Ibrexafungerp

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# Black Box Warning

# Overview
Ibrexafungerp is a triterpenoid antifungal that is FDA approved for the treatment of vulvovaginal candidiasis. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include nausea, dizziness, diarrhea, vomiting, and abdominal pain.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Treatment of VVC
- 300 mg Ibrexafungerp given 12 hours apart (600 mg in a day) for adult and post-menarchal pediatric females for one day of treatment.
- Total of four 150 mg tablets each day, two tablets every 12 hours for one day.
Reduction in the Incidence of RVVC
- 300 mg Ibrexafungerp given 12 hours apart (600 mg) for adult and post-menarchal pediatric females for one day.
- Dosages are given monthly for a total of 6 consecutive months of treatment.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ibrexafungerp in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ibrexafungerp in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ibrexafungerp FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ibrexafungerp in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ibrexafungerp in pediatric patients.

# Contraindications
- Pregnancy.
- Hypersensitive patients towards Ibrexafungerp.

# Warnings
Risk of Embryo-Fetal Toxicity
- Ibrexafungerp may cause fetal harm causing it to be contradicted in pregnancy.
- Absent ear pinna, absent forelimb, thoracogastroschisis, and absent hindpaw were some of the fetal malformations observed in pregnant rabbits given dosages that were greater or equal to 5 times the recommended dosage for humans.
- Advise female patients to take a pregnancy test before initiation of Ibrexafungerp treatment.
- Monitor a females pregnancy status throughout the treatment to ensure that female is not pregnant during treatment.
- Advise females of reproductive potential to use effective contraceptive methods during and for 4 days after the last dose of Ibrexafungerp treatment.

# Adverse Reactions

## Clinical Trials Experience
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a 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 VVC
- Trial 1 and 2 was made up of a population pool of 545 patients that were post-menarchal females with VVC.
- Patients were mostly White (68%) and ranged from 18 years of age to 76 years of age.
- Patients were given 300 mg of Ibrexafungerp 12 hours apart for one day (twice in the day).
- No serious adverse reactions reported by patients in the study.
- 2 patients had to discontinue Ibrexafungerp treatment due to dizziness and vomiting.
Table 1 summarizes Adverse Reactions with Rates 2% in BREXAFEMME-Treated Patients with VVC in Trials 1 and 2.
Insert Table 1
Other Adverse Reactions
- Flatulence, elevated transaminases, dysmenorrhea, rash/hypersensitivity reaction, and vaginal bleeding were also observed in Trial 1 and Trial 2.
Reduction in the Incidence of RVVC
- Trial 3 study was made up of a population pool of 130 patients that were post-menarchal females with RVVC.
- Patient population was mostly White (92%) and had ages ranging from 18 to 65 years of age.
- Patients were given 300 mg of Ibrexafungerp 12 hours apart for one day monthly for 6 consecutive months.
- No discontinuation or serious adverse reactions reported by patients in this trial.
Table 2 summarizes Adverse Reactions with Rates 2% in BREXAFEMME-Treated Patients with RVVC in Trial 3.
Insert Table 2

## Postmarketing Experience
There is limited information regarding Ibrexafungerp Postmarketing Experience in the drug label.

# Drug Interactions
- A substrate of CYP3A4 is Ibrexafungerp.
- Safety and efficacy of Ibrexafungerp can be altered, specifically plasma concentrations, by drugs that induce or inhibit CYP3A.
- P-gp, CYP3A4, and OATP1B3 transporter can be inhibited by Ibrexafungerp.
- Pharmacokinetic differences of P-gp, CYP3A4, and OATP1B3 transporters are not clinically significant during short treatment of VVC using Ibrexafungerp.
Table 3 summarizes Effect of Coadministered Drugs on Ibrexafungerp Pharmacokinetics.
Insert Table 3

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Fetal harm may occur with Ibrexafungerp based on animal studies. Data on pregnant humans is insufficient when looking into Ibrexafungerp effects on any drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Absent ear pinna, absent forelimb, thoracogastroschisis, and absent hindpaw were some of the fetal malformations observed in pregnant rabbits given dosages that were greater or equal to 5 times the recommended dosage for humans (25 mg/kg/day of Ibrexafungerp). Increased litter incidence was observed in pregant rabbits receiving 50 mg/kg/day of Ibrexafungerp. Pregnant rats did not have any fetal malformations or changes in embryo-fetal survival or fetal body weights when given doses up to 50 mg/kg/day of Ibrexafungerp.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ibrexafungerp in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Ibrexafungerp during labor and delivery.

