinical infections s ee Indications and Usage 1 ]: Candida albicansThe following in vitro data are available, but their clinical significance is unknown. Ibrexafungerp has in vitro activity against most isolates of the following microorganisms:Candida auris Candida dubliniensisCandida glabrata Candida guilliermondii Candida keyfrCandida kruseiCandida lusitaniae Candida parapsilosisCandida tropicalis.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Two randomized placebo-controlled clinical trials (Trial 1, NCT03734991 and Trial 2, NCT03987620) with similar design were conducted to evaluate the safety and efficacy of single day of BREXAFEMME 600 mg (two 150 mg tablets per dose, administered 12 hours apart) for the treatment of VVC. Non-pregnant post-menarchal females with diagnosis of VVC were eligible. diagnosis of VVC was defined as (a) minimum composite vulvovaginal signs and symptoms (VSS) score of >=4 with at least two signs or symptoms having score of (moderate) or greater; (b) positive microscopic examination with 10% KOH in vaginal sample revealing yeast forms (hyphae/pseudohyphae) or budding yeasts, and (c) normal vaginal pH (<=4.5). The total composite VSS score was based on the vulvovaginal signs (erythema, edema, excoriation) and vulvovaginal symptoms (itching, burning, or irritation) where each was scored as 0= absent, 1= mild, 2= moderate, or 3= severe. Study visits included the test of cure (TOC, Day to 14) visit and follow-up (Day 21 to 29) visit. The modified intent to treat (MITT) population included randomized subjects with baseline culture positive for Candida species who took at least dose of study medication. Trial was conducted in the United States. The MITT population consisted of 190 patients treated with BREXAFEMME and 100 patients treated with placebo. The average age was 34 years (range 17-67 years), with 91% less than 50 years. Fifty-four percent (54%) were White and 40% were Black or African American, 26% were of Hispanic or Latino ethnicity. The average BMI was 30 and 9% had history of diabetes. The median VSS score at baseline was (range 4-18). The majority (92%) of the subjects were culture-positive with C. albicans. Trial was conducted in the United States (39%) and Bulgaria (61%). The MITT population consisted of 189 patients treated with BREXAFEMME and 89 patients treated with placebo. The average age was 34 years (range 18-65 years), with 92% less than 50 years. Eighty-one percent (81%) were White and 19% were Black or African American, 10% were of Hispanic or Latino ethnicity. The average BMI was 26 and 5% had history of diabetes. The median VSS score at baseline was 10 (range 4-18). The majority (89%) of the subjects were culture-positive with C. albicans. Efficacy was assessed by clinical outcome at the TOC visit. complete clinical response was defined as the complete resolution of signs and symptoms (VSS score of 0). Additional endpoints included negative culture for Candida spp. at the TOC visit, and clinical outcome at the follow-up visit. Statistically significantly greater percentages of patients experienced complete clinical response at TOC, negative culture at TOC, and complete clinical response at follow-up with treatment with BREXAFEMME compared to placebo. The results for the clinical and mycological responses are presented in Table 3.Table 3. Clinical and Mycological Response, MITTPopulationTrial 1Trial 2BREXAFEMME = 190n (%)PlaceboN 100n (%)BREXAFEMME = 189n (%)PlaceboN 89n (%)Complete Clinical Response at TOC195 (50.0)28 (28.0)120 (63.5)40 (44.9)Difference (95% CI)P-value22.0 (10.2, 32.8) 0.001 18.6 (6.0, 30.6) 0.009 Negative Culture at TOC94 (49.5)19 (19.0)111 (58.7)26 (29.2)Difference (95% CI)P-value30.5 (19.4, 40.3) 0.001 29.5 (17.2, 40.6) 0.001 Complete Clinical Response at follow-up2113 (59.5)44 (44.0)137 (72.5)44 (49.4)Difference (95% CI)P-value15.5 (3.4, 27.1) 0.007 23.1 (10.8, 35.0) 0.006 1Absence of signs and symptoms (VSS Score of 0) without need for additional antifungal therapy or topical drug therapy for the treatment of vulvovaginal symptoms at test of cure (TOC) visit. 2Absence of signs and symptoms (VSS Score of 0) without need for further antifungal treatment or topical drug therapy for the treatment of vulvovaginal symptoms prior to follow-up visit.

DESCRIPTION SECTION.

