Nirogacestat Hydrobromide (Monograph)

Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Aug 6, 2024. Written by ASHP.

[Web]

Introduction

Antineoplastic agent; a gamma secretase inhibitor.

Uses for Nirogacestat Hydrobromide

Desmoid Tumors

Used for treatment of adults with progressing desmoid tumors who require systemic treatment (designated an orphan drug by FDA for this use).

The Desmoid Tumor Working Group recommends surgery, radiotherapy, and/or systemic treatment for patients with desmoid tumors with persistent progressive disease; specific place in therapy for nirogacestat has not yet been established.

Nirogacestat Hydrobromide Dosage and Administration

General

Pretreatment Screening

Perform dermatologic evaluation to assess for non-melanoma skin cancer occurrence.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor patients for diarrhea; modify dosage as recommended and manage using antidiarrheal medications.
Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency (e.g., hot flashes, night sweats, vaginal dryness).
Monitor ALT and AST regularly and modify dosage as recommended.
Monitor phosphate and potassium levels regularly; modify dosage and supplement as recommended.
Perform dermatologic evaluation to assess for non-melanoma skin cancers routinely during treatment.

Administration

Oral Administration

Administer orally with or without food. Swallow tablets whole; do not break, crush, or chew prior to swallowing.

Available as tablets containing 50, 100, or 150 mg.

If dose is missed or vomiting occurs, take next dose at its scheduled time.

Dosage

Dosage of nirogacestat hydrobromide is expressed in terms of nirogacestat.

Adults

Desmoid Tumors

Oral

150 mg orally twice daily; continue until disease progression or unacceptable toxicity.

Each 150-mg dose of nirogacestat consists of three 50-mg tablets or one 150-mg tablet.

<C> Dosage Modification for Toxicity

See Table 1 for recommended dosage modifications for selected severe adverse reactions.

For other severe adverse reactions, life-threatening adverse reactions, or persistent intolerable grade 2 adverse events, withhold nirogacestat until resolution to grade ≤1 or baseline. Only restart nirogacestat at a dosage of 100 mg twice daily after considering potential benefit and likelihood of recurrence of the adverse reaction. Permanently discontinue nirogacestat for recurrence of severe or life-threatening reaction upon rechallenge at the reduced dosage.

Table 1. Recommended Nirogacestat Dosage Modifications for Toxicity.1
Adverse Reaction	Severity	Dosage Modification
Diarrhea persisting for ≥3 days despite maximal medical therapy	Grades 3 or 4	Withhold nirogacestat until resolution to grade ≤1 or baseline, then restart at a dosage of 100 mg twice daily
Increased ALT or AST	Grade 2 (≥3–5 times ULN)	Withhold nirogacestat until ALT, AST, or both are resolved to <3 times ULN or baseline, then restart at a dosage of 100 mg twice daily
Increased ALT or AST	Grades 3 or 4 (>5 times ULN)	Permanently discontinue
Hypophosphatemia persisting for ≥3 days despite maximal replacement therapy	Grades 3 or 4	Withhold nirogacestat until resolution to grade ≤1 or baseline, then restart at a dosage of 100 mg twice daily
Hypokalemia dispite maximal replacement therapy	Grades 3 or 4	Withhold nirogacestat until resolution to grade ≤1 or baseline, then restart at a dosage of 100 mg twice daily

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time; however, hepatotoxicity during treatment requires dosage modification (see Table 1).

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Nirogacestat Hydrobromide

Contraindications

None.

Warnings/Precautions

Diarrhea

Diarrhea, sometimes severe, can occur during nirogacestat therapy.

Monitor patients and manage using antidiarrheal medications. Modify dosage as recommended.

Ovarian Toxicity

Female reproductive function and fertility may be impaired with nirogacestat therapy. Impact on fertility may depend on factors including duration of therapy and state of gonadal function at the time of treatment. Long-term effects on fertility not established.