### Nursing Mothers
No current data has been done on the effects of Ibrexafungerp on the breastfed infant and the effects on milk production in women when treated with Ibrexafungerp. Advise nursing patients about any potential adverse effects caused by Ibrexafungerp on the child.

### Pediatric Use
Post-menarchal pediatric patients usage of Ibrexafungerp is supported by clinical studies conducted on dult non-pregnant women with additional pharmacokinetic and safety data from post-menarchal pediatric females.

### Geriatic Use
When looking at the pharmacokinetics of geriatric patients compared to younger adults, there are no clinically meaningful differences.

### Gender
There is no FDA guidance on the use of Ibrexafungerp with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ibrexafungerp with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Ibrexafungerp in patients with renal impairment.

### Hepatic Impairment
Patients with mild or moderate hepatic impairment do not require dosage adjustment to Ibrexafungerp treatment.

### Females of Reproductive Potential and Males
Fetal harm may occur when Ibrexafungerp is given to pregnant females. Advise female patients with reproductive potential to take a pregnancy test before and during Ibrexafungerp treatment. Advise female patients with reproductive potential to use effective contraception during and 4 days after Ibrexafungerp treatment for VVC. Advise female patients with reproductive potential to use effective contraception during 6 month treatment to reduce incidence of RVVC and 4 days after Ibrexafungerp treatment.

### Immunocompromised Patients
There is no FDA guidance one the use of Ibrexafungerp in patients who are immunocompromised.

# Administration and Monitoring

### Administration
There is limited information regarding Ibrexafungerp Administration in the drug label.

### Monitoring
Dosage Modifications in Patients due to Concomitant Use of a Strong Inhibitor of Cytochrome P450 Isoenzymes (CYP) 3A
- Give 150 mg Ibrexafungerp 12 hours apart for one day with concomitant use of a strong CYP3A inhibitor.
- Concomitant use of a weak or moderate CYP3A inhibitor with Ibrexafungerp did not require a dosage adjustment.
- Verify a female patient with reproductive success is not pregnant before or during Ibrexafungerp treatment.

# IV Compatibility
There is limited information regarding the compatibility of Ibrexafungerp and IV administrations.

# Overdosage
- No experience of overdosage of Ibrexafungerp.
- No specific antidote for Ibrexafungerp.

# Pharmacology
There is limited information regarding Ibrexafungerp Pharmacology in the drug label.

## Mechanism of Action
- Ibrexafungerp is a triterpenoid antifungal drug.

## Structure
- The empirical formula of Ibrexafungerp is C44H67N5O4 - C6H8O7.
- The molecular weight of Ibrexafungerp is 922.18 grams.
Insert Structure

## Pharmacodynamics
- Ibrexafungerp pharmacodynamic responses are unknown.
Cardiac Electrophysiology
- QTc interval is not prolonged by ibrexafungerp at a concentration of 5 times or greater than that achieved after a single day 300 mg twice daily dose.