11 DESCRIPTION. BREXAFEMME, available as an oral tablet, contains ibrexafungerp citrate, triterpenoid antifungal agent. Ibrexafungerp is designated chemically as (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[(2R)-2-amino-2,3,3-trimethylbutoxy]-1,6a,8,10a-tetramethyl-8-[(2R)-3-methylbutan-2-yl]-14-[5-(pyridine-4-yl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-2H,4H-1,4a-propanophenanthro[1,2-c]pyran-7-carboxylic acid compound with 2-hydroxypropane-1,2,3-tricarboxylic acid (1:1) with an empirical formula of 44H 67N 5O o 6H 8O and molecular weight of 922.18 grams per mole. The chemical structure is: C 6H 8O BREXAFEMME tablet for oral administration is purple, oval, biconvex shaped, film-coated tablet containing 189.5 mg of ibrexafungerp citrate equivalent to 150 mg of ibrexafungerp. In addition to the active ingredient, the tablet formulation contains butylated hydroxyanisole, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, and microcrystalline cellulose. The tablet film-coating contains FD&C Blue 2, FD&C Red 40, hydroxypropyl cellulose, hydroxypropylmethyl cellulose 2910, talc and titanium dioxide.. The chemical structure of Ibrexafungerp is designated chemically as (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[(2R)-2-amino-2,3,3-trimethylbutoxy]-1,6a,8,10a-tetramethyl-8-[(2R)-3-methylbutan-2-yl].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of BREXAFEMME in adult and post-menarchal pediatric females is 300 mg (two tablets of 150 mg) twice day for one day, for total treatment dosage of 600 mg. 2.1) BREXAFEMME may be taken with or without food. 2.1) Prior to initiating treatment, verify pregnancy status in females of reproductive potential. 2.3) The recommended dosage of BREXAFEMME in adult and post-menarchal pediatric females is 300 mg (two tablets of 150 mg) twice day for one day, for total treatment dosage of 600 mg. 2.1) BREXAFEMME may be taken with or without food. 2.1) Prior to initiating treatment, verify pregnancy status in females of reproductive potential. 2.3) 2.1 Recommended Dosage. The recommended dosage of BREXAFEMME in adult and post-menarchal pediatric females is 300 mg (two 150 mg tablets) administered approximately 12 hours apart (e.g., in the morning and in the evening) for one day, for total daily dosage of 600 mg (four 150 mg tablets). BREXAFEMME may be taken with or without food.. 2.2 Dosage Modifications in Patients due to Concomitant Use of Strong Inhibitor of Cytochrome P450 Isoenzymes (CYP) 3A With concomitant use of strong CYP3A inhibitor, administer BREXAFEMME 150 mg approximately 12 hours apart (e.g., in the morning and in the evening) for one day. No dosage adjustment is warranted in patients with concomitant use of weak or moderate CYP3A inhibitor [see Drug Interactions 7 and Clinical Pharmacology 12.3 ]. 2.3 Pregnancy Evaluation Prior to Initiating Treatment. Verify the pregnancy status in females of reproductive potential prior to initiating treatment with BREXAFEMME [see Contraindications 4 , Warning and Precautions 5.1 and Use in Specific Populations 8.1 8.3 ].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Ibrexafungerp is substrate of CYP3A4. Drugs that inhibit or induce CYP3A may alter the plasma concentrations of ibrexafungerp and affect the safety and efficacy of BREXAFEMME [see Clinical harmacology 12.3 ] Table Effect of Coadministered Drugs on Ibrexafungerp Pharmacokinetics:Concomitant Drugs Effect on Ibrexafungerp ConcentrationRecommendationStrong CYP3A inhibitors: (e.g., ketoconazole, itraconazole) Significantly increasedReduce the BREXAFEMME dosage [see Dosage and Administration 2.2 ] Strong and Moderate CYP3A inducers: (e.g., rifampin, carbamazepine, phenytoin, St. Johns wort, long acting barbiturates, bosentan, efavirenz, or etravirine) Not studied in vivo or in vitro, but likely to result in significant reduction Avoid concomitant administrationIbrexafungerp is an inhibitor of CYP3A4, P-gp and OATP1B3 transporter [(see Clinical Pharmacology 12.3 )]. However, given the short treatment duration for VVC, the effect of BREXAFEMME on the pharmacokinetics of substrates of CYP3A4, P-gp and OATP1B3 transporters is not considered to be clinically significant. Concomitant use of strong CYP3A inhibitors increases the exposure of ibrexafungerp. Reduce BREXAFEMME dose with concomitant use of strong CYP3A inhibitor to 150 mg twice daily for one day. 2.2, 7) Concomitant use of strong and moderate CYP3A inducers may significantly reduce the exposure of ibrexafungerp. Avoid concomitant administration of BREXAFEMME with strong or moderate CYP3A inducers. 