Nirogacestat is a gamma-secretase inhibitor. It is indicated for use in adult patients with progressing desmoid tumors who require systemic treatment. Severe diarrhea, hepatotoxicity, and ovarian toxicity resulting in impaired fertility have been reported with nirogacestat therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take nirogacestat with or without food.
-Swallow tablets whole; do not break, crush, or chew tablets.
-Avoid grapefruit products, Seville oranges, and starfruit.
-Separate the administration of nirogacestat and antacids by at least 2 hours.
-If a dose is missed (or vomited), skip the dose and take the next dose at the regularly scheduled time.
Diarrhea occurred more often in patients with progressing desmoid tumors who received nirogacestat (84%; grade 3, 16%) compared with placebo (35%; grade 3, 1.4%) in a randomized trial. Treat patients who develop diarrhea with antidiarrheal medications. Therapy interruption and a dosage reduction are recommended in patients who develop severe and persistent diarrhea despite maximal medical therapy. The median time to first diarrhea event was 9 (range, 2 to 434) days in nirogacestat-treated patients.
Nausea (54% vs. 1.4%; grade 3, 39% vs. 0%), stomatitis (39% vs. 4%; grade 3, 4% vs. 0%), and abdominal pain (22% vs. 14%; grade 3, 1.4% and 1.4%) were reported more often in patients with progressing desmoid tumors who received nirogacestat (n = 69) compared with placebo (n = 72) in a randomized trial.
Ovarian toxicity, including ovarian failure, premature menopause/menopause, and amenorrhea, occurred in 75% of patients with progressing desmoid tumors who received nirogacestat (n = 36) compared with no patients who received placebo (n = 37) in a randomized trial. Long-term effects on fertility have not been established.
Rash (68% vs. 14%; grade 3, 6% vs. 0%) and alopecia (19% vs. 1.4%) occurred more often in patients with progressing desmoid tumors who received nirogacestat (n = 69) compared with placebo (n = 72) in a randomized trial. Additionally, hidradenitis suppurativa and folliculitis each were reported in less than 15% of nirogacestat-treated patients.
Fatigue occurred more often in patients with progressing desmoid tumors who received nirogacestat (54%; grade 3, 2.9%) compared with placebo (38%; grade 3, 0%) in a randomized trial.
Headache occurred more often in patients with progressing desmoid tumors who received nirogacestat (30%) compared with placebo (15%) in a randomized trial.
Cough (20% vs. 6%) and dyspnea (16% vs. 6%) were reported more often in patients with progressing desmoid tumors who received nirogacestat (n = 69) compared with placebo (n = 72) in a randomized trial.
Upper respiratory tract infection occurred more often in patients with progressing desmoid tumors who received nirogacestat (17%) compared with placebo (2.8%) in a randomized trial. Additionally, influenza-like illness was reported in less than 15% of nirogacestat-treated patients.
New nonmelanoma skin cancer including cutaneous squamous cell carcinoma (2.9%) and basal cell carcinoma (1.4%) occurred in less than 15% of patients with progressing desmoid tumors who received nirogacestat (n = 69) in a randomized trial.
Epistaxis was reported in less than 15% of patients with progressing desmoid tumors who received nirogacestat (n = 69) in a randomized trial.
Elevated hepatic enzymes, including increased AST (33% vs. 18%; grade 3 or 4, 2.9% vs. 1.4%) and ALT (30% vs. 21%; grade 3 or 4, 6% vs. 1.4%) levels, were reported more often in patients with progressing desmoid tumors who received nirogacestat (n = 69) compared with placebo (n = 72) in a randomized trial. Therapy interruption, a dosage reduction, or therapy discontinuation may be necessary in patients who develop treatment-related hepatotoxicity.
Glycosuria/increased urine glucose level (51% vs. 0%) and proteinuria/increased urine protein level (40% vs. 25%) were reported more often in patients with progressing desmoid tumors who received nirogacestat (n = 69) compared with placebo (n = 72) in a randomized trial.
Hypophosphatemia/decreased phosphate level (65% vs. 11%) and hypokalemia/decreased potassium level (22% vs. 4.2%; grade 3 or 4, 1.4% vs. 0%) were reported more often in patients with progressing desmoid tumors who received nirogacestat (n = 69) compared with placebo (n = 72) in a randomized trial. Additionally, a phosphate level less than 2 mg/dL occurred in 20% of nirogacestat-treated patients. Administer electrolyte supplements as necessary. Therapy interruption and a dosage reduction are recommended in patients who develop severe and persistent electrolyte abnormalities despite maximal supplement therapy.
Monitor patients for symptoms of diarrhea during nirogacestat therapy; manage using antidiarrheal medications. Therapy interruption and a dosage reduction may be necessary in patients who develop severe diarrhea.
Monitor liver function tests regularly during nirogacestat therapy. Therapy interruption, a dosage reduction, or therapy discontinuation may be necessary in patients who develop treatment-related hepatic disease.
Perform dermatologic evaluations prior to starting nirogacestat and routinely during treatment for signs of skin cancer (e.g., cutaneous squamous cell carcinoma and basal cell carcinoma).
Evaluate patients for electrolyte imbalance regularly during nirogacestat therapy; administer supplements as necessary. Therapy interruption and a dosage reduction may be necessary in patients who develop severe hypophosphatemia or hypokalemia.
