Berotralstat is an oral plasma kallikrein inhibitor indicated for the prevention of hereditary angioedema (HAE) attacks in patients 12 years and older. Efficacy was established based on data from the APeX-2 trial (n = 120), which showed that berotralstat 150 mg/day and 110 mg/day significantly reduced HAE attacks by 44% and 30%, respectively, compared to placebo. Reductions were observed in the first month of treatment and were sustained through 24 weeks. In post-hoc analyses, 50% and 23% of patients receiving 150 mg/day and 27% and 10% of patients receiving 110 mg/day had at least a 70% or 90% reduction in HAE attack rates compared to baseline vs. 15% and 8% of patients who received placebo. Moderate or severe rated attacks decreased by 40% and 10% in patients receiving 150 mg/day and 110 mg/day, respectively, compared to placebo. Gastrointestinal reactions, including abdominal pain, vomiting, and diarrhea, occurred more frequently in patients receiving berotralstat 150 mg/day compared to berotralstat 110 mg/day and placebo. In general, these reactions occurred early after initiation, became less frequent with time, and typically resolved without intervention.
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 with food.
Gastrointestinal reactions, including abdominal pain (23% vs. 10% and 10%), vomiting (15% vs. 10% and 3%), and diarrhea (15% vs. 4% and 0%), occurred more frequently in patients receiving berotralstat 150 mg/day compared to berotralstat 110 mg/day and placebo, respectively. In general, these reactions occurred early after initiation, became less frequent with time, and typically resolved without intervention. Consider a reduced dose of 110 mg/day if gastrointestinal reactions persist. Gastroesophageal reflux (7%) and flatulence (6%) were also reported in berotralstat-treated patients during clinical trials.
QT prolongation was observed at dosages more than the recommended 150 mg/day and was concentration-dependent. Additional doses or doses of berotralstat more than 150 mg/day are not recommended.
Back pain (6%), headache (9%), and fatigue (6%) were reported in berotralstat-treated patients during clinical trials.
A maculopapular rash occurred in less than 1% of berotralstat-treated patients during clinical trials. The rash resolved, including in patients who continued treatment.
A single patient treated with berotralstat 150 mg/day discontinued treatment during clinical trials due to asymptomatic elevated hepatic enzymes (ALT more than 8 times the upper limit of normal [ULN] and AST more than 3 times the ULN). Total bilirubin was normal. No patients receiving berotralstat 110 mg/day or placebo developed transaminase concentrations more than 3 times the ULN. In addition to this patient, 2 berotralstat-treated patients developed laboratory-related hepatic adverse reactions compared to 1 placebo-treated patient. No serious adverse reactions related to elevated hepatic enzymes were reported.
Do not use berotralstat for treatment of acute attacks of hereditary angioedema (HAE). The safety and effectiveness of berotralstat for the treatment of acute HAE attacks have not been established.
Reduce the berotralstat dose to 110 mg/day in patients with moderate to severe hepatic disease (Child-Pugh Class B or C). No dosage adjustment is recommended for patients with mild impairment (Child-Pugh Class A).
Berotralstat is not recommended for use in patients with renal failure; it has not been studied in patients with end-stage renal disease (CrCl less than 15 mL/minute, eGFR less than 15 mL/minute/1.73 m2, or patients requiring dialysis). No dosage adjustment is recommended for patients with mild, moderate, or severe renal impairment.
There are insufficient data in pregnant women to inform drug-related risks with berotralstat use in pregnancy. No evidence of structural alterations was observed when berotralstat was administered to pregnant rats and rabbits during organogenesis at doses up to approximately 2 to 10 times the maximum recommended human daily dose in adults on an AUC basis.
There are no data on the presence of berotralstat in human milk, its effects on the breast-fed infant, or its effects on milk production. Berotralstat concentrations approximately 2% of the maternal plasma concentration were detected in rat pups when lactating dams were administered oral berotralstat. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for berotralstat and potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.
For angioedema prophylaxis in patients with hereditary angioedema:
Oral dosage:
Adults: 150 mg PO once daily.
Children and Adolescents 12 to 17 years: 150 mg PO once daily.
Maximum Dosage Limits:
-Adults
150 mg/day PO.
-Geriatric
150 mg/day PO.
-Adolescents
150 mg/day PO.
