Dosing & Uses
Dosage Forms & Strengths
tablet
- 50mg
Desmoid Tumors
Indicated for progressing desmoid tumors in adults who require systemic treatment
150 mg PO BID
Continue until disease progression or unacceptable toxicity
Dosage Modifications
Grade 3 or 4 diarrhea
- Described as persisting for ≥3 days despite maximal medical therapy
- Withhold until resolved to Grade ≤1 or baseline, then restart at 100 mg PO BID
Increased ALT or AST
- Grade 2 (≥3 to 5x ULN): Withhold until AST, ALT, or both are resolved to ≤3x or baseline, then restart at 100 mg PO BID
- Grade 3 or 4 (≥5x ULN): Permanently discontinue
Grade 3 or 4 hypophosphatemia
- Described as persisting for ≥3 days despite maximal replacement therapy
- Withhold until resolved to Grade ≤1 or baseline, then restart at 100 mg PO BID
Grade 3 or 4 hypokalemia
- Hypokalemia despite maximal replacement therapy
- Withhold until resolved to Grade ≤1 or baseline, then restart at 100 mg PO BID
Renal impairment
- Mild or moderate (eGFR ≥41 mL/min/1.73m2): No dosage adjustment necessary
Hepatic impairment
- Moderate (Child Pugh B): Mean AUC increased by up to 16% and mean Cmax decreased by up to 39%
- Severe (Child Pugh C): Insufficient data
Other adverse reactions
- Severe adverse reactions, life-threatening adverse reactions, or persistent intolerable
- Grade 2 adverse events: Withhold until resolved to Grade ≤1 or baseline
- Restart at 100 mg PO BID only after considering potential benefit and possible recurrence of adverse reaction
- Permanently discontinue if severe or life-threatening adverse reaction recurs despitedose reduction
Dosing Considerations
Verify pregnancy status of females of reproductive potential before initiating
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (0)
Monitor Closely (0)
Minor (0)
Adverse Effects
>10%
All grades
- Diarrhea (84%)
- Ovarian toxicity (75%)
- Rash (68%)
- Decreased phosphate (65%)
- Nausea (54%)
- Fatigue (54%)
- Increased urine glucose (51%)
- Increased urine protein (40%)
- Stomatitis (39%)
- Increased aspartate aminotransferase (AST) (33%)
- Increased alanine aminotransferase (ALT) (30%)
- Headache (30%)
- Abdominal pain (22%)
- Decreased potassium (22%)
- Cough (20%)
- Alopecia (19%)
- Upper respiratory tract infection (17%)
- Dyspnea (16%)
Grade 3
- Diarrhea (16%)
1-10%
Grade 3
- Rash (6%)
- Increased ALT (6%)
- Stomatitis (4%)
- Fatigue (2.9%)
- Increased AST (2.9%)
- Nausea (1.4%)
- Abdominal pain (1.4%)
- Decreased potassium (1.4%)
Warnings
Contraindications
None
Cautions
Diarrhea, sometimes severe, reported; monitor, and manage with antidiarrheal medication; modify dose as recommended
ALT or AST elevations occurred; monitor liver function tests regularly and modify dose as recommended
New non-melanoma skin cancers may occur; perform dermatologic evaluations before initiating and routinely during treatment
Electrolyte abnormalities reported; monitor phosphate and potassium levels regularly and supplement as necessary and modify dose as recommended
Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to pregnant females
Ovarian toxicity
May impair female reproductive function and fertility
Impact on fertility may be dependent on duration of therapy and gonadal function at time of treatment
Long-term effects on fertility have not been established
Advise patients on potential risks for ovarian toxicity before initiating
Monitor for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency, including hot flashes, night sweats, and vaginal dryness
Drug interaction overview
- CYP3A4 substrate
- Inhibits of CYP3A4 and CYP2C19 substrates
-
Strong or moderate CYP3A4 inhibitors
- Avoid coadministration
- Avoid eating or drinking grapefruit products, Seville oranges, and starfruit during treatment
- Strong or moderate CYP3A inhibitors increase nirogacestat exposure and increase risk of toxicities
-
Strong or moderate CYP3A4 inducers
- Avoid coadministration
- Strong or moderate CYP3A inducers decrease nirogacestat exposure and efficacy
-
Gastric acid reducing agents
- Avoid coadministration with proton pump inhibitors and H2 blockers
- May administer 2 hr before or 2 hr after antacids
-
Sensitive CYP3A4 substrates
- Avoid coadministration with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions
- Nirogacestat increases exposure of CYP3A substrates and increase the risk of adverse reactions related to these substrates
-
Sensitive CYP2C19 substrates
- Avoid coadministration with CYP2C19 substrates where minimal concentration changes may lead to serious adverse reactions
- Nirogacestat increases exposure of CYP2C19 substrates and increase the risk of adverse reactions related to these substrates
Pregnancy & Lactation
Pregnancy
Based on findings from animal studies and its mechanism of action, fetal harm or loss of pregnancy when administered to pregnant females
Verify pregnancy status of females of reproductive potential before initiating
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 1 week after last dose
- Males with female partners of reproductive potential: Use effective contraception during treatment and for 1 week after last dose
Infertility
- Based on findings in animal studies, female and male fertility may be impaired
- Nirogacestat interfere with folliculogenesis and spermatogenesis in nonclinical studies resulting in changes that included ovarian atrophy
Animal data
- Oral administration to pregnant rats during organogenesis resulted in embryofetal toxicity and embryofetal death at maternal exposures below human exposure at recommended dose of 150 mg PO BID
- There are no available data on the use in pregnant females
- Advise pregnant females of potential risk to fetus
Lactation
There are no data on presence of nirogacestat or its metabolites in human milk or effects of nirogacestat on breastfed children or milk production
Advise women not to breastfeed during treatment and for 1 week after last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Gamma secretase cleaves multiple transmembrane proteins, including Notch, that are believed to play a role in activating pathways that contribute to growth of desmoid tumors
Gamma secretase has been shown to cleave B-cell maturation antigen (BCMA), a therapeutic target that is specifically expressed on multiple myeloma cells
Absorption
Peak plasma concentration: 508 ng/mL
Peak plasma time: 1.5 hr
Steady-state reached at ~6 days
AUC: 3,370 ng⋅hr/mL
Bioavailability: 19%
Distribution
Vd: 1,430 L
Protein bound
- Serum protein binding: 99.6%
- Human serum albumin: 94.6%
- α-1 acid glycoprotein: 97.9%
Metabolism
Primary: N-dealkylation via CYP3A4
Secondary: Metabolism by CYP 3A4, 2C19, 2C9, and 2D6
Elimination
Clearance: 45 L/hr
Half-life: 23 hr
Excretion
- Feces: 38%
- Urine: 17% (<1%)
- Expired air: 9.7%
Administration
Oral Administration
Take with or without food
Swallow tablets whole and not to break, crush, or chew
Vomited or missed dose: Take next dose at its scheduled time
Avoid eating or drinking grapefruit products, Seville oranges, and starfruit during treatment
Avoid coadministration with proton pump inhibitors and H2 blockers
If unavoidable, space out nirogacestat administration with antacids (eg, administer 2 hr before or 2 hr after antacid use)
Storage
Store at 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF)
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Formulary
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