Before initiating nirogacestat, advise females of reproductive potential of possible risks for ovarian toxicity. Monitor patients for changes in menstrual cycle regularity or development of symptoms of estrogen deficiency (e.g., hot flashes, night sweats, vaginal dryness).

Hepatotoxicity

Elevations in ALT or AST reported.

Monitor liver function tests regularly. Modify dosage as recommended (See "Dosage Modification for Toxicity").

Non-Melanoma Skin Cancers

New non-melanoma skin cancers reported.

Perform dermatologic evaluations prior to initiation of nirogacestat and routinely during treatment.

Electrolyte Abnormalities

Electrolyte abnormalities can occur.

Monitor phosphate and potassium levels regularly and supplement as necessary. Modify nirogacestat dosage as recommended.

Fetal/Neonatal Morbidity and Mortality

Can cause fetal harm based on findings from animal studies and drug mechanism of action. Embryofetal toxicity and death demonstrated in animals.

Can impair female and male fertility based on findings in animal studies.

Verify pregnancy status in females of reproductive potential prior to initiating nirogacestat. Apprise pregnant women of the potential hazard to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with nirogacestat and for 1 week after the last dose.

Specific Populations

Pregnancy

Can cause fetal harm based on animal studies and mechanism of action.

Human data on nirogacestat use during pregnancy not available. Embryofetal toxicity and death demonstrated in animals.

Verify pregnancy status in females of reproductive potential prior to initiating nirogacestat. Apprise pregnant women of potential hazard to fetus.

Lactation

Unknown whether nirogacestat or its metabolites distribute into human milk, or affects milk production or the breast-fed child.

Advise women not to breast-feed during treatment with nirogacestat and for 1 week after the last dose.

Females and Males of Reproductive Potential

Can cause fetal harm; can impair female and male fertility based on findings in animal studies.

Verify pregnancy status in females of reproductive potential prior to initiating nirogacestat. Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with nirogacestat and for 1 week after the last dose.

Pediatric Use

Safety and effectiveness not established. Epiphyseal disorder, manifesting as a widening of the epiphyseal growth plate, reported in children with open growth plates treated with nirogacestat.

Geriatric Use

Experience in patients ≥65 years of age insufficient to determine whether they respond differently to nirogacestat than younger adults.

Hepatic Impairment

Moderate hepatic impairment (Child-Pugh class B, or National Cancer Institute-Organ Dysfunction Working Group group C criteria): mean AUC increased by ≤16% and mean peak plasma concentration decreased by ≤39% compared to patients with normal hepatic function.

Severe hepatic impairment: data insufficient to characterize nirogacestat pharmacokinetics.

Renal Impairment

Mild or moderate renal impairment (eGFR ≥41 mL/minute per 1.73m²): no clinically important effects on nirogacestat pharmacokinetics.

Common Adverse Effects

Most common adverse reactions (incidence ≥15%): diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, dyspnea.

Drug Interactions

Primarily metabolized by N-dealkylation via CYP3A4; also metabolized by CYP3A4, 2C19, 2C9, and 2D6 (secondary pathways).

Substrate of CYP3A. Not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6. Inducer of CYP2B6, 2C8, 2C9, and 2C19; not an inducer of CYP1A2.

Substrate of P-glycoprotein (P-gp); not a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, or OATP1B3.

Inhibitor of P-gp; not an inhibitor of BCRP, multidrug and toxin extrusion (MATE) 1, MATE2K, OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT2, or OAT3.

Drugs Affecting Hepatic Microsomal Enzymes

Strong or Moderate CYP3A Inhibitors

Concomitant use with a strong or moderate CYP3A inhibitor increases nirogacestat exposure, which may increase risk of adverse reactions.

Avoid concomitant use with strong or moderate CYP3A inhibitors including grapefruit products, Seville oranges, and starfruit.