## Pharmacokinetics
- When given a single dose administration from 10 to 1600 mg of Ibrexafungerp, the Cmax and AUC of Ibrexafungerp increased approximately dose-proportionally.
- When given multiple dose 300-800 mg of Ibrexafungerp, the Cmax and AUC of Ibrexafungerp increased approximately dose-proportionally.
- 6832 nghr/mL was the mean AUC 0-24 exposure when patients with VCC were given 300 mg twice a day for 2 doses of Ibrexafungerp under fasted conditions.
- 435 ng/mL was the mean Cmax when patients with VCC were given 300 mg twice a day for 2 doses of Ibrexafungerp under fasted conditions.
- 9867 nghr/mL was the mean AUC 0-24 exposure when patients with VCC were given 300 mg twice a day for 2 doses of Ibrexafungerp under fed conditions.
- 629 ng/mL was the mean Cmax when patients with VCC were given 300 mg twice a day for 2 doses of Ibrexafungerp under fed conditions.
Absorption
- After single and multiple dosing, maximum plasma concentrations occurs from 4 to 6 hours for Ibrexafungerp.
Effect of Food
- There was a 32% increase in Cmax for Ibrexafungerp with a high fat meal when compared to fasted conditions.
- There was a 38% increase in AUC for Ibrexafungerp with a high fat meal when compared to fasted conditions.
- Changes in exposure are not considered clinically significant.
Distribution
- For Ibrexafungerp, 600 L is the mean steady state volume of distribution.
- Ibrexafungerp is highly protein bound.
Elimination
- Biliary excretion and metabolism are primary methods in eliminating Ibrexafungerp.
- For Ibrexafungerp, 20 hours is the elimination half-life.
Metabolism
- CYP3A4 hydroxylates Ibrexafungerp in vitro studies,followed by glucuronidation and sulfation of a hydroxylated inactive metabolite
Excretion
- 90% of the radioactive dose of Ibrexafungerp was recovered in feces when patients were given  radio-labeled ibrexafungerp orally.
- 51% of the radioactive dose of Ibrexafungerp that was recovered in feces, was found unchanged when patients were given radio-labeled ibrexafungerp orally.
- 1% of the radioactive dose of Ibrexafungerp was recovered in urine when patients were given  radio-labeled ibrexafungerp orally.
Specific Populations 
Post-Menarchal Pediatric Females and Geriatric Patients
- For Ibrexafungerp, geriatric patients and post-menarchal pediatric females did not experience changes to pharmacokinetics.
Patients with Hepatic Impairment
- Patients with mild to moderate hepatic impairment did not experience changes to pharmacokinetics when compared to healthy patients.
Drug Interaction Studies
- The substrate of P-gp and CYP3A4 is Ibrexafungerp.
- P-gp transporter, CYP2C8, OATP1B3 transporter, and CYP3A4 are inhibited by Ibrexafungerp.
- CYP3A4 is not induced by Ibrexafungerp.
Effect of Coadministered Drugs on Ibrexafungerp Pharmacokinetics
Strong  CYP3A4 Inhibitor:
- The was a 5.8-fold increase of AUC in Ibrexafungerp when coadministered with Ketoconazole, a strong CYP3A4 and P-gp inhibitor.
- The was a 2.5-fold increase of Cmax in Ibrexafungerp when coadministered with Ketoconazole, a strong CYP3A4 and P-gp inhibitor.
Moderate CYP3A4 Inhibitor:
- The was a 2.5-fold increase of AUC in Ibrexafungerp when coadministered with Diltiazem.
- The was a 2.2-fold increase of Cmax in Ibrexafungerp when coadministered with Diltiazem.
- Exposure changes are not clinically significant.
Proton Pump Inhibitor:
- The was a 25% decrease of AUC in Ibrexafungerp when coadministered with Pantoprazole.
- The was a 22% decrease of Cmax in Ibrexafungerp when coadministered with Pantoprazole.
- Exposure changes are not clinically significant.
Effect of Ibrexafungerp on the Pharmacokinetics of Coadministered Drugs
CYP2C8 substrates:
- The C max or AUC 0-inf of Rosiglitazone were not increased by Ibrexafungerp.
CYP3A4 substrates:
- Ibrexafungerp caused a 1.4-fold increase in the AUC 0-i of the P-gp substrate tacrolimus and CYP3A4.
- Ibrexafungerp had no effects on the C max of the P-gp substrate tacrolimus and CYP3A4.
P-gp substrates:
- Ibrexafungerp caused a 1.4-fold increase in the AUC 0-i of the P-gp substrate dabigatran.
- Ibrexafungerp caused a 1.25-fold increase in the Cmax of the P-gp substrate dabigatran.
OATP1B3 transporters:
- Ibrexafungerp caused a 2.8-fold increase in the AUC 0-i of the OATP1B3 transporter substrate pravastatin.
- Ibrexafungerp caused a 3.5-fold increase in the Cmax of the OATP1B3 transporter substrate pravastatin.

## Nonclinical Toxicology
Carcinogenesis
- No carcinogenicity studies have been conducted on Ibrexafungerp.
Mutagenesis
- In vitro chromosomal aberration assay, vitro bacterial reverse mutation assay, and vivo bone marrow micronucleus assay, no clastogenic or mutagenic effects on rats were detected.
Impairment of Fertility
- When looking at male and female fertility study in rats, fertility was not impaired  in either sex when given doses up to 80 mg/kg/day Ibrexafungerp.
Animal Toxicity and/or Pharmacology
- There were signs in rats of marked, but reversible, phospholipidosis, marked irritation and metaplasia in gastric mucosa, foamy histiocytes in alveolar tissue in the lung and labored breathing, and peripheral nerve degeneration accompanied by hind-limb paralysis when given does of up to 80 mg/kg/day of Ibrexafungerp for a 26 week period.