7) Concomitant use of strong CYP3A inhibitors increases the exposure of ibrexafungerp. Reduce BREXAFEMME dose with concomitant use of strong CYP3A inhibitor to 150 mg twice daily for one day. 2.2, 7) Concomitant use of strong and moderate CYP3A inducers may significantly reduce the exposure of ibrexafungerp. Avoid concomitant administration of BREXAFEMME with strong or moderate CYP3A inducers. 7).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA approved patient labeling Patient Information) Risk of Fetal ToxicityBREXAFEMME is contraindicated in pregnancy since it may cause fetal harm. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions 5.1 and Use in Specific Populations 8.1 ]. Advise patients who have inadvertently taken BREXAFEMME during pregnancy that there is pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to SCYNEXIS, Inc. at 1-888-982-7299 [see Use in Specific Populations 8.1 ]. Advise females of reproductive potential to use effective contraception while taking BREXAFEMME and for days after the last dose [see Use in Specific Populations 8.3 )]. Important Administration InstructionsInform the patient that each BREXAFEMME dose consists of two tablets. total treatment course is two doses taken approximately 12 hours apart and consists of total of four tablets.If the first two tablets are taken in the morning, the second two tablets should be taken that same day in the evening. If the first two tablets are taken in the afternoon or evening, the second two tablets should be taken the following morning.Inform the patient that BREXAFEMME can be taken with or without food [see Dosage and dministration 2.1 ]. Concomitant MedicationsAdvise the patient to inform their health care provider if they are taking any other medications as certain medications can increase or decrease blood concentrations of BREXAFEMME or BREXAFEMME may increase or decrease blood concentrations of certain medications [see Dosage and dministration 2.2 ]. Manufactured for: SCYNEXIS, Inc. Jersey City, NJ 07302 Patent: www.scynexis.com/product/patentBREXAFEMME (R) is registered trademark of SCYNEXIS, Inc.

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionIbrexafungerp, triterpenoid antifungal agent, inhibits glucan synthase, an enzyme involved in the formation of 1,3--D-glucan, an essential component of the fungal cell wall.Ibrexafungerp has concentration-dependent fungicidal activity against Candida species as measured by time kill studies. Ibrexafungerp retains in vitro antifungal activity when tested at pH 4.5 (the normal vaginal pH). ResistanceThe potential for resistance to ibrexafungerp has been evaluated in vitro and is associated with mutations of the fks-2 gene; the clinical relevance of these findings is unknown. Ibrexafungerp retains activity against most fluconazole resistant Candida spp. Interaction with Other AntifungalsIn vitro studies have not demonstrated antagonism between ibrexafungerp and azoles or echinocandins. Antimicrobial ActivityIbrexafungerp has been shown to be active against most isolates of the following microorganism both in vitro and in clinical infections s ee Indications and Usage 1 ]: Candida albicansThe following in vitro data are available, but their clinical significance is unknown. Ibrexafungerp has in vitro activity against most isolates of the following microorganisms:Candida auris Candida dubliniensisCandida glabrata Candida guilliermondii Candida keyfrCandida kruseiCandida lusitaniae Candida parapsilosisCandida tropicalis.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. In healthy subjects, ibrexafungerp area under the curve (AUC) and maximal concentration (C max) increased approximately dose-proportionally following single dose administration from 10 to 1600 mg (0.02 to 2.67 times the approved recommended daily dose) and multiple-dose administration from 300-800 mg (0.50 to 1.33 times the approved recommended daily dose). Based on population pharmacokinetic analysis in patients with VVC, the model predicts that 300 mg twice day for doses achieves mean (%CV) AUC 0-24 exposure of 6832 (15%) ngohr/mL and max of 435 (15%) ng/mL under fasted conditions and mean AUC 0-24 exposure of 9867 (15%) ngoh/mL and max of 629 (15%) ng/mL under fed conditions. AbsorptionAfter oral administration of BREXAFEMME in healthy volunteers, ibrexafungerp generally reaches maximum plasma concentrations to hours after single and multiple dosing.Effect of FoodFollowing administration of BREXAFEMME to healthy volunteers, the ibrexafungerp max increased 32% and the AUC increased 38% with high fat meal (800-1000 calories; 50% fat), compared to fasted conditions. This exposure change is not considered clinically significant s ee Dosage