-Children
12 years: 150 mg/day PO.
1 to 11 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Reduce dose to 110 mg PO once daily in patients with moderate to severe hepatic impairment (Child-Pugh Class B or C). No dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Class A).
Patients with Renal Impairment Dosing
Berotralstat is not recommended for use in patients end-stage renal disease (CrCl less than 15 mL/minute, eGFR less than 15 mL/minute/1.73 m2, or patients requiring hemodialysis). No dosage adjustment is recommended for patients with mild, moderate, or severe renal impairment.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with berotralstat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with berotralstat 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 CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 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 berotralstat. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A substrate; berotralstat 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) Concomitant use of dihydrocodeine with berotralstat may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of berotralstat could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4; berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like berotralstat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If berotralstat 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 berotralstat is necessary. If berotralstat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like berotralstat 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 berotralstat 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.
Albuterol; Budesonide: (Moderate) Avoid coadministration of systemic budesonide with berotralstat due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. If berotralstat is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like berotralstat 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 berotralstat 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 berotralstat. Increased alfuzosin exposure may occur. Alfuzosin is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the alfuzosin AUC by 1.3-fold.
Alprazolam: (Major) Avoid coadministration of alprazolam and berotralstat 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 berotralstat, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
Amiodarone: (Moderate) Monitor for an increase in amiodarone-related adverse effects if concomitant use with berotralstat is necessary. Concomitant use may increase amiodarone exposure. Amiodarone is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 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 berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 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 berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 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 berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 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 berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 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 berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 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 berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amoxapine: (Major) Lower doses of amoxapine may be required during concurrent use of berotralstat due to the potential for increased amoxapine exposure. If berotralstat is discontinued, an increased dose of amoxapine may be necessary. Amoxapine is a CYP2D6 substrate; berotralstat is a CYP2D6 inhibitor.
Apalutamide: (Major) Avoid coadministration of berotralstat with apalutamide. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and apalutamide is a P-gp inducer.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of berotralstat and aprepitant/fosaprepitant due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Aprepitant is a CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. Administration of a moderate CYP3A4 inhibitor increased the aprepitant AUC by 2-fold.
Aripiprazole: (Major) Recommendations for managing aripiprazole and berotralstat vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; berotralstat is a moderate CYP2D6 and moderate CYP3A inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. If berotralstat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like berotralstat 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 berotralstat 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; Cobicistat: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with berotralstat as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving berotralstat. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Avapritinib: (Major) Avoid coadministration of avapritinib with berotralstat 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 CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of berotralstat with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and berotralstat is a CYP2C19 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like berotralstat 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 berotralstat 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.
Bosentan: (Moderate) Monitor for an increase in bosentan-related adverse reactions if concomitant use of berotralstat is necessary. Concomitant use of bosentan and berotralstat with a strong or moderate CYP2C9 inhibitor is not recommended. Concomitant use may increase bosentan exposure. Bosentan is a CYP3A and CYP2C9 substrate; berotralstat is a moderate CYP3A and weak CYP2C9 inhibitor.
Bosutinib: (Major) Avoid concomitant use of bosutinib and berotralstat 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 CYP3A4 substrate and berotralstat is a moderate CYP3A4 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 CYP3A4 inhibitor.
Brexpiprazole: (Major) Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose and monitor for brexpiprazole-related adverse effects if concomitant use with berotralstat is necessary. Concomitant use of a moderate CYP3A inhibitor with a moderate CYP2D6 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone. Brexpiprazole is a CYP3A and CYP2D6 substrate; berotralstat is a moderate CYP3A inhibitor and moderate CYP2D6 inhibitor.
Brigatinib: (Major) Avoid coadministration of brigatinib with berotralstat 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; berotralstat 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 berotralstat. 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 CYP3A4; berotralstat is a moderate inhibitor of CYP3A4. Coadministration with another moderate CYP3A4 inhibitor increased bromocriptine exposure by 2.8-fold.
Budesonide: (Moderate) Avoid coadministration of systemic budesonide with berotralstat due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Budesonide; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with berotralstat due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with berotralstat due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with berotralstat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with berotralstat is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and berotralstat is a weak CYP2C9 inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and berotralstat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when berotralstat 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 berotralstat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If berotralstat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and berotralstat is a CYP3A4 inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and berotralstat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when berotralstat 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 berotralstat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If berotralstat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and berotralstat is a CYP3A4 inhibitor.
Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with berotralstat is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and berotralstat is added or removed from therapy. Buspirone is a sensitive CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased buspirone exposure by 3.4 to 6-fold and was accompanied by increased buspirone-related adverse reactions.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Cabotegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with berotralstat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Capivasertib: (Major) Reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off if coadministration with berotralstat is necessary; monitor for adverse reactions. Concomitant use may increase capivasertib exposure which may increase the risk for capivasertib-related adverse effects. Capivasertib is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.5-fold.
Carbamazepine: (Major) Avoid coadministration of berotralstat with carbamazepine. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Concomitant use may also increase carbamazepine exposure and the risk for carbamazepine-related adverse effects. Berotralstat is a P-gp substrate and moderate CYP3A inhibitor; carbamazepine is a CYP3A substrate and P-gp inducer.
Celecoxib; Tramadol: (Moderate) Concurrent use of tramadol with berotralstat may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A4; berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like berotralstat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If berotralstat 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.
Chlorpromazine: (Moderate) Monitor for an increase in chlorpromazine-related adverse reactions, including QT prolongation, anticholinergic effects, orthostasis, and somnolence, if coadministration with berotralstat is necessary. Concomitant use may increase chlorpromazine exposure. Chlorpromazine is a CYP2D6 substrate and berotralstat is a CYP2D6 inhibitor.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with berotralstat and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of cilostazol (single dose) by 73%; the AUC of 4-trans-hydroxycilostazol increased by 141%.
Cisapride: (Major) Avoid concomitant use of cisapride and berotralstat; 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 berotralstat is a moderate CYP3A inhibitor. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program.
Citalopram: (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with berotralstat. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation. Citalopram is a sensitive CYP2C19 substrate; berotralstat is a weak inhibitor of CYP2C19.
Clomipramine: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with berotralstat; 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 CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of berotralstat. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; berotralstat is a CYP2C19 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with berotralstat and monitor for adverse reactions. If berotralstat 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 a CYP2D6 and CYP3A substrate and berotralstat is a moderate CYP2D6 and moderate CYP3A inhibitor.
Cobicistat: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with berotralstat as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Cobimetinib: (Major) Avoid using cobimetinib and berotralstat 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 berotralstat, resume cobimetinib 60 mg per day. Cobimetinib is a CYP3A substrate and berotralstat 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 berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with berotralstat may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or 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 adjustment of codeine until stable drug effects are achieved. Discontinuation of berotralstat could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If berotralstat is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Colchicine: (Major) Avoid concomitant use of colchicine and berotralstat 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 berotralstat is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if coadministration of berotralstat 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 CYP3A4 and berotralstat is a moderate CYP3A4 inhibitor.
Crizotinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with berotralstat is necessary; crizotinib exposure may increase. Crizotinib is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with berotralstat is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with berotralstat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and berotralstat 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 berotralstat. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; berotralstat is a moderate CYP3A inhibitor.
Darunavir: (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with berotralstat. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Darunavir; Cobicistat: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with berotralstat as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with berotralstat. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with berotralstat as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with berotralstat. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with berotralstat. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; berotralstat is a moderate inhibitor of CYP3A4.
Desipramine: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Desogestrel; Ethinyl Estradiol: (Moderate) Monitor for progestin-related adverse effects during concomitant use of desogestrel and berotralstat. Concomitant use has been observed to increase overall exposure to etonogestrel, the active metabolite of desogestrel, by 2.6-fold.
Dextromethorphan; Quinidine: (Moderate) Monitor ECG and for quinidine-related adverse reactions if coadministration with berotralstat is necessary. Concomitant use may result in increased plasma concentrations of quinidine. Quinidine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with berotralstat is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 and CYP3A substrate and berotralstat is a CYP2C19 and CYP3A inhibitor.
Diclofenac: (Moderate) Monitor for an increase in diclofenac-related adverse effects if concomitant use with berotralstat is necessary; a diclofenac dosage decrease may be required based on response. Concomitant use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and berotralstat is a CYP2C9 inhibitor.