Nirogacestat may cause fetal harm or pregnancy loss when administered during pregnancy, based on its mechanism of action and findings from animal studies. Advise pregnant patients of the potential risk to a fetus. Embryo-fetal toxicity (e.g., decreased fetal body weights, fetal subcutis edema) and embryo-fetal death were reported in the offspring of pregnant rats following oral nirogacestat dosages that resulted in maternal exposures below the human exposure at the recommended dose.
Counsel patients about the reproductive risk and contraception requirements during nirogacestat treatment. Perform pregnancy testing prior to starting therapy in patients of reproductive potential. These patients should use effective contraception during and for 1 week after treatment with nirogacestat. Based on a potential for male-mediated teratogenicity, advise males with partners of reproductive potential to use effective contraception during nirogacestat therapy and for 1 week after the last dose. Prior to starting nirogacestat therapy, advise patients on the potential risks for ovarian toxicity and infertility. The duration of nirogacestat therapy and gonadal functional status at the time of treatment may impact fertility. Monitor patients for menstrual cycle irregularity, hot flashes, night sweats, and vaginal dryness. Nirogacestat may result in infertility in females or males based on findings from animal studies; it may interfere with folliculogenesis and spermatogenesis resulting in changes including ovarian atrophy.
It is not known if nirogacestat or its metabolites are secreted in human milk or if it has effects on the breast-fed child or on milk production. Due to the potential for serious adverse reactions in breastfed children, discontinue breast-feeding during nirogacestat therapy and for 1 week after the last dose.
For the treatment of desmoid tumor:
NOTE: Nirogacestat is designated as an orphan drug by the FDA for this indication.
-for the treatment of progressive desmoid tumors that require systemic therapy:
Oral dosage:
Adults: 150 mg orally twice daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients who develop toxicity may require therapy interruption, a dosage reduction, or therapy discontinuation. At a median follow-up of 15.9 months, the median progression-free survival (PFS) time was significantly improved with nirogacestat compared with placebo (not estimable vs. 15.1 months; hazard ratio (HR) = 0.29; 95% CI, 0.15 to 0.55; p-value less than 0.001) in patients with progressing desmoid tumors in a randomized, double-blind, phase 3 (DeFi) trial (n = 142). Patients in this trial had either not received prior treatment for progressing desmoid tumors that were not amenable to surgery or had refractory or recurrent desmoid tumors after at least 1 line of therapy.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Diarrhea
Grade 3 or 4 toxicity (lasting for 3 days or more despite maximal medical therapy): Hold nirogacestat therapy. When the toxicity resolves to grade 1 or less or baseline, then restart at a reduced dosage of 100 mg twice daily.
Electrolyte Abnormalities
Grade 3 or 4 hypophosphatemia (lasting for 3 days or more despite maximal replacement therapy): Hold nirogacestat therapy. When the toxicity resolves to grade 1 or less or baseline, then restart at a reduced dosage of 100 mg twice daily.
Grade 3 or 4 hypokalemia (despite maximal replacement therapy): Hold nirogacestat therapy. When the toxicity resolves to grade 1 or less or baseline, then restart at a reduced dosage of 100 mg twice daily.
Other Toxicity
Other grade 3 (severe), grade 4 (life-threatening), or persistent intolerable grade 2 toxicity: Hold nirogacestat therapy until the toxicity resolves to grade 1 or less or baseline. After considering the potential benefit and likelihood of toxicity recurrence, may restart at a reduced dosage of 100 mg twice daily. Permanently discontinue nirogacestat therapy if the severe or life-threatening toxicity recurs upon rechallenge at the reduced dose.
Maximum Dosage Limits:
-Adults
300 mg/day PO.
-Geriatric
300 mg/day PO.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Specific guidelines for initial dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Treatment-Related Hepatotoxicity
Grade 2 elevated ALT or AST levels (3 to 5 times the ULN): Hold nirogacestat therapy. When the ALT and AST levels resolves to less than 3 times the ULN or baseline, then restart at a reduced dosage of 100 mg twice daily.
Grade 3 or 4 elevated ALT or AST levels (more than 5 times the ULN): Permanently discontinue nirogacestat therapy.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with nirogacestat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with nirogacestat is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with nirogacestat. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the AUC of acalabrutinib was increased by approximately 2- to 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. If nirogacestat is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with nirogacestat may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Nirogacestat is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like nirogacestat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If nirogacestat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. If nirogacestat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like nirogacestat can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If nirogacestat is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Avoid concomitant use of nirogacestat and adagrasib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide with nirogacestat due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. If nirogacestat is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like nirogacestat can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If nirogacestat is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Moderate) Monitor for evidence of alfuzosin-related adverse effects including hypotension and QT prolongation if coadministered with nirogacestat. Increased alfuzosin exposure may occur. Alfuzosin is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased the alfuzosin AUC by 1.3-fold.