and Administration 2.1 ]. DistributionThe mean steady state volume of distribution (Vss) of ibrexafungerp is approximately 600 L. Ibrexafungerp is highly protein bound (greater than 99%), predominantly to albumin. Animal studies demonstrate 9-fold higher exposure in vaginal tissue than in blood.EliminationIbrexafungerp is eliminated mainly via metabolism and biliary excretion. The elimination half-life is approximately 20 hours.MetabolismIn vitro studies show that ibrexafungerp undergoes hydroxylation by CYP3A4, followed by glucuronidation and sulfation of hydroxylated inactive metabolite. ExcretionFollowing oral administration of radio-labeled ibrexafungerp to healthy volunteers, mean of 90% of the radioactive dose (51% as unchanged ibrexafungerp) was recovered in feces and 1% was recovered in urine.Specific PopulationsGeriatric PatientsA comparison of elderly healthy males and females (range of 65 to 76 years) with young healthy males (range of 20 to 45 years) showed that the geometric means ratio (GMR) of pooled elderly males and females young males for the AUC 0- inf (90% CI) was 1.39 (1.19, 1.62). Dose adjustment for age is not required. Drug Interaction StudiesIbrexafungerp is substrate of CYP3A4 and P-gp. In vitro, ibrexafungerp is an inhibitor of CYP2C8, CYP3A4, P-gp transporter, and OATP1B3 transporter. Ibrexafungerp is not an inducer of CYP3A4.The effect of coadministration of drugs on the pharmacokinetics of ibrexafungerp and the effect of ibrexafungerp on the pharmacokinetics of coadministered drugs were studied in healthy subjects.Effect of Coadministered Drugs on Ibrexafungerp PharmacokineticsStrong CYP 3A4 nhibitor: Ketoconazole (400 mg once daily for 15 days), strong CYP3A4 and P-gp inhibitor, increased the ibrexafungerp AUC by 5.8-fold and max by 2.5-fold s ee Drug Interactions 7 ] Moderate CYP3A4 Inhibitor: Diltiazem (240 mg once daily for 15 days) increased the ibrexafungerp AUC by 2.5-fold and max by 2.2-fold. This exposure change is not considered clinically significant at the approved recommended dosage for VVC. Proton Pump Inhibitor: Pantoprazole (40 mg once daily for days) decreased ibrexafungerp AUC by approximately 25% and max by 22%. This exposure change is not considered clinically significant at the approved recommended dosage for VVC. Effect of Ibrexafungerp on the Pharmacokinetics of Coadministered Drugs The effects of ibrexafungerp on substrates of CYP2C8, CYP3A4, P-gp, and OATP1B3 transporters were evaluated in studies that included loading doses of ibrexafungerp of 1250 to 1500 mg (2.1 to 2.5 times the approved recommended daily dose) for two days followed by 750 mg (1.25 times the approved recommended daily dose) once daily for 3-7 days.CYP2C8 substrates: Ibrexafungerp did not increase the AUC 0-inf or max of rosiglitazone, moderate sensitive CYP2C8 substrate. CYP3A4 substrates: Ibrexafungerp resulted in 1.4-fold increase in the AUC 0-inf and no effect on the max of the sensitive CYP3A4 and P-gp substrate tacrolimus. P-gp substrates: Ibrexafungerp resulted in 1.4-fold increase in the AUC 0-48 and 1.25-fold increase in the max of the P-gp substrate dabigatran. OATP1B3 transporters: Ibrexafungerp resulted in 2.8-fold increase in the AUC 0-24 and 3.5 fold increase in the max of the OATP1B3 transporter substrate pravastatin.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies, BREXAFEMME use is contraindicated in pregnancy because it may cause fetal harm. In pregnant rabbits, oral ibrexafungerp administered during organogenesis was associated with rare malformations including absent forelimb(s), absent hindpaw, absent ear pinna, and thoracogastroschisis at dose exposures greater or equal to approximately times the human exposure at the RHD. Oral ibrexafungerp administered to pregnant rats during organogenesis was not associated with fetal toxicity or increased fetal malformations at dose exposure approximately times the human exposure at the RHD s ee Data . Available data on BREXAFEMME use in pregnant women are insufficient to draw conclusions about any drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There is pregnancy safety study for BREXAFEMME. If BREXAFEMME is inadvertently administered during pregnancy or if pregnancy is detected within days after patient receives BREXAFEMME, pregnant women exposed to BREXAFEMME and healthcare providers should report pregnancies to SCYNEXIS, Inc. at 1-888-982-SCYX (7299).DataAnimal DataIn rat embryo-fetal study, ibrexafungerp was administered to pregnant rats by oral gavage from gestation days (GDs) through 17 at doses of 10, 20, 35, and 50 mg/kg/day. No fetal malformations or changes in embryo-fetal