Diclofenac; Misoprostol: (Moderate) Monitor for an increase in diclofenac-related adverse effects if concomitant use with berotralstat is necessary; a diclofenac dosage decrease may be required based on response. Concomitant use may increase diclofenac exposure. Diclofenac is a CYP2C9 substrate and berotralstat is a CYP2C9 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 berotralstat. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with berotralstat is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with berotralstat is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 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 CYP3A4 inhibitors.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with berotralstat is necessary as concurrent use may increase dofetilide exposure. Dofetilide is a minor CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with berotralstat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with berotralstat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with berotralstat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with berotralstat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Doxepin: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with berotralstat due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP2D6 and CYP3A and berotralstat is a moderate CYP2D6 inhibitor and moderate CYP3A inhibitor. Concurrent use of CYP2D6 or CYP3A inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of doxorubicin with berotralstat due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP2D6 and CYP3A and berotralstat is a moderate CYP2D6 inhibitor and moderate CYP3A inhibitor. Concurrent use of CYP2D6 or 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 berotralstat. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP3A4 substrate; berotralstat is a moderate CYP3A inhibitor.
Dronedarone: (Moderate) Monitor for increased toxicity of dronedarone during coadministration of berotralstat as concurrent use may increase the exposure of dronedarone. Dronedarone is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of berotralstat with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg. The systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 and CYP2D6 substrate and berotralstat is a moderate CYP3A4 and CYP2D6 inhibitor. The effects of concomitant administration of a moderate CYP3A4/CYP2D6 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 inhibition.
Duvelisib: (Moderate) Monitor for increased toxicity if duvelisib is coadministered with berotralstat. Coadministration may increase the exposure of duvelisib, increasing the risk of toxicity. Duvelisib is a CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor.
Elacestrant: (Major) Avoid concomitant use of elacestrant and berotralstat due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with berotralstat. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4 and berotralstat is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with berotralstat; 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); berotralstat 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 berotralstat 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 berotralstat 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 berotralstat; 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; berotralstat 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: (Contraindicated) Coadministration of berotralstat and eliglustat is contraindicated in extensive or intermediate CYP2D6 metabolizers (EMs or IMs). Avoid coadministration in poor CYP2D6 metabolizers (PMs). In PMs also receiving a strong CYP3A inhibitor, coadministration is contraindicated. Eliglustat is a CYP3A and CYP2D6 substrate; berotralstat is a moderate inhibitor of CYP3A and moderate inhibitor of CYP2D6. 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: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with berotralstat as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with berotralstat as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of rilpivirine with berotralstat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of rilpivirine with berotralstat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Encorafenib: (Major) Avoid concomitant use of encorafenib and berotralstat due to the risk for increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use 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. Encorafenib is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold.
Entrectinib: (Major) Avoid coadministration of entrectinib with berotralstat 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 berotralstat is a strong moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with berotralstat in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving berotralstat, 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 berotralstat and periodically thereafter. Eplerenone is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4 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 berotralstat. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and berotralstat 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 berotralstat. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Etrasimod: (Major) Avoid concomitant use of etrasimod and berotralstat 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 berotralstat is a moderate CYP3A inhibitor.
Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if concomitant use of berotralstat is necessary. Etravirine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with berotralstat is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with berotralstat is necessary. Simvastatin is a sensitive CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor.
Fedratinib: (Moderate) Closely monitor for an increase in fedratinib-related adverse effects if coadministered with berotralstat. Coadministration may increase fedratinib exposure. Fedratinib is a CYP3A and CYP2C19 substrate; berotralstat is an inhibitor of both CYP3A and CYP2C19. Coadministration with another dual CYP3A and CYP2C19 inhibitor increased fedratinib exposure by approximately 1.5-fold at steady-state.
Felodipine: (Moderate) Concurrent use of felodipine and berotralstat 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 CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Concurrent use of another moderate CYP3A4 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 berotralstat is necessary. If berotralstat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like berotralstat 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 berotralstat 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 berotralstat 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 berotralstat is a moderate CYP3A inhibitor.
