Nirogacestat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kosar Doraghi, M.D.[2]
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Black Box Warning
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Warning: Severe Diarrhea, Electrolyte Abnormalities
See full prescribing information for complete Boxed Warning.
Diarrhea: Severe diarrhea can occur. Monitor and dose modify for Grade 3-4 diarrhea.
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Overview
Nirogacestat is a gamma secretase inhibitor that is FDA approved for the treatment of adult patients with progressing desmoid tumors who require systemic treatment. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.
Decreased phosphate, increased urine glucose, increased urine protein, increased AST, increased ALT, and decreased potassium.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
The recommended dosage of OGSIVEO is 150 mg administered orally twice daily until disease progression or unacceptable toxicity. Each 150 mg dose of OGSIVEO consists of three 50 mg tablets.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Nirogacestat FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
None.
Warnings
|
Warning: Severe Diarrhea, Electrolyte Abnormalities
See full prescribing information for complete Boxed Warning.
Diarrhea: Severe diarrhea can occur. Monitor and dose modify for Grade 3-4 diarrhea.
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- Diarrhea
- Ovarian Toxicity
- Hepatotoxicity
- Non-Melanoma Skin Cancers
- Electrolyte Abnormalities
- Embryo-Fetal Toxicity
Adverse Reactions
Clinical Trials Experience
Since clinical trials are conducted under varying conditions, the rates of adverse reactions observed in one drug's trials cannot be directly compared to those of another drug, and may not reflect real-world rates. The safety profile of OGSIVEO was assessed in a study involving 69 patients enrolled in DeFi with advancing desmoid tumor. Patients were administered OGSIVEO orally at a dose of 150 mg twice daily or a placebo orally twice daily until disease progression or unacceptable toxicity. The median exposure duration to OGSIVEO was 20.6 months (range: 0.3 to 33.6). Serious adverse reactions were experienced by 20% of patients treated with OGSIVEO. Serious adverse reactions noted in ≥ 2% of patients included ovarian toxicity (4%). Permanent discontinuation of OGSIVEO due to adverse reactions was necessary for 20% of patients. Adverse reactions leading to permanent discontinuation of OGSIVEO in ≥ 2% of patients were diarrhea, ovarian toxicity, increased ALT, and increased AST. Dosage interruptions of OGSIVEO due to adverse reactions were required for 51% of patients. Adverse reactions necessitating dosage interruption in ≥ 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, fatigue, folliculitis, nausea, and ovarian toxicity. Dose reductions of OGSIVEO due to adverse reactions were implemented in 42% of patients. Adverse reactions prompting dose reductions in ≥ 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, folliculitis, hidradenitis, and ovarian toxicity. The most common adverse reactions (≥ 15% with a difference between treatment arms of ≥ 5% compared to placebo) observed in patients receiving OGSIVEO included diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea.
Clinically significant adverse reactions observed in fewer than 15% of patients receiving OGSIVEO in the DeFi study encompassed non-melanoma skin cancers, epistaxis, hidradenitis suppurativa, folliculitis, and influenza-like illness.
The denominator utilized to compute the rate was 69 for nirogacestat and 72 for placebo, determined by the number of patients with a baseline value and at least one post-treatment value. CTCAE Version 5.0 does not establish numeric thresholds for grading *hypophosphatemia; all grades represent patients with a laboratory value below the Lower Limit of Normal (LLN). For the calculation, the denominator employed was 68 for nirogacestat and 69 for placebo, based on the number of patients with a baseline value and at least one post-treatment value. CTCAE Version 5.0 does not establish numeric thresholds for grading increased urine glucose.
Postmarketing Experience
There is limited information regarding Nirogacestat Postmarketing Experience in the drug label.
Drug Interactions
- Strong or moderate inhibitors of CYP3A: Concomitant use should be avoided.
- Concomitant use of strong or moderate inducers of CYP3A should be avoided.
- When using gastric acid reducing agents, it's best to avoid concurrent use with proton pump inhibitorsand H2-receptor antagonists. If simultaneous administration cannot be circumvented, consider staggering the administration of OGSIVEO with antacids.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
Animal studies have revealed evidence of embryofetal toxicity and death after oral administration of this drug during the period of organogenesis in pregnant rats.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nirogacestat in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Nirogacestat during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Nirogacestat in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Nirogacestat in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Nirogacestat in geriatric settings.
Gender
There is no FDA guidance on the use of Nirogacestat with respect to specific gender populations.
Race
There is no FDA guidance on the use of Nirogacestat with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Nirogacestat in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Nirogacestat in patients with hepatic impairment.
Females of Reproductive Potential and Males
OGSIVEO can cause fetal harm when administered to a pregnant woman
- Based on findings in animal studies, OGSIVEO can impair female and male fertility. OGSIVEO has been shown to interfere with folliculogenesis and spermatogenesis in nonclinical studies resulting in changes that included ovarian atrophy
Immunocompromised Patients
There is no FDA guidance one the use of Nirogacestat in patients who are immunocompromised.