survival or fetal body weights occurred with any of the doses of ibrexafungerp up to the high-dose of 50 mg/kg/day (approximately times the RHD based on plasma AUC comparison). In an embryo-fetal study in rabbits, ibrexafungerp was administered by oral gavage at doses of 10, 25, and 50 mg/kg/day from GD through GD 19. In the mid-dose group administered 25 mg/kg/day (approximately times the RHD based on AUC comparison), fetal malformations, including absent ear pinna, craniorachischisis, thoracogastroschisis, trunk kyphosis, absent forelimbs, absent forepaws, and absent hindpaw occurred in single fetus. Malformations including absent hindpaw and anencephaly occurred with an increased litter incidence in the high-dose group of 50 mg/kg/day (approximately 13 times the RHD based on AUC comparison), and other malformations occurred in single fetuses and litters including absent ear pinna, thoracogastroschisis, absent forelimb, and absent thyroid gland. No changes in embryo-fetal survival or fetal body weights were observed with any of the ibrexafungerp doses, and fetal malformations were not observed with the 10 mg/kg/day dose of ibrexafungerp (approximately times the RHD based on AUC comparison).In pre-postnatal study in rats, ibrexafungerp was administered by oral gavage from GD through the lactation period until lactation day 20 in maternal doses of 10, 20, 35, and 50 mg/kg/day. No maternal toxicity or adverse effects on the survival, growth, behavior, or reproduction of first-generation offspring occurred with any of the ibrexafungerp doses up to the high dose of 50 mg/kg/day (approximately times the RHD based on AUC comparison).

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONBREXAFEMME(R) [brex fem](ibrexafungerp tablets) for oral useWhat is BREXAFEMMEBREXAFEMME is prescription medicine used to treat vaginal yeast infection. It is not known if BREXAFEMME is safe and effective in pre-adolescent females who have not started their menstruation. Do not take BREXAFEMME if you: Are pregnant or plan to become pregnant. BREXAFEMME may harm your unborn baby. Tell your healthcare provider if you are pregnant, think you might be pregnant, or plan to become pregnant. Are allergic to ibrexafungerp. Before you take BREXAFEMME, tell your healthcare provider about all of your medical conditions, including if you:See Do not take BREXAFEMME if you: Women who can become pregnant may be asked by their healthcare provider to take pregnancy test before starting treatment with BREXAFEMME. Women who can become pregnant should use effective birth control while taking BREXAFEMME and for days after the last dose of BREXAFEMME. Talk to your healthcare provider about birth control methods that may be right for you. Are breastfeeding or plan to breastfeed. It is not known if BREXAFEMME passes into your breast milk. You and your healthcare provider should decide if you will take BREXAFEMME or breast feed. BREXAFEMME may affect the way other medicines work, and other medicines may affect how BREXAFEMME works. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take BREXAFEMMETake BREXAFEMME exactly as your healthcare provider tells you to take it. Take BREXAFEMME tablets by mouth with or without food. What are the possible side effects of BREXAFEMMEThe most common side effects of BREXAFEMME include: loose stools, nausea, stomach pain, dizziness, and vomiting. These are not all the possible side effects of BREXAFEMME. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store BREXAFEMMEStore BREXAFEMME at room temperature between 68F to 77F (20C to 25C). BREXAFEMME is supplied in child resistant packaging. Keep BREXAFEMME and all medicines out of reach of children. General information about the safe and effective use of BREXAFEMME.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use BREXAFEMME for condition for which it was not prescribed. Do not give BREXAFEMME to other people even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about BREXAFEMME that is written for health professionals. What are the ingredients in BREXAFEMMEActive ingredient: ibrexafungerp Inactive ingredients: Tablet core: butylated hydroxyanisole, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, and microcrystalline cellulose. Tablet film coating: FD&C Blue 2, FD&C Red 40, hydroxypropyl cellulose, hydroxypropylmethyl cellulose 2910, talc and titanium dioxide. BREXAFEMME is registered trademark of SCYNEXIS, Inc. Manufactured for: SCYNEXIS, Inc., Jersey City, New Jersey, 07302 (C)2021 SCYNEXIS, Inc. For more information, call 1-888-982-SCYX (7299) or go to www.brexafemme.com This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 05/2021.