Alprazolam: (Major) Avoid coadministration of alprazolam and nirogacestat due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with nirogacestat, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
Aluminum Hydroxide: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Amiodarone: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with nirogacestat is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amobarbital: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of nirogacestat and clarithromycin due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 3.46-fold. (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Antacids: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Apalutamide: (Major) Avoid concomitant use of nirogacestat and apalutamide. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Aprepitant, Fosaprepitant: (Major) Avoid concomitant use of nirogacestat and aprepitant/fosaprepitant. Concomitant use may increase the exposure of both medications and the risk for adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold. Administration of a moderate CYP3A inhibitor increased the aprepitant AUC by 2-fold.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of nirogacestat. Patients receiving both a CYP2D6 inhibitor plus nirogacestat may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; nirogacestat is a moderate CYP3A inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. If nirogacestat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like nirogacestat can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If nirogacestat is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid concomitant use of nirogacestat and atazanavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of nirogacestat and atazanavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold. (Major) Avoid concomitant use of nirogacestat and cobicistat due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase cobicistat exposure and the risk for cobicistat-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving nirogacestat. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Administration of another moderate CYP3A inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Avapritinib: (Major) Avoid coadministration of avapritinib with nirogacestat due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration of avapritinib 300 mg PO once daily with another moderate CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 210% at steady-state.
Barbiturates: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like nirogacestat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If nirogacestat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Berotralstat: (Major) Avoid concomitant use of nirogacestat and berotralstat due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Bexarotene: (Major) Avoid concomitant use of nirogacestat and bexarotene. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Bosentan: (Major) Avoid concomitant use of nirogacestat and bosentan. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Concomitant use may also increase bosentan exposure and the risk for bosentan-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; bosentan is a CYP3A substrate and moderate CYP3A inducer. Concomitant with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Bosutinib: (Major) Avoid concomitant use of bosutinib and nirogacestat as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A inhibitor.
Brexpiprazole: (Moderate) Use caution if coadministration of nirogacestat with brexpiprazole is necessary, as the systemic exposure of brexpiprazole may be increased resulting in an increase in brexpiprazole-related adverse reactions. Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and nirogacestat are coadministered with a moderate to strong inhibitor of CYP2D6 or if the patient is a poor metabolizer of CYP2D6. If nirogacestat is discontinued, adjust the brexpiprazole dosage to its original level. Brexpiprazole is a CYP3A and CYP2D6 substrate; nirogacestat is a moderate CYP3A inhibitor. Concomitant use of moderate CYP3A inhibitors with a strong or moderate CYP2D6 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
Brigatinib: (Major) Avoid coadministration of brigatinib with nirogacestat if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg). Brigatinib is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of nirogacestat. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A; nirogacestat is a moderate inhibitor of CYP3A. Coadministration with another moderate CYP3A inhibitor increased bromocriptine exposure by 2.8-fold.
Budesonide: (Moderate) Avoid coadministration of oral budesonide with nirogacestat due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide with nirogacestat due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide with nirogacestat due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with nirogacestat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and nirogacestat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when nirogacestat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping nirogacestat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If nirogacestat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and nirogacestat is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and nirogacestat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when nirogacestat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping nirogacestat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If nirogacestat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and nirogacestat is a CYP3A inhibitor.
Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with nirogacestat is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and nirogacestat is added or removed from therapy. Buspirone is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors increased buspirone exposure by 3.4 to 6-fold and was accompanied by increased buspirone-related adverse reactions.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%. (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%. (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Cabotegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with nirogacestat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Calcium Carbonate: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Avoid concomitant use of nirogacestat and H2 receptor blockers. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours. (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Calcium Carbonate; Simethicone: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Calcium; Vitamin D: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Carbamazepine: (Major) Avoid concomitant use of nirogacestat and carbamazepine. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Concomitant use may also increase carbamazepine exposure and the risk for carbamazepine-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; carbamazepine is a CYP3A substrate and strong CYP3A inducer. Concomitant with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with nirogacestat is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of nirogacestat, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Major) Avoid concomitant use of nirogacestat and cenobamate. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Ceritinib: (Major) Avoid concomitant use of nirogacestat and ceritinib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Chloramphenicol: (Major) Avoid concomitant use of nirogacestat and chloramphenicol due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like nirogacestat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If nirogacestat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with nirogacestat and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the AUC of cilostazol (single dose) by 73%; the AUC of 4-trans-hydroxycilostazol increased by 141%.
Cimetidine: (Major) Avoid concomitant use of nirogacestat and H2 receptor blockers. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Ciprofloxacin: (Major) Avoid concomitant use of nirogacestat and ciprofloxacin due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ciprofloxacin is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Cisapride: (Major) Avoid concomitant use of cisapride and nirogacestat; use increases cisapride exposure and the risk for adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program.
Clarithromycin: (Major) Avoid concomitant use of nirogacestat and clarithromycin due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 3.46-fold.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with nirogacestat; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with nirogacestat and monitor for adverse reactions. If nirogacestat is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A; nirogacestat is a moderate CYP3A inhibitor.
Cobicistat: (Major) Avoid concomitant use of nirogacestat and cobicistat due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase cobicistat exposure and the risk for cobicistat-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Cobimetinib: (Major) Avoid using cobimetinib and nirogacestat together for more than 14 days due to the risk for cobimetinib toxicity. For short-term coadministration, defined as 14 days or less of combination therapy, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg per day; consider alternative therapy for patients already taking a reduced dose of cobimetinib (40 or 20 mg per day). After discontinuation of nirogacestat, resume cobimetinib 60 mg per day. Cobimetinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Simulations have demonstrated that a short course of cobimetinib 20 mg once daily taken with a moderate CYP3A inhibitor produces similar concentrations to cobimetinib 60 mg per day alone.
Codeine: (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with nirogacestat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of nirogacestat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nirogacestat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Nirogacestat is a moderate inhibitor of CYP3A.