Finasteride; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with berotralstat is necessary. Tadalafil is a CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or berotralstat; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Flecainide: (Moderate) Monitor for an increase in flecainide-related adverse reactions, including QT prolongation, if coadministration with berotralstat is necessary. Flecainide is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor. Plasma concentrations of flecainide may increase, especially in extensive CYP2D6 metabolizers.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and berotralstat is contraindicated due to increased flibanserin exposure, which can result in severe hypotension and syncope. If initiating flibanserin following use of berotralstat, start flibanserin at least 2 weeks after the last dose of berotralstat. If initiating berotralstat following flibanserin use, start berotralstat at least 2 days after the last dose of flibanserin. Flibanserin is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with berotralstat. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with berotralstat is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Fosamprenavir: (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with berotralstat. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Fosphenytoin: (Major) Avoid coadministration of berotralstat with fosphenytoin. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Concomitant use may also increase phenytoin exposure and the risk for phenytoin-related adverse effects. Berotralstat is a P-gp substrate and CYP2C9 and CYP2C19 inhibitor; phenytoin is a CYP2C9 and CYP2C19 substrate and P-gp inducer.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with berotralstat is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and berotralstat is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Grapefruit juice: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking grapefruit juice. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp substrate and grapefruit juice is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
Guanfacine: (Major) Decrease the dose of extended-release guanfacine by 50% if coadministration with berotralstat is necessary; if berotralstat 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 berotralstat is a moderate CYP3A inhibitor.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like berotralstat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If berotralstat 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 berotralstat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like berotralstat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If berotralstat 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 berotralstat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like berotralstat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If berotralstat 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 berotralstat, 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 berotralstat 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; berotralstat 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; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. If berotralstat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like berotralstat 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 berotralstat 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.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with berotralstat is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites; berotralstat is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Imipramine: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Infigratinib: (Major) Avoid concomitant use of infigratinib and berotralstat. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of berotralstat with rifampin. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and rifampin is a P-gp inducer.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of berotralstat with rifampin. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and rifampin is a P-gp inducer.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with berotralstat is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Ivabradine: (Major) Avoid coadministration of ivabradine and berotralstat as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4 and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased the AUC of ivabradine by 2- to 3-fold.
Ivacaftor: (Major) If berotralstat 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 berotralstat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with berotralstat 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 CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of berotralstat is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with berotralstat is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with berotralstat as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A substrate; berotralstat is a moderate CYP3A inhibitor.
Lemborexant: (Major) Avoid coadministration of lemborexant and berotralstat as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with berotralstat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with berotralstat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with berotralstat is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and berotralstat. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; berotralstat is a CYP2D6 inhibitor.
Lomitapide: (Contraindicated) Concomitant use of berotralstat and lomitapide is contraindicated due to increased lomitapide exposure. If treatment with berotralstat is unavoidable, lomitapide should be stopped during the course of treatment. Lomitapide is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 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 CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and berotralstat is contraindicated; concurrent use may increase lonafarnib exposure and the risk for lonafarnib-related adverse effects. Lonafarnib is a CYP2C9 and sensitive CYP3A substrate and berotralstat is a weak CYP2C9 and moderate CYP3A inhibitor.
Lorlatinib: (Major) Avoid coadministration of berotralstat with lorlatinib. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and lorlatinib is a P-gp inducer.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with berotralstat is necessary. Coadministration may increase the exposure of lovastatin. Lovastatin is a sensitive substrate of CYP3A4 and berotralstat is a moderate CYP3A4 inhibitor.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of berotralstat and lumacaftor. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and lumacaftor is a P-gp inducer. (Major) If berotralstat 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 berotralstat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of berotralstat and lumacaftor. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and lumacaftor is a P-gp inducer.
Lumateperone: (Major) Avoid coadministration of lumateperone and berotralstat as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A substrate; berotralstat is a moderate CYP3A inhibitor. Coadministration with a 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 berotralstat is necessary. Reduce the lurasidone dose to half of its original dose level if berotralstat is added to existing lurasidone therapy. Lurasidone is a sensitive CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased lurasidone exposure by 116%.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and berotralstat 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 berotralstat is a moderate CYP3A inhibitor.
Macitentan; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with berotralstat is necessary. Tadalafil is a CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Maprotiline: (Moderate) Monitor for an increase in maprotiline-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of maprotiline may be necessary. Concurrent use may increase exposure of maprotiline. Maprotiline is a CYP2D6 substrate and berotralstat is a CYP2D6 inhibitor.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with berotralstat is necessary. Maraviroc is a sensitive CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors may result in increased maraviroc concentrations.
