nirogacestat (Rx)

Brand and Other Names:Ogsiveo

Dosing & Uses

AdultPediatric

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

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Interactions

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                    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%)
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                    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
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                    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.

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                    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%
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                    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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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Formulary

                    FormularyPatient Discounts

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                    The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                    Tier Description
                    1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                    2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                    3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                    4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    NC NOT COVERED – Drugs that are not covered by the plan.
                    Code Definition
                    PA Prior Authorization
                    Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                    QL Quantity Limits
                    Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
                    ST Step Therapy
                    Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
                    OR Other Restrictions
                    Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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                    Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.