Administration and Monitoring
Administration
The suggested dose of OGSIVEO is 150 mg taken orally twice daily until disease progression or if unacceptable toxicity occurs. Each 150 mg dose of OGSIVEO comprises three 50 mg tablets. OGSIVEO can be ingested with or without food. Patients should be advised to swallow OGSIVEO tablets whole and refrain from breaking, crushing, or chewing them before swallowing. In the event of vomiting or a missed dose, patients should be instructed to take the next dose at the scheduled time. Dosage Adjustments for Adverse Reactions: The recommended adjustments to the dosage of OGSIVEO for specific severe adverse reactions are outlined in TABLE 1. For other severe adverse reactions, life-threatening adverse reactions, or persistent intolerable Grade 2 adverse events, the drug should be withheld until symptoms resolve to Grade ≤ 1 or baseline. Subsequently, OGSIVEO may be restarted at a dose of 100 mg twice daily after considering the potential benefits and likelihood of adverse reaction recurrence. In case of severe or life-threatening adverse reactions recurring upon rechallenge at the reduced dose, OGSIVEO should be permanently discontinued. Table 1. Recommended Dosage Adjustments for Adverse Reactions Adverse Reaction Severity OGSIVEO Dosage Adjustments Diarrhea persisting for ≥ 3 days despite maximal medical therapy Grades 3 or 4 Withhold OGSIVEO until symptoms resolve to Grade ≤ 1 or baseline, then restart at a dose of 100 mg twice daily. AST ALT Increase, Grade 2 (≥ 3 to 5 × ULN) Withhold OGSIVEO until ALT, AST, or both return to < 3 × ULN or baseline, then restart at a dose of 100 mg twice daily. Grades 3 or 4 (> 5 × ULN) Permanently discontinue. Hypophosphatemia persisting for ≥ 3 days despite maximal replacement therapy Grades 3 or 4 Withhold OGSIVEO until symptoms resolve to Grade ≤ 1 or baseline, then restart at a dose of 100 mg twice daily. Hypokalemia despite maximal replacement therapy Grades 3 or 4 Withhold OGSIVEO until symptoms resolve to Grade ≤ 1 or baseline, then restart at a dose of 100 mg twice daily.
Monitoring
There is limited information regarding Nirogacestat Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Nirogacestat and IV administrations.
Overdosage
There is limited information regarding Nirogacestat overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Nirogacestat Pharmacology in the drug label.
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.
Structure
OGSIVEO oral tablets contain nirogacestat (as nirogacestat hydrobromide), a gamma secretase inhibitor. Nirogacestat hydrobromide is chemically known as (S)-2-(((S)-6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl) pentanamide dihydrobromide. The empirical formula is C27H43Br2F2N5O and the molecular weight is 651.48 g/mol. Nirogacestat hydrobromide is a white to off white powder with an aqueous solubility of 11.4 mg/mL and a pH of 4.4 in water at 25°C. Nirogacestat dihydrobromide is highly soluble at low pH, however the solubility significantly decreases at pH > 6.0. The molecule has pKa’s of 5.77 and 7.13. The structural formula for nirogacestat hydrobromide is:
The structural formula for nirogacestat hydrobromide is: OGSIVEO oral tablets contain nirogacestat (as nirogacestat hydrobromide), a gamma secretase inhibitor. Nirogacestat hydrobromide is chemically known as (S)-2-(((S)-6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl) pentanamide dihydrobromide. The empirical formula is C27H43Br2F2N5O and the molecular weight is 651.48 g/mol. Nirogacestat hydrobromide is a white to off white powder with an aqueous solubility of 11.4 mg/mL. Nirogacestat dihydrobromide is highly soluble at low pH, however the solubility significantly decreases at pH > 6.0. The molecule has pKa’s of 5.77 and 7.13.
OGSIVEO (nirogacestat) tablets are immediate release (IR), film-coated tablets intended for oral administration. Each tablet contains 50 mg nirogacestat as 66.525 mg nirogacestat hydrobromide. OGSIVEO tablets are round, biconvex with an approximate diameter of 8 mm. They are film coated, orange in color, and debossed with “50” on one face and plain on the other face. OGSIVEO tablets contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate type A.
Pharmacodynamics
There is an exposure-response relationship between nirogacestat exposure and Grade 3 hypophosphatemia with a higher risk of Grade 3 hypophosphatemia at higher exposure.
