Version May 2024
Desmoid tumors, progressive: Oral: 150 mg twice daily; continue until disease progression or unacceptable toxicity (Ref).
Missed doses: If dose of nirogacestat is missed or if vomiting occurs following administration, skip dose and resume with next scheduled dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Kidney impairment prior to treatment initiation:
eGFR ≥41 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling; however, no clinically significant differences in nirogacestat pharmacokinetics were observed.
eGFR <41 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling.
Hepatic impairment prior to treatment initiation:
Mild hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling.
Moderate hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, mean AUC increased by up to 16% and mean Cmax decreased by up to 39% in subjects with moderate hepatic impairment when compared to subjects with normal hepatic function.
Severe hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Acute hepatotoxicity during treatment:
AST or ALT ≥3 to 5 × ULN (grade 2): Withhold nirogacestat until ALT, AST, or both have resolved to <3 × ULN or baseline; resume nirogacestat at 100 mg twice daily.
AST or ALT >5 × ULN (grades 3 or 4): Permanently discontinue nirogacestat.
|
Adverse reaction |
Severity |
Nirogacestat dosage modification |
|---|---|---|
|
GI toxicity: diarrhea |
Any |
May require management with antidiarrheal medications. |
|
Grades 3 or 4 (persisting ≥3 days despite maximal medical therapy) |
Withhold nirogacestat until resolved to grade ≤1 or baseline; resume nirogacestat at 100 mg twice daily. | |
|
Hypophosphatemia (persisting ≥3 days despite maximal replacement therapy) |
Grades 3 or 4 |
Withhold nirogacestat until resolved to grade ≤1 or baseline; resume nirogacestat at 100 mg twice daily. |
|
Hypokalemia (despite maximal replacement therapy) |
Grades 3 or 4 |
Withhold nirogacestat until resolved to grade ≤1 or baseline; resume nirogacestat at 100 mg twice daily. |
|
Other adverse reactions (clinically significant) |
Severe; or Life-threatening; or Persistent, intolerable grade 2 |
Withhold nirogacestat until resolved to grade ≤1 or baseline; resume nirogacestat at 100 mg twice daily only after consideration of potential benefit and likelihood of toxicity recurrence. Recurrence of severe or life-threatening adverse reactions following rechallenge at the reduced dose: Permanently discontinue nirogacestat. |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Dermatologic: Alopecia (19%), folliculitis (<15%), dermatologic disorder (hidradenitis suppurativa: <15%), skin carcinoma (nonmelanoma: <15%; including basal cell carcinoma of skin [1%], squamous cell carcinoma of skin [3%]), skin rash (68%)
Endocrine & metabolic: Decreased serum phosphate (20% to 65%), decreased serum potassium (22%)
Gastrointestinal: Abdominal pain (22%), diarrhea (84%; grade 3: 16%), nausea (54%; grade 3: 1%), stomatitis (39%; grade 3: 4%)
Genitourinary: Glycosuria (51%), ovarian disease (75%, including amenorrhea, ovarian failure, menopause, and premature menopause; serious: 4%), proteinuria (40%)
Hepatic: Increased serum alanine aminotransferase (30%), increased serum aspartate aminotransferase (33%)
Nervous system: Fatigue (54%), headache (30%)
Respiratory: Cough (20%), dyspnea (16%), epistaxis (<15%), flu-like symptoms (<15%), upper respiratory tract infection (17%)
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Electrolyte abnormalities: Alterations in potassium and phosphate levels may occur during treatment with nirogacestat. In a clinical study, two-thirds of patients experienced decreased phosphate and one-quarter of patients experienced decreased potassium; phosphate <2 mg/dL and grade 3 hypokalemia also occurred.
• GI toxicity: Diarrhea, including severe cases, can occur with nirogacestat treatment. A majority of patients treated with nirogacestat in a clinical study experienced diarrhea; grade 3 events were also observed. Median time to first event of diarrhea was 9 days (range: 2 to 434 days).
• Hepatotoxicity: AST or ALT elevations occurred in approximately one-third of nirogacestat-treated patients; grade 3 events were also observed.
• Skin cancers: Treatment with nirogacestat may result in the occurrence of new nonmelanoma skin cancers (including cutaneous squamous cell carcinoma and basal cell carcinoma).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrobromide:
Ogsiveo: 50 mg [contains fd&c yellow #6(sunset yellow)alumin lake]
No
Tablets (Ogsiveo Oral)
50 mg (per each): $193.33
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Nirogacestat is available through specialty pharmacies/distributors and various specialty institutions/accounts. Examples from the manufacturer may be found at: https://www.ogsiveo.com/files/download/OGSIVEO_Product_Fact_Sheet_and_Ordering_Guide.pdf.