Colchicine: (Major) Avoid concomitant use of colchicine and nirogacestat due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Conivaptan: (Major) Avoid concomitant use of nirogacestat and conivaptan due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if coadministration of nirogacestat with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A; nirogacestat is a moderate CYP3A inhibitor.
Crizotinib: (Major) Avoid concomitant use of nirogacestat and crizotinib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase crizotinib exposure and the risk for crizotinib-related adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Cyclosporine: (Major) Avoid concomitant use of nirogacestat and cyclosporine due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase cyclosporine exposure and the risk for cyclosporine-related adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Dabrafenib: (Major) Avoid concomitant use of nirogacestat and dabrafenib. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Danazol: (Major) Avoid concomitant use of nirogacestat and danazol due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and danazol is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with nirogacestat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Darifenacin: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with nirogacestat. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor.
Darunavir: (Major) Avoid concomitant use of nirogacestat and darunavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase darunavir exposure and the risk for darunavir-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Darunavir; Cobicistat: (Major) Avoid concomitant use of nirogacestat and cobicistat due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase cobicistat exposure and the risk for cobicistat-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold. (Major) Avoid concomitant use of nirogacestat and darunavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase darunavir exposure and the risk for darunavir-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of nirogacestat and cobicistat due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase cobicistat exposure and the risk for cobicistat-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold. (Major) Avoid concomitant use of nirogacestat and darunavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase darunavir exposure and the risk for darunavir-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with nirogacestat. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A substrate; nirogacestat is a moderate inhibitor of CYP3A.
Delavirdine: (Major) Avoid concomitant use of nirogacestat and delavirdine due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Dexlansoprazole: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Dextromethorphan; Quinidine: (Moderate) Monitor ECG and for quinidine-related adverse reactions if coadministration with nirogacestat is necessary. Concomitant use may result in increased plasma concentrations of quinidine. Quinidine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Diazepam: (Moderate) Monitor for changes in diazepam response if concomitant use with nirogacestat is necessary. Nirogacestat may have an unpredictable effect on diazepam overall exposure which may increase the risk for diazepam-related adverse reactions, including sedation and respiratory depression, or decrease diazepam efficacy. Diazepam is a CYP2C19 and CYP3A substrate and nirogacestat is a CYP2C19 inducer and CYP3A inhibitor.
Dihydroergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of ergotamine and nirogacestat. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Diltiazem: (Major) Avoid concomitant use of nirogacestat and diltiazem due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase diltiazem exposure and the risk for diltiazem-related adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with nirogacestat is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with other moderate CYP3A inhibitors.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with nirogacestat is necessary as concurrent use may increase dofetilide exposure. Nirogacestat is a moderate CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmia (torsade de pointes).
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with nirogacestat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with nirogacestat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with nirogacestat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with nirogacestat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with nirogacestat due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP3A and nirogacestat is a moderate CYP3A inhibitor. Concurrent use of CYP3A inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of doxorubicin with nirogacestat due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP3A and nirogacestat is a moderate CYP3A inhibitor. Concurrent use of CYP3A inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Monitor for increased toxicity (e.g., feeling high, dizziness, confusion, somnolence) of dronabinol if coadministered with nirogacestat. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor.
Dronedarone: (Major) Avoid concomitant use of nirogacestat and dronedarone due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase dronedarone exposure and the risk for dronedarone -related adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of nirogacestat with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Duvelisib: (Major) Avoid concomitant use of nirogacestat and duvelisib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase duvelisib exposure and the risk for duvelisib-related adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Efavirenz: (Major) Avoid concomitant use of nirogacestat and efavirenz. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use is predicted to reduce nirogacestat overall exposure by 67%.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of nirogacestat and efavirenz. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use is predicted to reduce nirogacestat overall exposure by 67%.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of nirogacestat and efavirenz. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use is predicted to reduce nirogacestat overall exposure by 67%.
Elacestrant: (Major) Avoid concomitant use of elacestrant and nirogacestat due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
Elagolix: (Major) Avoid concomitant use of nirogacestat and elagolix. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of nirogacestat and elagolix. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with nirogacestat. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A, and nirogacestat is a moderate CYP3A inhibitor. Coadministration of other moderate CYP3A inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with nirogacestat; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); nirogacestat is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If nirogacestat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with nirogacestat; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; nirogacestat is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
Eliglustat: (Major) Avoid coadministration of eliglustat with nirogacestat in intermediate or poor CYP2D6 metabolizers (IMs or PMs). In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Concurrent use is contraindicated in EMs and IMs also receiving a strong or moderate CYP2D6 inhibitor. Eliglustat is a CYP3A and CYP2D6 substrate; nirogacestat is a moderate inhibitor of CYP3A. Concurrent use may result in unexpectedly high plasma concentrations of eliglustat, further increasing the risk of serious adverse events (e.g., cardiac arrhythmias).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of nirogacestat and cobicistat due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase cobicistat exposure and the risk for cobicistat-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of nirogacestat and cobicistat due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase cobicistat exposure and the risk for cobicistat-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of rilpivirine with nirogacestat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of rilpivirine with nirogacestat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Encorafenib: (Major) Avoid concomitant use of nirogacestat and encorafenib. Concurrent use may decrease nirogacestat exposure and efficacy and increase encorafenib exposure and the risk for encorafenib-related adverse effects. While concomitant use is not recommended, if coadministration is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Entrectinib: (Major) Avoid coadministration of entrectinib with nirogacestat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and nirogacestat is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Enzalutamide: (Major) Avoid concomitant use of nirogacestat and enzalutamide. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with nirogacestat in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving nirogacestat, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating nirogacestat and periodically thereafter. Eplerenone is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Ergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of ergotamine and nirogacestat. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Ergotamine; Caffeine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of ergotamine and nirogacestat. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Erythromycin: (Major) Avoid concomitant use of nirogacestat and erythromycin due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and erythromycin is a moderate CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 2.73-fold.