Pharmacokinetics
- Steady-state exposure (Mean %CV):
Cmax: 508 (62) ng/mL AUC0-tau: 3370 (58) ng·h/mL Time to steady-state: Approximately 6 days
- Accumulation ratio (Median Min, Max): 1.6 (1.3, 4.6)
- Absorption:
Tmax (Median Min, Max): 1.5 (0.5, 6.5) hours Absolute bioavailability: 19% Food effect (dose-normalized GMR% 90% CI): Cmax: 93% (55%, 166%) AUC: 114% (76%, 171%)
- Distribution:
Serum protein binding: 99.6% Protein Binding: Human serum albumin: 94.6% α-1 acid glycoprotein: 97.9% Apparent volume of distribution (Vz/F) (Mean %CV): 1430 (65) L
- Elimination:
Apparent Systemic Clearance (CL/F) (Mean %CV): 45 (58) L/hr Terminal elimination half-life (t1/2) (Mean %CV): 23 (37) hr
- Metabolism:
Primary pathway: N-dealkylation via CYP3A4 (85%) Secondary pathways: Metabolism by CYP 3A4, 2C19, 2C9, and 2D6
Nonclinical Toxicology
A 6-month carcinogenicity study on transgenic rasH2 mice receiving up to 100 mg/kg/day of oral nirogacestat found no statistically significant neoplastic findings. Exposure levels were lower than those in humans at the recommended dose of 150 mg twice daily. The carcinogenic potential in rats remains unassessed. Mutagenesis tests, including bacterial reverse mutation and chromosome aberration assays, revealed nirogacestat to be non-mutagenic and non-clastogenic. In fertility studies on rats, nirogacestat led to reduced fertility at doses ≥ 5 mg/kg/day and caused complete infertility at doses ≥ 40 mg/kg/day. Adverse effects included ovarian atrophy, reduced testes weights, and decreased sperm concentration and motility.
Clinical Studies
The efficacy of OGSIVEO was assessed in the DeFi trial involving 142 adult patients with progressing desmoid tumors not suitable for surgery. Patients received either 150 mg OGSIVEO or placebo orally twice daily until disease progression or unacceptable toxicity. The primary efficacy outcome was progression-free survival (PFS) based on RECIST v1.1 criteria, evaluated by blinded independent central review or clinical progression by the investigator. Additional efficacy measures included objective response rate (ORR) and assessment of worst pain using the Brief Pain Inventory-Short Form (BPI-SF).
- Patient Characteristics:
Median age: 34 years; 65% female; 83% White. Tumor characteristics: 23% intra-abdominal, 41% multifocal disease, 81% CTNNB1 mutation. Prior therapy: 23% received no prior therapy, 44% received ≥3 prior lines of therapy. BPI-SF item 3 (worst pain) score of ≥2 in 50% of patients.
- Efficacy Results:
OGSIVEO demonstrated significant improvement compared to placebo: Progression-free survival: Median not reached vs. 15.1 months; Hazard ratio 0.29, p < 0.001. Objective response rate: 41% vs. 8%, p < 0.001. Radiographic progression accounted for most events. Kaplan-Meier analysis supported PFS improvement with OGSIVEO. Exploratory analysis of PFS based on radiographic progression alone showed similar benefits.
- Conclusion:
OGSIVEO significantly improved progression-free survival and objective response rate compared to placebo in patients with progressing desmoid tumors, with favorable pain relief observed in the OGSIVEO arm.
How Supplied
OGSIVEO (nirogacestat) is supplied as orange, film-coated 50 mg tablets debossed with a “50” on one side. The tablets are packaged in high density polyethylene (HDPE) bottles with child-resistant closures. Each bottle contains 180 tablets: NDC # 82448-050-18.
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.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
1.Diarrhea: OGSIVEO may cause diarrhea, including severe cases. If you experience persistent diarrhea that doesn't improve with supportive care, please contact your healthcare provider promptly. 2. Ovarian Toxicity: Females of reproductive potential should be aware that OGSIVEO can lead to ovarian toxicity, potentially impacting fertility even after discontinuation. If you notice symptoms like hot flashes or menstrual irregularities, inform your healthcare provider. 3. Liver Toxicity: Be aware that OGSIVEO might elevate liver transaminase levels (ALT or AST). Your healthcare provider will monitor these levels regularly. 4. Non-Melanoma Skin Cancers: OGSIVEO may increase the risk of developing new non-melanoma skin cancers. Keep an eye out for any new or changing skin lesions and promptly report them to your healthcare provider. 5. Electrolyte Abnormalities: OGSIVEO can lead to electrolyte imbalances such as hypophosphatemia or hypokalemia. If you experience muscle pain or weakness, notify your healthcare provider. 6. Embryo-Fetal Toxicity: Pregnant women and females of reproductive potential should understand the potential risks to the fetus. Effective contraception should be used during OGSIVEO treatment and for one week after the last dose. Male partners should also use effective contraception during this time. 7. Lactation: Avoid breastfeeding while taking OGSIVEO and for one week after the last dose. 8. Drug Interactions: Inform your healthcare provider about all medications you're taking, including over-the-counter drugs, vitamins, and herbal products. Avoid starfruit, Seville oranges, grapefruit, and their juices while on OGSIVEO. For further information, please refer to the FDA-approved patient labeling.
Precautions with Alcohol
Alcohol-Nirogacestat interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Nirogacestat Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Nirogacestat Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.