Oral: Administer with or without food. Swallow tablets whole; do not break, crush, or chew.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Nirogacestat may cause developmental and reproductive toxicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (Ref).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (Ref). Refer to institution-specific handling policies/procedures.
Desmoid tumors, progressive: Treatment of progressing desmoid tumors in adults who require systemic treatment.
Nirogacestat may be confused with niraparib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Antacids: May decrease the serum concentration of Nirogacestat. Management: If acid-reducing therapy is required, separate nirogacestat administration from antacids by 2 hours. Risk D: Consider therapy modification
Bitter Orange: May increase the serum concentration of Nirogacestat. Risk X: Avoid combination
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Nirogacestat. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Nirogacestat. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Nirogacestat. Risk X: Avoid combination
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Nirogacestat. Risk X: Avoid combination
CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors): Nirogacestat may increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Erdafitinib: Serum Phosphate Level-Altering Agents may diminish the therapeutic effect of Erdafitinib. Management: Avoid coadministration of serum phosphate level-altering agents with erdafitinib before initial dose increase period based on serum phosphate levels (Days 14 to 21). Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Histamine H2 Receptor Antagonists: May decrease the serum concentration of Nirogacestat. Risk X: Avoid combination
Inhibitors of the Proton Pump (PPIs and PCABs): May decrease the serum concentration of Nirogacestat. Risk X: Avoid combination
Star Fruit: May increase the serum concentration of Nirogacestat. Risk X: Avoid combination
Grapefruit, Seville oranges, and starfruit may interact with nirogacestat. Management: Avoid concomitant use of nirogacestat with grapefruit products, Seville oranges, and starfruit.
Verify pregnancy status prior to treatment initiation.
Patients who could become pregnant and patients with partners who could become pregnant should use effective contraception during therapy and for 1 week after the last dose of nirogacestat.
Nirogacestat may cause ovarian toxicity and impair fertility; impact may depend on multiple factors including duration of therapy and gonadal function at the start of treatment. Monitor for menstrual cycle changes and symptoms of estrogen deficiency (eg, hot flashes, night sweats, vaginal dryness).
Based on the mechanism of action and data from animal reproduction studies using doses less than the recommended human dose (based on AUC), in utero exposure to nirogacestat may cause fetal harm.
It is not known if nirogacestat is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 1 week after the last dose of nirogacestat.
Avoid grapefruit products, Seville oranges, and starfruit.
Monitor LFTs, phosphate, and potassium levels regularly during treatment. Perform dermatologic evaluations at baseline and routinely during treatment. Verify pregnancy status prior to treatment initiation in patients who could become pregnant.
Monitor for signs/symptoms of electrolyte disturbances (phosphate, potassium), GI toxicity (diarrhea), ovarian toxicity (changes in menstrual cycle regularity or symptoms of estrogen deficiency [eg, hot flashes, night sweats, vaginal dryness]), and/or nonmelanoma skin cancers. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (Ref) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
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. Gamma-secretase inhibitors, such as nirogacestat, impair Notch signaling through selective inhibition of gamma-secretase-mediated cleavage of Notch receptors and in studies have shown to prevent the release of the Notch intracellular domain (Ref).
Absorption: Poorly soluble at pH ≥6.
Distribution: Vd: 1,430 L.
Protein binding: Serum protein binding: 99.6%, human serum albumin: 94.6%; alpha-1 acid glycoprotein: 97.9%.
Metabolism: Primary: N-dealkylation via CYP3A4 (85%); secondary: metabolism via CYP3A4, 2C19, 2C9, and 2D6.
Bioavailability: 19%.
Half-life elimination: 23 hours.
Time to peak: 1.5 hours (range: 0.5 to 6.5 hours).
Excretion: Feces: 38%; urine: 17% (<1% as unchanged drug); expired air: 9.7%.
Clearance: 45 L/hour.
Hepatic function impairment: The mean AUC increased by up to 16% and the mean Cmax decreased by up to 39% in subjects with moderate hepatic impairment (Child-Turcotte-Pugh class B or NCI-ODWG group C) when compared to subjects with normal hepatic function.
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