Mavacamten: (Major) 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 berotralstat therapy. Avoid initiation of berotralstat 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 berotralstat therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP2C19 and CYP3A substrate and berotralstat is a weak CYP2C19 and moderate CYP3A inhibitor. Concomitant use with another weak CYP2C19 inhibitor in CYP2C19 normal and rapid metabolizers increased overall mavacamten exposure by 48%. 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%.
Meclizine: (Moderate) Monitor for meclizine-related adverse effects, such as drowsiness and anticholinergic effects, when coadministered with berotralstat. Concomitant use may increase the exposure to meclizine. Meclizine is a CYP2D6 substrate and berotralstat is a CYP2D6 inhibitor.
Medroxyprogesterone: (Moderate) Use caution if coadministration of berotralstat 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 CYP3A4 and berotralstat is a moderate CYP3A4 inhibitor.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with berotralstat is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A and berotralstat is a moderate CYP3A inhibitor.
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with berotralstat is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and berotralstat is a weak CYP2C9 inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. If berotralstat 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 CYP3A4 and berotralstat is a moderate CYP3A4 inhibitor. Concomitant use with berotralstat 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.
Meropenem: (Major) Avoid coadministration of berotralstat and meropenem. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and meropenem is a P-gp inducer.
Meropenem; Vaborbactam: (Major) Avoid coadministration of berotralstat and meropenem. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and meropenem is a P-gp inducer.
Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with berotralstat is necessary. Repaglinide is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. If berotralstat is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; berotralstat is a moderate CYP3A, weak CYP2C19, weak CYP2C9, and moderate CYP2D6 inhibitor. Concomitant use with berotralstat can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
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 berotralstat. Concomitant use may increase methylergonovine exposure. Methylergonovine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions, including bradycardia and hypotension, during coadministration with berotralstat. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and berotralstat is a CYP2D6 inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased metoprolol adverse reactions, including bradycardia and hypotension, during coadministration with berotralstat. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and berotralstat is a CYP2D6 inhibitor.
Mexiletine: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with berotralstat. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
Midazolam: (Major) Avoid coadministration of midazolam with berotralstat. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and berotralstat is a CYP3A4 inhibitor.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with berotralstat and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and berotralstat; 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 berotralstat 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%.
Naldemedine: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with berotralstat. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a CYP3A substrate; berotralstat is a moderate CYP3A inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and berotralstat 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 CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 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 berotralstat is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 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 CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of berotralstat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Nateglinide: (Moderate) Monitor for an increase in nateglinide-related adverse effects, such as hypoglycemia, if concomitant use with berotralstat is necessary; a nateglinide dosage reduction may be required. Concomitant use may increase nateglinide exposure. Nateglinide is a CYP2C9 substrate and berotralstat is a CYP2C9 inhibitor.
Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with berotralstat; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with berotralstat; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
Nelfinavir: (Moderate) Monitor for increased toxicity of nelfinavir if coadministered with berotralstat. Concomitant use may increase the plasma concentrations of nelfinavir. Nelfinavir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
NIFEdipine: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with berotralstat as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with berotralstat is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Nirogacestat: (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.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with berotralstat due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and berotralstat is a CYP3A4 inhibitor. Coadministration with another CYP3A4 inhibitor increased the AUC of nisoldipine by 30% to 45%.
Nortriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Olanzapine; Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with berotralstat. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
Olaparib: (Major) Avoid coadministration of olaparib with berotralstat 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 berotralstat is discontinued. Olaparib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the 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 berotralstat is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and berotralstat may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If berotralstat is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 and CYP2D6 substrate and berotralstat is a moderate CYP3A4 and CYP2D6 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and berotralstat. 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 berotralstat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Oxybutynin: (Moderate) Monitor for oxybutynin-related adverse reactions if coadministration with berotralstat is necessary. Oxybutynin is a CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor. Concomitant use with moderate CYP3A4 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 berotralstat is necessary. If berotralstat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with moderate CYP3A4 inhibitors like berotralstat 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 berotralstat 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 berotralstat is necessary due to the risk of increased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 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 CYP3A4 inhibitors.
