DRUG INTERACTIONS-(summary)

 • Concomitant use of strong CYP3A inhibitors increases the exposure of ibrexafungerp. Reduce BREXAFEMME dose with concomitant use of a strong CYP3A inhibitor to 150 mg twice daily for one day.

 • 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.

BRIEF SUMMARY

IBREXAFUNGERP tablets-(June 2021)

Indn- To treat vulvovaginal cndidiatis in adult females and pediatric females who have been menstruating 

Comp- Tablets: 150 mg of ibrexafungerp. The recommended dosage of BREXAFEMME in adult and post-menarchal pediatric females is 300 mg (two tablets of 150 mg) twice a day for one day, for a total treatment dosage of 600 mg. •  may be taken with or without food.

ADR-  The most frequent adverse reactions reported  in clinical trials of vulvovaginal candidiasis treatment were diarrhea, nausea, abdominal pain, dizziness, and vomiting.

CI-  ­ • Pregnancy   Hypersensitivity to ibrexafungerp. 

WARNINGS - 

­ Risk of Fetal Toxicity: May cause fetal harm based on animal studies. Advise females of reproductive potential to use effective contraception during treatment.

Pat Inform-

Risk of Fetal Toxicity-  is contraindicated in pregnancy since it may cause fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy

Advise patients who have inadvertently taken during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes.

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U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 26

Name of the Drug-    BREXAFEMME

Active Ingredient -   Ibrexafungerp tablets

Pharmacological Classification-    To treat vulvovaginal cndidiatis in adult females                                                              and pediatric females who have been                                                                              menstruating                                                                                                                                                                                           

   Date of Approval-          6/1/2021                                                                                                                                              

HIGHLIGHTS OF PRESCRIBING INFORMATION -                           

These highlights do not include all the information needed to use                          BREXAFEMME® safely and effectively.

See full prescribing information for BREXAFEMME®. BREXAFEMME® (ibrexafungerp tablets), for oral use

Initial US Approval: 2021

INDICATIONS AND USAGE- 

­ BREXAFEMME is a triterpenoid antifungal indicated for the treatment of adult and post-menarchal pediatric females with vulvovaginal candidiasis (VVC).

DOSAGE AND ADMINISTRATION- 

­ • The recommended dosage of BREXAFEMME in adult and post-menarchal pediatric females is 300 mg (two tablets of 150 mg) twice a day for one day, for a total treatment dosage of 600 mg.

 • BREXAFEMME may be taken with or without food. (2.1) • Prior to initiating treatment, verify pregnancy status in females of reproductive potential. (2.3) --

DOSAGE FORMS AND STRENGTHS-

­ Tablets: 150 mg of ibrexafungerp

CONTRAINDICATIONS

­ • Pregnancy (4) • Hypersensitivity to ibrexafungerp. (4)

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.

CONTRAINDICATIONS

­ • Pregnancy  • Hypersensitivity to ibrexafungerp. 

WARNINGS AND PRECAUTIONS- 

­ Risk of Fetal Toxicity: May cause fetal harm based on animal studies. Advise females of reproductive potential to use effective contraception during treatment.

.

DOSAGE AND ADMINISTRATION- 

­ • The recommended dosage of BREXAFEMME in adult and post-menarchal pediatric females is 300 mg (two tablets of 150 mg) twice a day for one day, for a total treatment dosage of 600 mg.

 • BREXAFEMME may be taken with or without food. (2.1) • Prior to initiating treatment, verify pregnancy status in females of reproductive potential. (2.3) --

DOSAGE FORMS AND STRENGTHS-

­ Tablets: 150 mg of ibrexafungerp

 PATIENT COUNSELING INFORMATION-

Advise the patient to read the FDA approved patient labeling (Patient Information)

Risk of Fetal Toxicity-                                                                                             BREXAFEMME is contraindicated in pregnancy since it may cause fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy

Advise patients who have inadvertently taken BREXAFEMME during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes.

Encourage these patients to report their pregnancy to SCYNEXIS, Inc. at 1-888-982-7299 

Advise females of reproductive potential to use effective contraception while taking BREXAFEMME and for 4 days after the last dose.

Important Administration Instructions- Inform the patient that each BREXAFEMME dose consists of two tablets.

A total treatment course is two doses taken approximately 12 hours apart and consists of a 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 

Concomitant Medications -                                                                                       Advise 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 .

