Ibrexafungerp Citrate (Monograph)

Drug class: Triterpenoids

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Warning

Ibrexafungerp is contraindicated in pregnancy because it may cause fetal harm based on findings from animal reproductive studies.
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 ibrexafungerp is used monthly for 6 months for reduction in the incidence of recurrent vulvovaginal candidiasis.
Advise females of reproductive potential to use effective contraception during treatment of vulvovaginal candidiasis and throughout the 6-month treatment period for reduction in the incidence of recurrent vulvovaginal candidiasis with ibrexafungerp and for 4 days after the last dose.

Introduction

Triterpenoid antifungal drug.

Uses for Ibrexafungerp Citrate

Vulvovaginal Candidiasis

Treatment of vulvovaginal candidiasis in adult and post-menarchal females.

CDC and IDSA treatment guidelines recommend topical (i.e., intravaginal) azole antifungal in single-dose or short-course (generally 3–7 days) regimen or single dose of oral fluconazole for uncomplicated vulvovaginal candidiasis. Ibrexafungerp not addressed in current guidelines; current clinical practice guidelines are available from CDC at [Web] and IDSA at [Web].

In weighing potential risks and benefits of oral versus intravaginal therapy, consider potential for toxicity, adverse effects, and drug interactions, as there are generally greater risks with oral therapy compared to intravaginal therapy.

Recurrent Vulvovaginal Candiasisis

Used for reduction in incidence of recurrent vulvovaginal candidiasis.

CDC and IDSA treatment guidelines define recurrent vulvovaginal candidiasis as 3 or 4 or more episodes of symptomatic vulvovaginal candidiasis in <1 year. Treatment guidelines recommend prolonged courses of treatment for recurrent vulvovaginal candidiasis, typically with induction with 7—14 days of topical azole antifungal therapy or oral fluconazole every 3 days for total of 3 doses, followed by maintenance with oral fluconazole weekly for 6 months. Ibrexafungerp is only drug currently approved by FDA for reduction in incidence of recurrent vulvovaginal candidiasis but is not addressed in current guidelines; current clinical practice guidelines are available from the CDC at [Web] and IDSA at [Web].

Ibrexafungerp Citrate Dosage and Administration

General

Pretreatment Screening

For females of reproductive potential, verify that the patient is not pregnant prior to initiating ibrexafungerp..

Patient Monitoring

When used monthly for 6 months, assess pregnancy status prior to each dose of ibrexafungerp.

Administration

Take orally with or without food.

Take doses approximately 12 hours apart. If first dose is taken in the morning, second dose should be taken the same day in the evening. If first dose is taken in the afternoon or evening, second dose should be taken the following morning.

Dosage

Available as ibrexafungerp citrate; dosage expressed in terms of ibrexafungerp.

Pediatric Patients

Treatment of Vulvovaginal Candidiasis

Oral

In post-menarchal females, 300 mg (two 150 mg tablets) administered 12 hours apart for one day (total dosage 600 mg).

Reduction in Incidence of Recurrent Vulvovaginal Candidiasis

Oral

In post-menarchal females, 300 mg (two 150 mg tablets) administered 12 hours apart for one day (total daily dosage 600 mg); repeat monthly for 6 months total.

Adults

Treatment of Vulvovaginal Candidiasis

Oral

300 mg (two 150 mg tablets) administered 12 hours apart for one day (total dosage 600 mg).

Reduction in Incidence of Recurrent Vulvovaginal Candidiasis

Oral

300 mg (two 150 mg tablets) administered 12 hours apart for one day (total daily dosage 600 mg); repeat monthly for 6 months.

Dosage Modifications for Toxicity

Reduce dosage to 150 mg administered 12 hours apart for one day with concomitant use of strong CYP3A inhibitor. No dosage adjustment needed with concomitant use of a weak or moderate CYP3A inhibitor.

Special Populations

Hepatic Impairment

No specific population dosage recommendations at this time.

Renal Impairment

No specific population dosage recommendations at this time.

Geriatric Patients

No specific population dosage recommendations at this time.

Cautions for Ibrexafungerp Citrate

Contraindications

Pregnancy.
Hypersensitivity to ibrexafungerp.

Warnings/Precautions

Warnings

Embryo-fetal Toxicity

Contraindicated in pregnancy; may cause fetal harm. (See Boxed Warning.)

Verify pregnancy status prior to initiating treatment. Reassessment of pregnancy status prior to each dose recommended when used monthly for 6 months. Advise females of reproductive potential to use effective contraception during treatment, throughout the 6-month treatment period, and for 4 days after the last dose.

