Ogsiveo

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  • Miscellaneous musculoskeletal disorders
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Ogsiveo Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Nirogacestat 50mg; tabs.

    Pharmacological Class

    Gamma secretase inhibitor.

    How Supplied

    Tabs—180

    Storage

    Store at 20°C-25°C (68°F-77°F). Excursions permitted between 15°C-30°C (59°F-86°F). See USP Controlled Room Temperature.

    Manufacturer

    SpringWorks Therapeutics, Inc.

    Generic Availability

    NO

    Mechanism of Action

    Nirogacestat is a gamma secretase inhibitor that blocks proteolytic activation of the Notch receptor. When dysregulated, Notch can activate pathways that contribute to tumor growth.

    Ogsiveo Indications

    Indications

    In adults with progressing desmoid tumors who require systemic treatment.

    Ogsiveo Dosage and Administration

    Adult

    Swallow whole. 150mg twice daily until disease progression or unacceptable toxicity. Dose modifications for adverse reactions: see full labeling.

    Children

    Not established.

    Ogsiveo Contraindications

    Not Applicable

    Ogsiveo Boxed Warnings

    Not Applicable

    Ogsiveo Warnings/Precautions

    Warnings/Precautions

    Monitor and manage appropriately if diarrhea occurs. Risk for ovarian toxicity. Monitor for changes in menstrual cycle regularity or symptoms of estrogen deficiency. Hepatotoxicity. Non-melanoma skin cancer. Perform dermatologic evaluations prior to initiation and routinely during treatment. Electrolyte abnormalities. Monitor LFTs, phosphate, and potassium levels regularly; adjust dose accordingly or provide supplement, as needed. Embryo-fetal toxicity. Advise females of reproductive potential and males (w. female partners) to use effective contraception during and for 1 week after the last dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended (during and for 1 week after the last dose).

    Pregnancy Considerations

    Risk Summary

    • No available data on the use of Ogsiveo in pregnant women. May cause fetal harm or loss of pregnancy when administered to a pregnant women.
    • During the period of organogenesis in pregnant rats, the oral administration of nirogacestat resulted in embryo-fetal toxicity and embryo-fetal death at maternal exposures.

    Nursing Mother Considerations

    Risk Summary

    • No data on the presence of nirogacestat or its metabolites in human milk or the effects of nirogacestat on a breastfed child or milk production.
    • Advise women not to breastfeed during treatment with Ogsiveo and for 1 week after the last dose.

     

    Pediatric Considerations

    Safety and efficacy of Ogsiveo have not been established in pediatric patients.

    Epiphyseal disorder has been reported in pediatric patients with open growth plates treated with Ogsiveo.

    Geriatric Considerations

    Clinical studies of Ogsiveo did not include sufficient numbers of patients 65 years of age and older to determine whether they respond
    differently than younger adult patients.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • May cause fetal harm when administered to a pregnant women.
    • Pregnancy Testing: Verify pregnancy status prior to initiating treatment.
    • Contraception: Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during and for 1 week after the last dose.

     

    Ogsiveo Pharmacokinetics

    Absorption

    Tmax: 1.5 hours. Absolute bioavailability: 19%.

    Distribution

    Apparent volume of distribution: 1430 L. Serum protein binding: 99.6%; Human serum albumin binding: 94.6%.

    Metabolism

    Primary metabolic pathway: N-dealkylation via CYP3A4. Secondary metabolic pathways: CYP3A4, 2C19, 2C9, and 2D6.

    Elimination

    Fecal (38%), renal (17%). Half-life: 23 hours. Apparent systemic clearance: 45 L/hr.

    Ogsiveo Interactions

    Interactions

    Potentiated by strong or moderate CYP3A inhibitors (eg, itraconazole, ketoconazole, clarithromycin, erythromycin, fluconazole, grapefruit products, Sevilles oranges, starfruit); avoid. Antagonized by strong or moderate CYP3A inducers (eg, rifampin, efavirenz); avoid. Antagonized by gastric acid reducing agents (eg, PPI, H2-receptor antagonists): avoid; if unavoidable, give nirogacestat 2hrs before or 2hrs after antacid use. Potentiates certain CYP3A substrates (eg, midazolam); avoid. Antagonizes certain CYP2C19 substrates; avoid.

    Ogsiveo Adverse Reactions

    Adverse Reactions

    Diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, dyspnea, lab abnormalities (decreased phosphate, increased urine glucose, increased urine protein, increased AST/ALT, decreased potassium); infertility.

    Ogsiveo Clinical Trials

    Clinical Trials

    The approval was based on data from the double-blind, placebo-controlled phase 3 DeFi trial (ClinicalTrials.gov Identifier: NCT03785964), which included 142 adult patients with progressing desmoid tumors not amenable to surgery. Patients were randomly assigned to receive either nirogacestat 150mg orally twice daily (n=70) or placebo (n=72). The primary endpoint was progression free survival.

    Findings demonstrated that treatment with nirogacestat significantly reduced the risk of disease progression by 71% compared with placebo (hazard ratio, 0.29 [95% CI, 0.15-0.55]; P <.001). The median Kaplan-Meier estimate of PFS was not reached in the nirogacestat arm and was 15.1 months in the placebo arm. 

    Ogsiveo Note

    Not Applicable

    Ogsiveo Patient Counseling

    Patient Counseling

    Diarrhea

    • Advise patients that Ogsiveo may cause diarrhea, which can be severe.
    • Contact your health care provider if sustained diarrhea that does not respond to supportive care develops.

    Ovarian Toxicity

    • Advise females of reproductive potential that Ogsiveo may cause ovarian toxicity and impair fertility, and these effects may continue after stopping Ogsiveo treatment.
    • Contact your health care provider if you experience symptoms of ovarian toxicity, including hot flashes or menstrual irregularities.

    Liver Toxicity

    • Advise patients that Ogsiveo may cause ALT or AST elevations, and that your health care provider should monitor liver transaminase levels regularly.

    Non-Melanoma Skin Cancers

    • Advise patients that Ogsiveo may cause new non-melanoma skin cancers, that they will be monitored for these.
    • Contact their healthcare provider for any new or changing lesions on their skin.

    Electrolyte Abnormalities

    • Advise patients that Ogsiveo may cause hypophosphatemia and/or hypokalemia which may require phosphate and/or potassium supplementation. 
    • Contact your health care provider if you experience muscle pain or weakness.

    Embryo-Fetal Toxicity

    • Advise pregnant women and females of reproductive potential of the potential harm to a fetus.
    • Inform your health care provider of a known of suspected pregnancy, and to stop taking Ogsiveo if you become pregnant.
    • Advise to use effective contraception during and for 1 week after the last dose.

    Lactation

    • Do not breastfeed during and for 1 week after the last dose.

    Drug Interactions

    • Advise patients to inform their health care provider of all concomitant medications.
    • Avoid starfruit, Seville oranges, grapefruit, and juice from any of these fruits during treatment.

    Cost Savings Program

    SpringWorks Care Connection

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