Eslicarbazepine: (Major) Avoid concomitant use of nirogacestat and eslicarbazepine. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Esomeprazole: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Etrasimod: (Major) Avoid concomitant use of etrasimod and nirogacestat in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Etrasimod is a CYP2C9 and CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Etravirine: (Major) Avoid concomitant use of nirogacestat and etravirine. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Concomitant use may also increase etravirine exposure and the risk for etravirine-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; etravirine is a CYP3A substrate and moderate CYP3A inducer. Concomitant with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with nirogacestat is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with nirogacestat is necessary. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Famotidine: (Major) Avoid concomitant use of nirogacestat and H2 receptor blockers. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Fedratinib: (Major) Avoid concomitant use of nirogacestat and fedratinib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Felodipine: (Moderate) Concurrent use of felodipine and nirogacestat should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concurrent use of another moderate CYP3A inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. If nirogacestat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like nirogacestat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If nirogacestat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fexinidazole: (Major) Avoid concomitant use of fexinidazole and nirogacestat and monitor for decreased fexinidazole efficacy if coadministration is necessary. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and nirogacestat is a moderate CYP3A inhibitor.
Finasteride; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with nirogacestat is necessary. Tadalafil is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or nirogacestat; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and nirogacestat is contraindicated due to increased flibanserin exposure, which can result in severe hypotension and syncope. If initiating flibanserin following use of nirogacestat, start flibanserin at least 2 weeks after the last dose of nirogacestat. If initiating nirogacestat following flibanserin use, start nirogacestat at least 2 days after the last dose of flibanserin. Flibanserin is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Fluconazole: (Major) Avoid concomitant use of nirogacestat and fluconazole due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 3.18-fold.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with nirogacestat is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Fluvoxamine: (Major) Avoid concomitant use of nirogacestat and fluvoxamine due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and fluvoxamine is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Fosamprenavir: (Major) Avoid concomitant use of nirogacestat and fosamprenavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase fosamprenavir exposure and the risk for fosamprenavir-related adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Fosphenytoin: (Major) Avoid concomitant use of nirogacestat and phenytoin/fosphenytoin. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during nirogacestat treatment due to the risk of increased nirogacestat exposure and adverse reactions. Nirogacestat is a CYP3A substrate and grapefruit juice is a CYP3A inhibitor.
Guanfacine: (Major) Decrease the dose of extended-release guanfacine by 50% if coadministration with nirogacestat is necessary; if nirogacestat is discontinued, the dose of extended-release guanfacine may be increased to the recommended level. Monitor patients closely for adverse effects including hypotension, drowsiness, lethargy, and bradycardia. Recommendations for immediate-release guanfacine are not available. Guanfacine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
H2-blockers: (Major) Avoid concomitant use of nirogacestat and H2 receptor blockers. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like nirogacestat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If nirogacestat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like nirogacestat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If nirogacestat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like nirogacestat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If nirogacestat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibrutinib: (Major) If ibrutinib is coadministered with nirogacestat, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for a B-cell malignancy. Resume ibrutinib at the previous dose if nirogacestat is discontinued. No initial ibrutinib dosage reduction is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen; Famotidine: (Major) Avoid concomitant use of nirogacestat and H2 receptor blockers. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. If nirogacestat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like nirogacestat can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If nirogacestat is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Avoid concomitant use of nirogacestat and idelalisib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with nirogacestat is necessary. Ifosfamide is metabolized by CYP3A to its active alkylating metabolites. Nirogacestat is a moderate CYP3A inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Imatinib: (Major) Avoid concomitant use of nirogacestat and imatinib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Indinavir: (Major) Avoid concomitant use of nirogacestat and indinavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Infigratinib: (Major) Avoid concomitant use of infigratinib and nirogacestat. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Isavuconazonium: (Major) Avoid concomitant use of nirogacestat and isavuconazonium due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and isavuconazonium is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of nirogacestat and rifampin. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use is predicted to reduce nirogacestat overall exposure by 85%.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of nirogacestat and rifampin. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use is predicted to reduce nirogacestat overall exposure by 85%.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with nirogacestat is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Itraconazole: (Major) Avoid concomitant use of nirogacestat and itraconazole due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 6.33- to 8.2-fold.
Ivabradine: (Major) Avoid coadministration of ivabradine and nirogacestat as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A and nirogacestat is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors increased the AUC of ivabradine by 2- to 3-fold.
Ivacaftor: (Major) If nirogacestat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with nirogacestat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling. Multiple doses of the moderate CYP3A inhibitor are predicted to increase the ivosidenib steady-state AUC to 190% of control.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of nirogacestat is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Ketoconazole: (Major) Avoid concomitant use of nirogacestat and ketoconazole due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 5.19-fold.