# Clinical Studies
Treatment of VVC
- The safety and efficacy of Ibrexafungerp was tested in Trial 1 and 2 clinical studies.
- Patients, with VVC, were given two 150 mg tablets per dose, administered 12 hours apart for a single day.
- VVC diagnosis was defined as minimum composite vulvovaginal signs and symptoms (VSS) score of 4 with at least two signs or symptoms having a score of 2 (moderate) or greater. It also includes a positive microscopic examination with 10% KOH in a vaginal sample revealing yeast forms (hyphae/pseudohyphae) or budding yeasts, and (c) normal vaginal pH (4.5).
- Trial 1 had a patient population that consisted of 100 patients who received a placebo and 190 patients treated with Ibrexafungerp.
- The patient population had an average age of 34 years of age, majority White (81%), and an average BMI of 26.
- 9 was the median VSS score of Trial 1 patients.
- 92% of subjects in Trial 1 were culture-positive with  C. albicans.
- Trial 2 had a patient population that consisted of 89 patients who received a placebo and 189 patients treated with Ibrexafungerp.
- The patient population had an average age of 34 years of age, majority White (81%), and an average BMI of 26.
- 10 was the median VSS score of Trial 1 patients.
- 89% of subjects in Trial 1 were culture-positive with  C. albicans.
Table 4 summarizes Clinical and Mycological Response in Post-menarchal Females with VVC in Trials 1 and 2, MITT Population.
Insert Table 4
Reduction in the Incidence of RVVC
- Trial 3 clinical study looked into the safety and efficacy of Ibrexafungerp when patients were given two 150 mg tablets of Ibrexafungerp 12 hours apart for one day.
- Patients were either part of the group that received double-blind Ibrexafungerp or the group that received the placebo.
- The trial was a single-day treatment repeated every 4 weeks for a total of 6 single-day treatments.
- The patient population consisted of 130 patients who received the placebo and 130 patients who received Ibrexafungerp.
- The patient population was mostly White (90%), with an average age of 34, and an average BMI of 25.
- Clinical success was used to determine the efficacy of Ibrexafungerp.
- Clinical success is defined as subjects with No Culture Proven, Presumed or Suspected Recurrence of VVC requiring antifungal therapy up to TOC at Week 24.
Table 5 summarizes  Clinical and Mycological Response in Post-menarchal Females with RVVC in Trial 3, ITT Population.
Insert Table 5

# How Supplied
- 150 mg of Ibrexafungerp per tablet.
- Ibrexafungerp are purple, biconvex shaped tablets.

## Storage
- Store Ibrexafungerp at 20C to 25C.
- It is permitted if there is brief exposure of Ibrexafungerp tablets to 15C to 30C.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Risk of Embryo-Fetal Toxicity
- Ibrexafungerp is contraindicated in pregnancy due to the potential it has to cause harm to the fetus.
- Advise female patients with potential to reproduce to take a pregnancy test before to confirm patient is not pregnant.
- Advise female patients with potential to reproduce to reassess pregnancy status during Ibrexafungerp treatment.
- Advise female patients with reproductive potential to use effective contraception during and 4 days after Ibrexafungerp treatment for VVC.
- Advise female patients with reproductive potential to use effective contraception during 6 month treatment to reduce incidence of RVVC and 4 days after Ibrexafungerp treatment.
- Advise female patients to inform doctor if they have a suspected or know pregnancy during Ibrexafungerp treatment.
- Encourage female patients that took Ibrexafungerp during pregnancy to report their pregnancy to SCYNEXIS, Inc. at 1-888-982-7299.
Important Administration Instructions
- One dose for patients using Ibrexafungerp to treat VVC is 2 tablets.
- Total treatment should be two doses (4 tablets) taken approximately 12 hours apart for patients using Ibrexafungerp to treat VVC.
- 6 months is total treatment time for patients using Ibrexafungerp to reduce the incidence of RVVC.
- Two tablets of Ibrexafungerp should be taken 12 hours apart monthly for a total of 6 months.
- If 2 tablets of Ibrexafungerp are taken in the morning, then 2 more tablets should be taken in the evening of the same day.
- If 2 tablets of Ibrexafungerp are taken in the afternoon, then 2 more tablets should be taken in the morning of the following day.
- Ibrexafungerp tablets can be taken with or without food.
Concomitant Medications
- Advise patients that use of other medications with Ibrexafungerp can cause increase or decrease blood concentrations of Ibrexafungerp.
- Advise patients that use of other medications with Ibrexafungerp can cause increase or decrease blood concentrations of other medications.

# Precautions with Alcohol
Alcohol-Ibrexafungerp interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Brexafemme

# Look-Alike Drug Names
There is limited information regarding Ibrexafungerp Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price