Strong or Moderate CYP3A Inducers

Concomitant use with a strong or moderate CYP3A inducer decreases serum nirogacestat exposure, which may reduce effectiveness of nirogacestat.

Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A Substrates

Nirogacestat increases exposure of certain CYP3A substrates, which may increase risk of adverse effects related to these substrates.

Avoid concomitant use with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions.

CYP2C19 Substrates

Nirogacestat decreases exposure of certain CYP2C19 substrates, which may decrease efficacy of these substrates.

Avoid concomitant use with nirogacestat where decreased concentrations of CYP2C19 substrates may lead to significant decreases in efficacy of the CYP2C19 substrate, unless otherwise recommended in the prescribing information for the CYP2C19 substrate.

Drugs Affecting Gastric Acidity

Nirogacestat poorly soluble at pH ≥6. Gastric acid reducing agents (proton pump inhibitors, histamine type 2 [H2] blockers, or antacids) may decrease serum nirogacestat exposure, which may reduce effectiveness of nirogacestat.

Avoid concomitant use with proton pump inhibitors and H2 blockers. If concomitant use cannot be avoided, stagger administration with antacids (e.g., administer nirogacestat 2 hours before or 2 hours after antacid).

Specific Drugs

Drug	Interaction	Comments
Antacids (e.g., calcium)	Concomitant administration expected to reduce nirogacestat plasma concentrations; may reduce the effectiveness of nirogacestat	Avoid concomitant use; if concomitant use cannot be avoided, can stagger administration (e.g., administer nirogacestat 2 hours before or 2 hours after antacid )
Cimetidine	No clinically important differences in nirogacestat pharmacokinetics predicted when used concomitantly with cimetidine (weak CYP3A inhibitor)
Clarithromycin	Nirogacestat AUC predicted to increase by 3.46-fold following coadministration of multiple doses of nirogacestat (150 mg twice daily) with clarithromycin (strong CYP3A inhibitor)	Avoid concomitant use
Dabigatran	Peak plasma concentrations and AUC of dabigatran (P-gp substrate) not affected
Efavirenz	Nirogacestat AUC predicted to decrease by 67% following coadministration of multiple doses of nirogacestat (150 mg twice daily) with efavirenz (moderate CYP3A inducer)	Avoid concomitant use
Erythromycin	Nirogacestat AUC predicted to increase by 2.73-fold following coadministration of multiple doses of nirogacestat (150 mg twice daily) with erythromycin (moderate CYP3A inhibitor)	Avoid concomitant use
Fluconazole	Nirogacestat AUC predicted to increase by 3.18-fold following coadministration of multiple doses of nirogacestat (150 mg twice daily) with fluconazole (moderate CYP3A inhibitor)	Avoid concomitant use
Histamine type 2 (H2) blockers (e.g., famotidine)	Concomitant administration expected to reduce nirogacestat plasma concentrations; may reduce effectiveness of nirogacestat	Avoid concomitant use
Itraconazole	Nirogacestat peak plasma concentration and AUC increased by 2.5- and 8.2-fold, respectively, when coadministered with itraconazole (strong CYP3A inhibitor) Nirogacestat AUC predicted to increase by 6.33-fold following coadministration of multiple doses of nirogacestat (150 mg twice daily) with itraconazole	Avoid concomitant use
Ketoconazole	Nirogacestat AUC predicted to increase by 5.19-fold following coadministration of multiple doses of nirogacestat (150 mg twice daily) with ketoconazole (strong CYP3A inhibitor)	Avoid concomitant use
Midazolam	Peak plasma concentration and AUC of midazolam (CYP3A substrate) predicted to increase by 1.77- and 2.07-fold, respectively, following concomitant use with multiple doses of nirogacestat (150 mg twice daily)	Avoid concomitant use
Proton pump inhibitors (e.g., omeprazole)	Concomitant administration expected to reduce nirogacestat plasma concentrations; may reduce effectiveness of nirogacestat	Avoid concomitant use
Rifampin	Nirogacestat AUC predicted to decrease by 85% following coadministration of multiple doses of nirogacestat (150 mg twice daily) with rifampin (strong CYP3A inducer)	Avoid concomitant use
Rosiglitazone	No clinically important differences in pharmacokinetics of rosiglitazone (CYP2C8 substrate) predicted
Warfarin	No clinically important differences in pharmacokinetics of S-warfarin (CYP2C9 substrate) predicted

Nirogacestat Hydrobromide Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability: 19%.