Lansoprazole: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of nirogacestat and clarithromycin due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 3.46-fold. (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with nirogacestat is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lefamulin: (Major) Avoid concomitant use of nirogacestat and oral lefamulin due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase exposure from oral lefamulin tablets and the risk for lefamulin-related adverse effects. An interaction is not expected with intravenous lefamulin. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; oral lefamulin is a CYP3A substrate and moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Lemborexant: (Major) Avoid coadministration of lemborexant and nirogacestat as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the lemborexant overall exposure by up to 4.5-fold.
Lenacapavir: (Major) Avoid concomitant use of nirogacestat and lenacapavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Letermovir: (Major) Avoid concomitant use of nirogacestat and letermovir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and letermovir is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Levoketoconazole: (Major) Avoid concomitant use of nirogacestat and ketoconazole due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 5.19-fold.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with nirogacestat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with nirogacestat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with nirogacestat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Lomitapide: (Contraindicated) Concomitant use of nirogacestat and lomitapide is contraindicated due to increased lomitapide exposure. If treatment with nirogacestat is unavoidable, lomitapide should be stopped during the course of treatment. Lomitapide is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Although concomitant use of moderate CYP3A inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use based on the 27-fold increase in exposure observed with coadministration of a strong CYP3A inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and nirogacestat is contraindicated as concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Concomitant use may also increase nirogacestat exposure. Lonafarnib is a CYP3A substrate and strong CYP3A inhibitor; nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Lopinavir; Ritonavir: (Major) Avoid concomitant use of nirogacestat and ritonavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Lorlatinib: (Major) Avoid concomitant use of nirogacestat and lorlatinib. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and lorlatinib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with nirogacestat is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a sensitive substrate of CYP3A and nirogacestat is a moderate CYP3A inhibitor.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of nirogacestat and lumacaftor; ivacaftor. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%. (Major) If nirogacestat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of nirogacestat and lumacaftor; ivacaftor. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use with nirogacestat is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased lumateperone exposure by approximately 2-fold.
Lurasidone: (Major) The recommended starting dose of lurasidone is 20 mg daily (maximum, 80 mg daily) if coadministration with nirogacestat is necessary. Reduce the lurasidone dose to half of its original dose level if nirogacestat is added to existing lurasidone therapy. Lurasidone is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased lurasidone exposure by 116%.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and nirogacestat due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Macitentan; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with nirogacestat is necessary. Tadalafil is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
Magnesium Hydroxide: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Magnesium Salts: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with nirogacestat is necessary. Maraviroc is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors may result in increased maraviroc concentrations.
Mavacamten: (Major) Avoid concomitant use of nirogacestat and mavacamten. Concurrent use may decrease nirogacestat exposure and reduce its efficacy and increase mavacamten exposure and the risk for mavacamten-related adverse effects. While concomitant use is not recommended, if coadministration is necessary, a mavacamten dosage reduction may be required. Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting nirogacestat therapy. Avoid initiation of nirogacestat in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable nirogacestat therapy. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; mavacamten is a CYP3A substrate and moderate CYP3A inducer. Concomitant with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Medroxyprogesterone: (Moderate) Use caution if coadministration of nirogacestat with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A; nirogacestat is a moderate CYP3A inhibitor.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with nirogacestat is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A and nirogacestat is a moderate CYP3A inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. If nirogacestat is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with nirogacestat can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with nirogacestat is necessary. Repaglinide is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Methadone: (Moderate) Monitor for an altered clinical response to methadone therapy if concomitant use of nirogacestat is necessary; a methadone dosage adjustment may be required. Concomitant use may have an unpredictable effect on methadone overall exposure and may increase the risk for methadone-related adverse effects or decrease methadone efficacy. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6 and nirogacestat is a weak CYP2C19 inducer and moderate CYP3A inhibitor.
Methohexital: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Methylergonovine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of methylergonovine and nirogacestat. Concomitant use may increase methylergonovine exposure. Methylergonovine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Midazolam: (Major) Avoid coadministration of midazolam with nirogacestat. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and nirogacestat is a CYP3A inhibitor. Concomitant use has been observed to increase midazolam overall exposure by 2.07-fold.
Mifepristone: (Major) Avoid concomitant use of nirogacestat and mifepristone due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with nirogacestat and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mitotane: (Major) Avoid concomitant use of nirogacestat and mitotane. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and nirogacestat; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions. Mobocertinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Nafcillin: (Major) Avoid concomitant use of nirogacestat and nafcillin. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Naldemedine: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with nirogacestat. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and nirogacestat due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with nirogacestat is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. In vitro, coadministration with both strong and moderate CYP3A inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of nirogacestat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Naproxen; Esomeprazole: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Nefazodone: (Major) Avoid concomitant use of nirogacestat and nefazodone due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Nelfinavir: (Major) Avoid concomitant use of nirogacestat and nelfinavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase nelfinavir exposure and the risk for nelfinavir-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; nelfinavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid concomitant use of nirogacestat and netupitant due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
NIFEdipine: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with nirogacestat as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor.
Nilotinib: (Major) Avoid concomitant use of nirogacestat and nilotinib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with nirogacestat is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of nirogacestat and ritonavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with nirogacestat due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and nirogacestat is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Nizatidine: (Major) Avoid concomitant use of nirogacestat and H2 receptor blockers. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Olaparib: (Major) Avoid coadministration of olaparib with nirogacestat due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after nirogacestat is discontinued. Olaparib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and nirogacestat is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and nirogacestat may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If nirogacestat is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and nirogacestat. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Omeprazole: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours. (Major) Avoid concomitant use of nirogacestat and rifabutin. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Omeprazole; Sodium Bicarbonate: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours. (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with nirogacestat is necessary. Oxybutynin is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with moderate CYP3A inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. If nirogacestat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like nirogacestat can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If nirogacestat is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of paclitaxel with nirogacestat is necessary due to the risk of increased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. In vitro, coadministration with both strong and moderate CYP3A inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A inhibitors.