Specific Populations

Pregnancy

Insufficient evidence in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

There is a pregnancy safety study for ibrexafungerp. If inadvertently administered during pregnancy or if pregnancy detected within 4 days after a patient receives ibrexafungerp, pregnant women exposed to ibrexafungerp and their clinician should report pregnancy to the manufacturer (SCYNEXIS, Inc.) at 888-982-7299 .

Lactation

No data on presence of ibrexafungerp in human milk, effects on the breast-fed child, or effects on milk production. Consider developmental and health benefits of breastfeeding along with mother’s clinical need for ibrexafungerp and any potential adverse effects on breast-fed child from drug or from underlying maternal condition.

Females and Males of Reproductive Potential

Verify pregnancy status prior to initiating treatment; reassess pregnancy status prior to each dose when used for 6 months. Advise females of reproductive potential to use effective contraception during treatment, throughout the 6-month treatment period, and for 4 days after the last dose.

Pediatric Use

Safety and effectiveness established in post-menarchal pediatric females. Safety and effectiveness have not been established in pre-menarchal pediatric females.

Geriatric Use

Clinical studies did not include sufficient numbers of subjects ≥65 years of age to determine whether they respond differently than younger subjects. No clinically meaningful differences in the pharmacokinetics of ibrexafungerp were observed in geriatric patients compared to younger adults.

Hepatic Impairment

Pharmacokinetics not altered in mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment; no dosage adjustment recommended. Ibrexafungerp not studied in severe (Child-Pugh class C) hepatic impairment.

Renal Impairment

Not studied in renal impairment; does not undergo significant active renal secretion.

Common Adverse Effects

Most common adverse effects (≥2%) in vulvovaginal candidasis: diarrhea, nausea, abdominal pain, dizziness, vomiting.

Most common adverse effects (≥2%) in recurrent vulvovaginal candidiasis: headache, abdominal pain, diarrhea, nausea, urinary tract infection, fatigue.

Drug Interactions

Ibrexafungerp is a substrate of CYP3A4 and an inhibitor of CYP2C8 and CYP3A4.

Ibrexafungerp is a substrate of P-glycoprotein (P-gp). Ibrexafungerp is an inhibitor of organic anion transporter polypeptide (OATP) 1B3 and P-gp.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Ibrexafungerp is a substrate and inhibitor of CYP3A4. Due to short treatment duration, effect of ibrexafungerp on the pharmacokinetics of substrates of CYP3A4 not considered clinically significant.

Drugs that inhibit or induce CYP3A may alter plasma concentrations of ibrexafungerp and may affect safety and efficacy.

Concomitant administration of ibrexafungerp with strong CYP3A4 inhibitors results in significantly increased ibrexafungerp concentrations. A reduction in ibrexafungerp dosage is recommended when used concomitantly with strong CYP3A4 inhibitors.

While not studied, concomitant administration of ibrexafungerp with strong and moderate CYP3A inducers is likely to result in significant reduction in ibrexafungerp concentration; avoid concomitant administration.

Drugs Affecting or Affected by Transport Systems

Ibrexafungerp is a substrate of P-gp. Ibrexafungerp is an inhibitor of OATP1B3 and P-gp. Due to short treatment duration, effect of ibrexafungerp on the pharmacokinetics of substrates of P-gp and OATP1B3 not considered to be clinically significant.

Specific Drugs

Drug	Interaction	Comments
Barbiturates (long-acting)	Not studied but likely to significatly reduce ibrexafungerp concentration.	Avoid concomitant administration.
Bosentan	Not studied but likely to significatly reduce ibrexafungerp concentration.	Avoid concomitant administration.
Carbamazepine	Not studied but likely to significatly reduce ibrexafungerp concentration.	Avoid concomitant administration.
Dabigatran	Increased dabigatran AUC_0-48 and C_max by 1.4- and 1.25-fold, respectively.	Not considered clinically significant.
Diltiazem	Increases ibrexafungerp AUC and C_max by 2.5- and 2.2-fold, respectively.	Not considered clinically significant.
Echinocandin Antifungals	No antagonism of antifungal activity.
Efavirenz	Not studied but likely to significatly reduce ibrexafungerp concentration.	Avoid concomitant administration.
Etravirine	Not studied but likely to significantly reduce ibrexafungerp concentration.	Avoid concomitant administration.
Itraconazole	Significantly increases ibrexafungerp concentration. No antagonism of antifungal activity.	Reduce ibrexafungerp dosage to 150 mg (instead of 300 mg/dose).
Ketoconazole	Increases ibrexafungerp AUC and C_max by 5.8- and 2.5-fold, respectively. No antagonism of antifungal activity.	Reduce ibrexafungerp dosage to 150 mg (Instead of 300 mg/dose).
Pantoprazole	Decreased ibrexafungerp AUC and C_maxby 25% and 22%, respectively.	Not considered clinically significant.
Phenytoin	Not studied but likely to significatly reduce ibrexafungerp concentration.	Avoid concomitant administration.
Pravastatin	Increased pravastatin AUC_0-24 and C_max by 2.8- and 3.5-fold, respectively.	Not considered clinically significant.
Rifampin	Not studied but likely to significatly reduce ibrexafungerp concentration.	Avoid concomitant administration.
Rosiglitazone	No clinically significant drug interaction.
St. John's Wort (Hypericum perforatum)	Not studied but likely to significatly reduce ibrexafungerp concentration.	Avoid concomitant administration.
Tacrolimus	Increased tacrolimus AUC_0-inf by 1.4-fold with no change in C_max.	Not considered clinically significant.