Manufactured for: SCYNEXIS, Inc. Jersey City, NJ Patent: www.scynexis.com/product/patent BREXAFEMME® is a registered trademark of SCYNEXIS, Inc.

 CLINICAL PHARMACOLOGY

1. Mechanism of Action Ibrexafungerp is a triterpenoid antifungal drug 

2. Pharmacodynamics-                                                                                           Ibrexafungerp exposure-response relationships and the time course of pharmacodynamic response are unknown.

Cardiac Electrophysiology-  At a concentration of 5 times or greater than that achieved after a single day 300 mg twice daily dose, ibrexafungerp does not prolong the QTc interval to any clinically relevant extent.

3. Pharmacokinetics- In healthy subjects, ibrexafungerp area under the curve (AUC) and maximal concentration (Cmax) 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).

 Absorption- After oral administration of BREXAFEMME in healthy volunteers, ibrexafungerp generally reaches maximum plasma concentrations 4 to 6 hours after single and multiple dosing.

Effect of Food- Following administration of BREXAFEMME to healthy volunteers, the ibrexafungerp Cmax increased 32% and the AUC increased 38% with a high fat meal (800-1000 calories; 50% fat), compared to fasted conditions. This exposure change is not considered clinically significant 

Distribution- The 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 a 9-fold higher exposure in vaginal tissue than in blood.

Elimination-  Ibrexafungerp is eliminated mainly via metabolism and biliary excretion. The elimination halflife is approximately 20 hours. Metabolism In vitro studies show that ibrexafungerp undergoes hydroxylation by CYP3A4, followed by glucuronidation and sulfation of a hydroxylated inactive metabolite.

Excretion -Following oral administration of radio-labeled ibrexafungerp to healthy volunteers, a mean of 90% of the radioactive dose (51% as unchanged ibrexafungerp) was recovered in feces and 1% was recovered in urine.

Specific Populations -Geriatric Patients- A 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 AUC0-inf (90% CI) was 1.39 (1.19, 1.62).

Dose adjustment for age is not required.

Drug Interaction Studies- Ibrexafungerp is a 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 Pharmacokinetics -                      Strong CYP3A4 Inhibitor: Ketoconazole (400 mg once daily for 15 days), a strong CYP3A4 and P-gp inhibitor, increased the ibrexafungerp AUC by 5.8-fold and Cmax by 2.5-fold 

Moderate CYP3A4 Inhibitor: Diltiazem (240 mg once daily for 15 days) increased the ibrexafungerp AUC by 2.5-fold and Cmax 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 5 days) decreased ibrexafungerp AUC by approximately 25% and Cmax 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 AUC0-inf or Cmax of rosiglitazone, a moderate sensitive CYP2C8 substrate.

CYP3A4 substrates: Ibrexafungerp resulted in 1.4-fold increase in the AUC0-inf and no effect on the Cmax of the sensitive CYP3A4 and P-gp substrate tacrolimus.

P-gp substrates: Ibrexafungerp resulted in a 1.4-fold increase in the AUC0-48 and a 1.25-fold increase in the Cmax of the P-gp substrate dabigatran.

OATP1B3 transporters: Ibrexafungerp resulted in a 2.8-fold increase in the AUC0-24 and a 3.5 fold increase in the Cmax of the OATP1B3 transporter substrate pravastatin. R

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

Based on findings from animal studies, BREXAFEMME use is contraindicated in pregnancy because it may cause fetal harm.

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 a pregnancy safety study for BREXAFEMME. If BREXAFEMME is inadvertently administered during pregnancy or if pregnancy is detected within 4 days after a patient receives BREXAFEMME, pregnant women exposed to BREXAFEMME and healthcare providers should report pregnancies to SCYNEXIS, Inc. at 1-888-982-SCYX (7299).

2 Lactation Risk Summary-                                                                                            There 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 mother’s clinical need for BREXAFEMME and any potential adverse effects on the breastfed child from BREXAFEMME or from the underlying maternal condition.

3. Females and Males of Reproductive Potential -                                                 Based on animal data, BREXAFEMME may cause fetal harm when administered to a pregnant female 

Pregnancy Testing- Verify the pregnancy status in females of reproductive potential prior to initiating treatment with BREXAFEMME

Contraception- Females- Advise females of reproductive potential to use effective contraception during treatment with BREXAFEMME and for 4 days after the last dose.

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 

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

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

OVERDOSAGE -

There is no experience with overdosage of BREXAFEMME. There is no specific antidote for ibrexafungerp. Treatment should be supportive with appropriate monitoring.