Pacritinib: (Major) Avoid concurrent use of pacritinib with nirogacestat due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Palovarotene: (Major) Avoid concomitant use of palovarotene and nirogacestat due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Pantoprazole: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and nirogacestat due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If nirogacestat is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of nirogacestat. Pemigatinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Pentobarbital: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Pexidartinib: (Major) Avoid concomitant use of nirogacestat and pexidartinib. Concurrent use may decrease nirogacestat exposure and reduce its efficacy and may increase pexidartinib exposure and the risk for pexidartinib-related adverse effects. While concomitant use is not recommended, if coadministration is necessary, a pexidartinib dosage reduction is required as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. Nirogacestat is a CYP3A substrate and and moderate CYP3A inhibitor; pexidartinib is a CYP3A substrate and moderate CYP3A inducer. Concomitant with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenobarbital: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Phenytoin: (Major) Avoid concomitant use of nirogacestat and phenytoin/fosphenytoin. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and phenytoin/fosphenytoin is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Pimozide: (Major) Avoid concomitant use of pimozide and nirogacestat. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate, and nirogacestat is a moderate CYP3A inhibitor.
Posaconazole: (Major) Avoid concomitant use of nirogacestat and posaconazole due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Pralsetinib: (Major) Avoid concomitant use of nirogacestat with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of pralsetinib by 71%.
Primidone: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and nirogacestat due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with nirogacestat; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and nirogacestat with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; nirogacestat is a moderate CYP3A inhibitor.
Proton pump inhibitors: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Quinidine: (Moderate) Monitor ECG and for quinidine-related adverse reactions if coadministration with nirogacestat is necessary. Concomitant use may result in increased plasma concentrations of quinidine. Quinidine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Quinine: (Moderate) Monitor for quinine-related adverse reactions if coadministration with nirogacestat is necessary. Concurrent use may increase quinine exposure. Quinine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Rabeprazole: (Major) Avoid concomitant use of nirogacestat and proton pump inhibitors. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Ranitidine: (Major) Avoid concomitant use of nirogacestat and H2 receptor blockers. Concurrent use may impair nirogacestat absorption which may decrease nirogacestat exposure and reduce its efficacy. Antacids may be used with nirogacestat but administration should be separated by at least 2 hours.
Ranolazine: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with nirogacestat is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with nirogacestat is necessary. Repaglinide is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Repotrectinib: (Major) Avoid concomitant use of nirogacestat and repotrectinib. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Ribociclib: (Major) Avoid concomitant use of nirogacestat and ribociclib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Ribociclib; Letrozole: (Major) Avoid concomitant use of nirogacestat and ribociclib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Rifabutin: (Major) Avoid concomitant use of nirogacestat and rifabutin. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Rifampin: (Major) Avoid concomitant use of nirogacestat and rifampin. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use is predicted to reduce nirogacestat overall exposure by 85%.
Rifapentine: (Major) Avoid concomitant use of nirogacestat and rifapentine. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Rilpivirine: (Moderate) Coadministration of rilpivirine with nirogacestat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with nirogacestat; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Ritlecitinib: (Major) Avoid concomitant use of nirogacestat and ritlecitinib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Ritonavir: (Major) Avoid concomitant use of nirogacestat and ritonavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with nirogacestat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the exposure of roflumilast by 70%.
Saquinavir: (Major) Avoid concomitant use of nirogacestat and saquinavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase saquinavir exposure and the risk for saquinavir -related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; saquinavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Secobarbital: (Major) Avoid concomitant use of nirogacestat and barbiturates. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and nirogacestat due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If nirogacestat is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of nirogacestat. Selpercatinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and nirogacestat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If nirogacestat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of nirogacestat. Selumetinib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase selumetinib exposure by 41%.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with nirogacestat is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. In a drug interaction study, coadministration with a moderate CYP3A inhibitor increased the AUC of sildenafil by 182%. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
Silodosin: (Moderate) Monitor for silodosin-related adverse reactions if coadministration with nirogacestat is necessary. Silodosin is a substrate of CYP3A and nirogacestat is a moderate CYP3A inhibitor. The effect of moderate CYP3A inhibitors has not been evaluated; however, plasma concentrations of silodosin may increase based on its interaction with strong CYP3A inhibitors.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with nirogacestat is necessary. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Siponimod: (Moderate) Concomitant use of siponimod and nirogacestat may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP2C9/CYP3A dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of nirogacestat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Sodium Bicarbonate: (Moderate) Separate the administration of nirogacestat and antacids by at least 2 hours. Simultaneous coadministration may impair nirogacestat absorption resulting in reduced exposure and efficacy.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and nirogacestat as concurrent use may increase sonidegib exposure. If concomitant use is necessary, administer nirogacestat for less than 14 days and monitor for an increased risk of sonidegib-related adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Sotorasib: (Major) Avoid concomitant use of nirogacestat and sotorasib. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with nirogacestat is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of nirogacestat and St. John's wort. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if nirogacestat must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of nirogacestat is necessary. If nirogacestat is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a moderate CYP3A inhibitor like nirogacestat can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If nirogacestat is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with nirogacestat. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor increased the suvorexant AUC by 2-fold.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with nirogacestat is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; nirogacestat is a moderate CYP3A inhibitor.
Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with nirogacestat is necessary. Tadalafil is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
Tamsulosin: (Moderate) Use caution if coadministration of nirogacestat with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with nirogacestat as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If nirogacestat is discontinued, wait at least 3 half-lives of nirogacestat before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with nirogacestat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with nirogacestat; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); nirogacestat is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If nirogacestat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with nirogacestat. Coadministration may increase the exposure of ticagrelor. Ticagrelor is a sensitive substrate of CYP3A; nirogacestat is a moderate inhibitor of CYP3A.
Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with nirogacestat is necessary. Concurrent use may increase the exposure of tinidazole. Tinidazole is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Tipranavir: (Major) Avoid concomitant use of nirogacestat and tipranavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase tipranavir exposure and the risk for tipranavir-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; tipranavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Tolvaptan: (Major) Avoid coadministration of nirogacestat when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with nirogacestat. In ADPKD patients receiving tolvaptan 90 mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased the tolvaptan AUC by 200%.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with nirogacestat is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of nirogacestat, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with nirogacestat is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of nirogacestat, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Major) Avoid concomitant use of nirogacestat and verapamil due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase verapamil exposure and the risk for verapamil-related adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with nirogacestat. Coadministration may increase the exposure of triazolam. Triazolam is a sensitive CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Tucatinib: (Major) Avoid concomitant use of nirogacestat and tucatinib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with nirogacestat. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with nirogacestat due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A; nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the AUC of vardenafil by 4-fold.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with nirogacestat due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of nirogacestat. Venetoclax is a CYP3A substrate; nirogacestat is a moderate CYP3A inhibitor.
Verapamil: (Major) Avoid concomitant use of nirogacestat and verapamil due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase verapamil exposure and the risk for verapamil-related adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of nirogacestat and clarithromycin due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use is predicted to increase nirogacestat overall exposure by 3.46-fold.
Voriconazole: (Major) Avoid concomitant use of nirogacestat and voriconazole due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Voxelotor: (Major) Avoid concomitant use of nirogacestat and voxelotor due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Nirogacestat is a gamma-secretase inhibitor. It works by blocking the proteolytic activation of the Notch receptor. Dysregulation of the Notch pathway is associated with the development and progression of desmoid tumors.
Nirogacestat is administered orally. It is highly protein bound (serum protein, 99.6%; serum albumin, 94.6%; alfa-1 acid glycoprotein, 97.9%) and has a mean apparent volume of distribution of 1,430 L (coefficient of variation (CV), 65%). The mean apparent systemic clearance is 45 L/hour (CV, 58%) and the mean terminal elimination half-life is 23 hours (CV, 37%) in patients with desmoid tumors who received nirogacestat. Nirogacestat is primarily metabolized by N-dealkylation via CYP3A4 (85%) and by CYP2C19, CYP2C9, and CYP2D6 to a lesser extent. Excretion occurs 38% in the feces, 17% in the urine, and 9.7% in expired air.
Affected cytochrome P450 isoenzymes or transporters: CYP3A4, CYP2C19
Nirogacestat is a CYP3A4 substrate, a moderate CYP3A4 inhibitor, and a CYP2C19 inducer. In vitro, nirogacestat is a P-gp substrate and an inducer of CYP2B6, CYP2C8, CYP2C9, and CYP2C19.
-Route-Specific Pharmacokinetics
Oral Route
The absolute bioavailability of nirogacestat is 19%. The mean Cmax and AUC(0 to tau) values were 508 nanograms (ng)/mL (coefficient of variation (CV), 62%) and 3,370 ng x hour/mL (CV, 58%) following nirogacestat administration in patients with desmoid tumors; the median Tmax was 1.5 (range, 0.5 to 6.5) hours. The time to steady-state was about 6 days and the median accumulation ratio was 1.6 (range, 1.3 to 4.6).
Effects of food: The dose-normalized geometric mean ratio values for the fed versus fasted states were 93% (90% CI, 55% to 166%) for Cmax and 114% (90% CI, 76% to 171%) for AUC in subjects that received nirogacestat. Therefore, nirogacestat may be taken with or without food.
-Special Populations
Hepatic Impairment
The mean Cmax and AUC values increased by up to 39% and 16%, respectively, in subjects with moderate hepatic impairment (Child-Pugh class B or NCI-ODWG group C) compared with subjects who had normal hepatic function. The impact of severe hepatic impairment on the pharmacokinetic parameters of nirogacestat is not known.
Renal Impairment
Mild or moderate renal impairment (estimated glomerular filtration rate of 41 mL/min/1.73 m2 or more) does not significantly impact the pharmacokinetic parameters of nirogacestat. Due to the high level of protein binding, nirogacestat is not expected to be dialyzable.
Geriatric
Age (range, 18 to 80 years) does not significantly impact the pharmacokinetic parameters of nirogacestat.
Gender Differences
Sex does not significantly impact the pharmacokinetic parameters of nirogacestat.
Ethnic Differences
Race (Asian, Black or African American, and White) does not significantly impact the pharmacokinetic parameters of nirogacestat.