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryBased on findings from animal studies, BREXAFEMME use is contraindicated in pregnancy because it may cause fetal harm. In pregnant rabbits, oral ibrexafungerp administered during organogenesis was associated with rare malformations including absent forelimb(s), absent hindpaw, absent ear pinna, and thoracogastroschisis at dose exposures greater or equal to approximately times the human exposure at the RHD. Oral ibrexafungerp administered to pregnant rats during organogenesis was not associated with fetal toxicity or increased fetal malformations at dose exposure approximately times the human exposure at the RHD s ee Data . Available data on BREXAFEMME use in pregnant women are insufficient to draw conclusions about any drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There is pregnancy safety study for BREXAFEMME. If BREXAFEMME is inadvertently administered during pregnancy or if pregnancy is detected within days after patient receives BREXAFEMME, pregnant women exposed to BREXAFEMME and healthcare providers should report pregnancies to SCYNEXIS, Inc. at 1-888-982-SCYX (7299).DataAnimal DataIn rat embryo-fetal study, ibrexafungerp was administered to pregnant rats by oral gavage from gestation days (GDs) through 17 at doses of 10, 20, 35, and 50 mg/kg/day. No fetal malformations or changes in embryo-fetal survival or fetal body weights occurred with any of the doses of ibrexafungerp up to the high-dose of 50 mg/kg/day (approximately times the RHD based on plasma AUC comparison). In an embryo-fetal study in rabbits, ibrexafungerp was administered by oral gavage at doses of 10, 25, and 50 mg/kg/day from GD through GD 19. In the mid-dose group administered 25 mg/kg/day (approximately times the RHD based on AUC comparison), fetal malformations, including absent ear pinna, craniorachischisis, thoracogastroschisis, trunk kyphosis, absent forelimbs, absent forepaws, and absent hindpaw occurred in single fetus. Malformations including absent hindpaw and anencephaly occurred with an increased litter incidence in the high-dose group of 50 mg/kg/day (approximately 13 times the RHD based on AUC comparison), and other malformations occurred in single fetuses and litters including absent ear pinna, thoracogastroschisis, absent forelimb, and absent thyroid gland. No changes in embryo-fetal survival or fetal body weights were observed with any of the ibrexafungerp doses, and fetal malformations were not observed with the 10 mg/kg/day dose of ibrexafungerp (approximately times the RHD based on AUC comparison).In pre-postnatal study in rats, ibrexafungerp was administered by oral gavage from GD through the lactation period until lactation day 20 in maternal doses of 10, 20, 35, and 50 mg/kg/day. No maternal toxicity or adverse effects on the survival, growth, behavior, or reproduction of first-generation offspring occurred with any of the ibrexafungerp doses up to the high dose of 50 mg/kg/day (approximately times the RHD based on AUC comparison).. 8.2 Lactation. Risk SummaryThere are no data on the presence of ibrexafungerp in either human or animal milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BREXAFEMME and any potential adverse effects on the breastfed child from BREXAFEMME or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential. Based on animal data, BREXAFEMME may cause fetal harm when administered to pregnant female [see Use in Specific Populations 8.1 ]. Pregnancy TestingVerify the pregnancy status in females of reproductive potential prior to initiating treatment with BREXAFEMME s ee Dosage and Administration 2.3 , Contraindications 4 and Use in Specific Population ( 8.1 ]. ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with BREXAFEMME and for days after the last dose.. 8.4 Pediatric Use. The safety and effectiveness of BREXAFEMME for treatment of VVC have been established in post-menarchal pediatric females. Use of BREXAFEMME in post-menarchal pediatric patients is supported by evidence from adequate and well-controlled studies of BREXAFEMME in adult non-pregnant women with additional safety data from post-menarchal pediatric females [see Adverse Reactions 6.1 and Clinical Studies (14.1) ]. The safety and effectiveness of BREXAFEMME have not been established in pre-menarchal pediatric females.. 8.5 Geriatric Use. Clinical studies with ibrexafungerp did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. No clinically meaningful differences in the pharmacokinetics of ibrexafungerp were observed in geriatric patients compared to younger adults see Clinical Pharmacology 12.3 ].

BOXED WARNING SECTION.