Median time to peak plasma concentration: 1.5 hours (range, 0.5–6.5 hours).

Time to steady state: approximately 6 days.

Median accumulation ratio: 1.6 (range, 1.3–4.6).

Food

When administered with food, dose-normalized geometric mean ratio of nirogacestat peak plasma concentration and AUC is 93 and 114%, respectively.

Distribution

Extent

Unknown whether nirogacestat or its metabolites distribute into human milk.

Plasma Protein Binding

Serum protein binding: 99.6%.

Protein binding to human serum albumin: 94.6%.

Protein binding to alpha-1 acid glycoprotein: 97.9%.

Elimination

Metabolism

Primary pathway (85%): N-dealkylation via CYP3A4.

Secondary pathways: CYP3A4, 2C19, 2C9, and 2D6.

Elimination Route

Feces (38%), urine (17%, with <1% unchanged), and expired air (9.7%).

Half-life

23 hours.

Special Populations

No clinically important differences in nirogacestat pharmacokinetics observed based on age (18–80 years), sex, or race (Asian, Black or African American, and white).

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

Gamma secretase inhibitor that blocks proteolytic activation of Notch receptors; when dysregulated, Notch can activate pathways that contribute to tumor growth.
Mechanism of action in desmoid tumors not yet fully elucidated; antitumor activity demonstrated in patients with desmoid tumors.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise patients that nirogacestat can cause diarrhea, which may be severe, and to contact their clinician for sustained diarrhea that does not respond to supportive care.
Advise females of reproductive potential that nirogacestat can cause ovarian toxicity and impair fertility, and that these effects may continue following discontinuation of the drug. Advise patients to inform their clinician if they experience symptoms of ovarian toxicity, such as hot flashes or menstrual irregularities.
Advise patients that nirogacestat can cause elevations of ALT or AST, and that liver transaminase levels will be monitored regularly during treatment.
Advise patients that nirogacestat can cause new non-melanoma skin cancers, and that they will be monitored for development of these cancers. Inform patients to contact their clinician for any new or changing lesions on their skin.
Advise patients that nirogacestat can cause hypophosphatemia and/or hypokalemia which may require phosphate and/or potassium supplementation. Advise patients that they will be monitored for electrolyte abnormalities, and to contact their clinician if they experience muscle pain or weakness.
Advise pregnant women and females of reproductive potential of the potential hazard to a fetus. Advise females of reproductive potential to inform their clinician of a known or suspected pregnancy, and to stop taking nirogacestat if they become pregnant. Advise females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with nirogacestat and for 1 week after the last dose.
Advise women not to breast-feed during treatment with nirogacestat and for 1 week after the last dose.
Advise patients to inform their clinician of all existing or contemplated concomitant medications, including prescription and OTC drugs, vitamins, and herbal products, as well as any concomitant illnesses. Inform patients to avoid starfruit, Seville oranges, grapefruit, and juice from any of these fruits when taking nirogacestat.
Inform 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. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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.

Nirogacestat is available through specialty pharmacies and specialty distributors. Consult the Ogsiveowebsite ([Web]) for specific availability information.

Nirogacestat Hydrobromide
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	50 mg (of nirogacestat)	Ogsiveo	SpringWorks Therapeutics
		100 mg (of nirogacestat)	Ogsiveo	SpringWorks Therapeutics
		150 mg (of nirogacestat)	Ogsiveo	SpringWorks Therapeutics