Ibrexafungerp Citrate Pharmacokinetics

Absorption

Onset

T_max: 4–6 hours after single and multiple dosing.

Effect of Food

AUC and maximum serum concentration (C_max) increase 38% and 32%, respectively, when administered with high-fat meal (800–1000 calories, 50% fat) compared to fasted conditions; not considered clinically significant.

Distribution

Extent

9-fold higher exposure in vaginal tissue than blood.

Plasma Protein Binding

Highly protein bound (>99%), predominantly to albumin.

Elimination

Metabolism

Undergoes hydroxylation by CYP3A4, followed by glucuronidation and sulfation of a hydroxylated inactive metabolite.

Elimination Route

Eliminated mainly via metabolism and biliary excretion.

Eliminated in the feces (90%, 51% as unchanged drug) and urine (1%).

Half-Life

Approxmiately 20 hours.

Special Populations

Pharmacokinetics not altered in post-menarchal pediatric females (ages 13—17 years), geriatric patients (ages 65—75 years), or mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment. Impact of severe (Child-Pugh class C) hepatic impairment on pharmacokinetics not known.

Stability

Storage

Oral

Tablets, film-coated

Store at 20–25ºC; brief exposure to 15–30ºC permitted.

Actions

Triterpenoid antifungal agent that inhibits glucan synthase, an enzyme involved in formation of 1,3-ß-D-glucan (an essential component of the fungal cell wall).
Concentration-dependent fungicidal activity against Candida species as measured by time-kill studies.
In vitro activity against Candida albicans, C. auris, C. dubliniensis, C. glabrata, C. guilliermondii, C. keyfr, C. krusei, C. lusitaniae, C. parapsilosis, and C. tropicalis.
Demonstrated activity against C. albicans in clinical infection. Clinical significance of in vitro activity against remaining Candida species currently unknown.
Retains in vitro antifungal activity at pH 4.5 (normal vaginal pH).
Potential for resistance evaluated in vitro and is associated with mutations in fks-2 gene; clinical relevance unknown.
Retains activity against most fluconazole-resistant Candidaspecies.
No resistance development observed after monthly dosing in patients with recurrent vulvovaginal candidiasis.

Advice to Patients

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).
Inform patients that ibrexafungerp can be taken with or without food. Advise patients that if the first 2 tablets are taken in the morning, the second 2 tablets should be taken the same day in the evening. If the first 2 tablets are taken in the afternoon or evening, the second 2 tablets should be taken the following morning.
Advise patients that ibrexafungerp is contraindicated in pregnancy and may cause fetal harm. Inform females of reproductive potential that their clinician will verify that they are not pregnant prior to initiating ibrexafungerp treatment. Advise patients to inform their clinician of a known or suspected pregnancy.
When used for a reduction in the incidence of recurrent vulvovaginal candidiasis, advise females of reproductive potential that reassessing pregnancy status is recommended prior to each ibrexafungerp dose. Advise females of reproductive potential to use effective contraception throughout the 6-month treatment period with ibrexafungerp and for 4 days after the last dose. Advise patients to inform their clinician of a known or suspected pregnancy.
Advise patients who have inadvertently taken ibrexafungerp during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage patients to report their pregnancy to the manufacturer (SCYNEXIS, Inc.) at 888-982-7299.
Advise females that there are no data on the presence of ibrexafungerp in human milk, the effects on the breast-fed child, or the effects on milk production. Advise females to inform their clinician if they plan to breast-feed.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.
Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.