WARNING: RISK OF EMBRYO-FETAL TOXICITY. BREXAFEMME is contraindicated in pregnancy because it may cause fetal harm based on findings from animal reproductive studies [see Contraindications (4) and Warnings and Precautions (5.1)]. For females of reproductive potential, verify that the patient is not pregnant prior to initiating BREXAFEMME treatment. Reassessing pregnancy status prior to each dose is recommended when BREXAFEMME is used monthly for months for reduction in the incidence of recurrent vulvovaginal candidiasis (RVVC) [see Dosage and Administration (2.3), Warnings and Precautions (5.1) and Use in Specific Populations (8.3)]. Advise females of reproductive potential to use effective contraception during treatment of vulvovaginal candidiasis (VVC) and throughout the 6-month treatment period for reduction in the incidence of RVVC with BREXAFEMME and, for days after the last dose [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].. BREXAFEMME is contraindicated in pregnancy because it may cause fetal harm based on findings from animal reproductive studies [see Contraindications (4) and Warnings and Precautions (5.1)]. For females of reproductive potential, verify that the patient is not pregnant prior to initiating BREXAFEMME treatment. Reassessing pregnancy status prior to each dose is recommended when BREXAFEMME is used monthly for months for reduction in the incidence of recurrent vulvovaginal candidiasis (RVVC) [see Dosage and Administration (2.3), Warnings and Precautions (5.1) and Use in Specific Populations (8.3)]. Advise females of reproductive potential to use effective contraception during treatment of vulvovaginal candidiasis (VVC) and throughout the 6-month treatment period for reduction in the incidence of RVVC with BREXAFEMME and, for days after the last dose [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].. WARNING: RISK OF EMBRYO-FETAL TOXICITYSee full prescribing information for the complete boxed warning.BREXAFEMME is contraindicated in pregnancy because it may cause fetal harm based on findings from animal reproductive studies. (4, 5.1)For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment. Reassessing pregnancy status prior to each dose is recommended when BREXAFEMME is used monthly for months for reduction in the incidence of recurrent vulvovaginal candidiasis (RVVC). (2.3, 5.1)Advise females of reproductive potential to use effective contraception during treatment of vulvovaginal candidiasis (VVC) and throughout the 6-month treatment period for reduction in the incidence of RVVC with BREXAFEMME and for days after the last dose. (5.1, 8.3). BREXAFEMME is contraindicated in pregnancy because it may cause fetal harm based on findings from animal reproductive studies. (4, 5.1). For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment. Reassessing pregnancy status prior to each dose is recommended when BREXAFEMME is used monthly for months for reduction in the incidence of recurrent vulvovaginal candidiasis (RVVC). (2.3, 5.1). Advise females of reproductive potential to use effective contraception during treatment of vulvovaginal candidiasis (VVC) and throughout the 6-month treatment period for reduction in the incidence of RVVC with BREXAFEMME and for days after the last dose. (5.1, 8.3).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Treatment of VVCA total of 545 patients were exposed to BREXAFEMME in two clinical trials of post-menarchal females with VVC (Trial and Trial 2). The patients were treated with BREXAFEMME 300 mg (two 150 mg tablets) twice day, 12 hours apart, for one day. The patients were 18 to 76 years of age (mean 34 years); 69% were White and 28% were Black or African American; 18% were of Hispanic or Latina ethnicity. The most frequently reported adverse reactions are presented in Table 1.There were no serious adverse reactions and out of 545 (0.4%) patients discontinued treatment with BREXAFEMME due to vomiting (1 patient) and dizziness (1 patient). Table 1. Adverse Reactions with Rates >=2% in BREXAFEMME-Treated Patients with VVC in Trials and 2Adverse ReactionBREXAFEMMEN 545 (%) PlaceboN 275 (%) Diarrhea Nausea Abdominal pain Dizziness Vomiting 91 (16.7%) 65 (11.9%) 62 (11.4%) 18 (3.3%) 11 (2.0%) (3.3%) 11 (4.0%) 14 (5.1%) (2.5%) (0.7%) Includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort Includes dizziness and postural dizziness Other Adverse ReactionsThe following adverse reactions occurred in 2% of patients receiving BREXAFEMME in Trial and Trial 2: dysmenorrhea, flatulence, back pain, elevated transaminases, vaginal bleeding, rash/hypersensitivity reaction.Reduction in the Incidence of RVVCA total of 130 patients were exposed to BREXAFEMME in clinical trial of post-menarchal females with RVVC (Trial 3). The patients were treated with BREXAFEMME 300 mg (two 150 mg tablets) twice day, 12 hours apart, for one day, monthly for six consecutive months. The patients were 18 to 65 years of age (mean 34 years), of which, 59% of patients were between 18 to 35 years, and 41% between 36 to 65 years. Ninety two percent (92%) were White, 7% were Black or African American, and 1% were Asian. Nine percent (9%) of patients were of Hispanic or Latina ethnicity.The most frequently reported adverse reactions are presented in Table 2.There were no serious adverse reactions and no patients discontinued treatment with BREXAFEMME due to adverse reaction.Table 2. Adverse Reactions with Rates >=2% in BREXAFEMME-Treated Patients with RVVC in Trial 3Adverse Reaction1BREXAFEMMEN 130 (%) PlaceboN 130 (%) Headache Abdominal pain Diarrhea Nausea Urinary tract infection Fatigue 23 (17.6) 13 (10.0) 10 (7.7) (5.4) (3.8) (3.1) 10 (7.6) (6.9) (3.8) (3.8) 1(0.8) 1 single patient may have had multiple instances of adverse reactions. Only one episode of adverse reaction is counted per patient Includes abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEBREXAFEMME(R) [brex fem](ibrexafungerp tablets) for oral useWhat is the most important information should know about BREXAFEMME BREXAFEMME may cause serious side effects, including: Harm to your unborn baby. Treatment with BREXAFEMME during pregnancy can cause harm to your unborn baby. Women who can become pregnant may be asked by their healthcare provider to take pregnancy test before each treatment with BREXAFEMME. Women who can become pregnant should use effective birth control throughout the duration of treatment with BREXAFEMME and for days after the last dose of BREXAFEMME. Talk to your healthcare provider about birth control methods that may be right for you. See Do not take BREXAFEMME if you:What is BREXAFEMMEBREXAFEMME is prescription medicine used to treat vaginal yeast infection and reduce the number of recurrent vaginal yeast infections in adults and adolescent females who have started their menstruation. It is not known if BREXAFEMME is safe and effective in pre-adolescent females who have not started their menstruation.Do not take BREXAFEMME if you: Are pregnant or plan to become pregnant. BREXAFEMME may harm your unborn baby. Tell your healthcare provider if you are pregnant, think you might be pregnant, or plan to become pregnant. Are allergic to ibrexafungerp.Before you take BREXAFEMME, tell your healthcare provider about all of your medical conditions, including if you:Are breastfeeding or plan to breastfeed. It is not known if BREXAFEMME passes into your breast milk. You and your healthcare provider should decide if you will take BREXAFEMME or breast feed.BREXAFEMME may affect the way other medicines work, and other medicines may affect how BREXAFEMME works. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take BREXAFEMMETake BREXAFEMME exactly as your healthcare provider tells you to take it. Take BREXAFEMME tablets by mouth with or without food.What are the possible side effects of BREXAFEMMESee What is the most important information should know about BREXAFEMMEThe most common side effects of BREXAFEMME include headache, loose stools, nausea, stomach pain, dizziness, and vomiting. These are not all the possible side effects of BREXAFEMME. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store BREXAFEMMEStore BREXAFEMME at room temperature between 68F to 77F (20C to 25C). BREXAFEMME is supplied in child resistant packaging. Keep BREXAFEMME and all medicines out of reach of children.General information about the safe and effective use of BREXAFEMME.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use BREXAFEMME for condition for which it was not prescribed. Do not give BREXAFEMME to other people even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about BREXAFEMME that is written for health professionals. What are the ingredients in BREXAFEMMEActive ingredient: ibrexafungerp Inactive ingredients: Tablet core: butylated hydroxyanisole, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, and microcrystalline cellulose. Tablet film coating: FD&C Blue 2, FD&C Red 40, hydroxypropyl cellulose, hydroxypropylmethyl cellulose 2910, talc and titanium dioxide. BREXAFEMME is registered trademark of SCYNEXIS, Inc. Manufactured for: SCYNEXIS, Inc., Jersey City, New Jersey, 07302 (C)202 SCYNEXIS, Inc. For more information, call 1-888-982-SCYX (7299) or go to www.brexafemme.com This Medication Guide -has been approved by the U.S. Food and Drug Administration Revised: 11/2022. Harm to your unborn baby. Treatment with BREXAFEMME during pregnancy can cause harm to your unborn baby. BREXAFEMME is prescription medicine used to treat vaginal yeast infection and reduce the number of recurrent vaginal yeast infections in adults and adolescent females who have started their menstruation. It is not known if BREXAFEMME is safe and effective in pre-adolescent females who have not started their menstruation.. Are pregnant or plan to become pregnant. BREXAFEMME may harm your unborn baby. Tell your healthcare provider if you are pregnant, think you might be pregnant, or plan to become pregnant. Are allergic to ibrexafungerp.. Are breastfeeding or plan to breastfeed. It is not known if BREXAFEMME passes into your breast milk. You and your healthcare provider should decide if you will take BREXAFEMME or breast feed.. Take BREXAFEMME exactly as your healthcare provider tells you to take it. Take BREXAFEMME tablets by mouth with or without food.. See What is the most important information should know about BREXAFEMME. Store BREXAFEMME at room temperature between 68F to 77F (20C to 25C). BREXAFEMME is supplied in child resistant packaging.