Pacritinib: (Major) Avoid concurrent use of pacritinib with berotralstat due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Palovarotene: (Major) Avoid concomitant use of palovarotene and berotralstat 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 berotralstat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with berotralstat is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and berotralstat 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 berotralstat is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of berotralstat. Pemigatinib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Perphenazine; Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and berotralstat due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage 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. If berotralstat is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of berotralstat. Pexidartinib is a CYP3A substrate; berotralstat is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenobarbital: (Major) Avoid coadministration of berotralstat with phenobarbital. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and phenobarbital is a P-gp inducer.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of berotralstat with phenobarbital. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and phenobarbital is a P-gp inducer.
Phenytoin: (Major) Avoid coadministration of berotralstat with phenytoin. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Concomitant use may also increase phenytoin exposure and the risk for phenytoin-related adverse effects. Berotralstat is a P-gp substrate and CYP2C9 and CYP2C19 inhibitor; phenytoin is a CYP2C9 and CYP2C19 substrate and P-gp inducer.
Pimozide: (Major) Avoid concomitant use of pimozide and berotralstat. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is a CYP2D6 and CYP3A substrate, and berotralstat is a moderate CYP2D6 and moderate CYP3A inhibitor.
Pralsetinib: (Major) Avoid concomitant use of berotralstat 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 berotralstat 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 coadministration of berotralstat with primidone. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and primidone is a P-gp inducer.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and berotralstat 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 berotralstat is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Propafenone: (Major) Avoid concurrent use of propafenone and berotralstat; concurrent use may increase plasma concentrations of propafenone, which may lead to cardiac arrhythmias and exaggerated beta-blocking activity. Propafenone is a CYP2D6 and CYP3A substrate; berotralstat is a moderate CYP2D6 inhibitor and a moderate 3A inhibitor.
Propranolol: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of berotralstat as concurrent use may increase propranolol exposure. Propranolol is a CYP2D6 substrate and berotralstat is moderate CYP2D6 inhibitor.
Protriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Quinidine: (Moderate) Monitor ECG and for quinidine-related adverse reactions if coadministration with berotralstat is necessary. Concomitant use may result in increased plasma concentrations of quinidine. Quinidine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Quinine: (Moderate) Monitor for quinine-related adverse reactions if coadministration with berotralstat is necessary. Concurrent use may increase quinine exposure. Quinine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Ranolazine: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with berotralstat is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A substrate and berotralstat 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 berotralstat is necessary. Repaglinide is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with berotralstat due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a CYP3A and P-gp substrate and berotralstat is a moderate CYP3A and P-gp inhibitor.
Rifampin: (Major) Avoid coadministration of berotralstat with rifampin. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and rifampin is a P-gp inducer.
Rilpivirine: (Moderate) Coadministration of rilpivirine with berotralstat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with berotralstat; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with berotralstat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the exposure of roflumilast by 70%.
Saquinavir: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with berotralstat is necessary. Concomitant use may increase the plasma concentrations of saquinavir. Saquinavir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and berotralstat 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 berotralstat is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of berotralstat. Selpercatinib is a CYP3A substrate and berotralstat 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 berotralstat 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 berotralstat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of berotralstat. Selumetinib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with berotralstat is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A4 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 berotralstat is necessary. Silodosin is a substrate of CYP3A and berotralstat 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 berotralstat is necessary. Simvastatin is a sensitive CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor.
Siponimod: (Moderate) Concomitant use of siponimod and berotralstat 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 CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 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 berotralstat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and berotralstat as concurrent use may increase sonidegib exposure. If concomitant use is necessary, administer berotralstat for less than 14 days and monitor for an increased risk of sonidegib-related adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 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.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with berotralstat is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and berotralstat 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 coadministration of berotralstat with St. John's Wort. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and St. John's Wort is a P-gp inducer.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if berotralstat must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of berotralstat is necessary. If berotralstat is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate CYP3A4 inhibitor like berotralstat 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 berotralstat 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 berotralstat. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 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 berotralstat is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; berotralstat is a moderate CYP3A inhibitor.
Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with berotralstat is necessary. Tadalafil is a CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Tamsulosin: (Moderate) Use caution if coadministration of berotralstat with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg. The systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 and CYP2D6 substrate and berotralstat is a moderate CYP3A4 and CYP2D6 inhibitor. The effects of concomitant administration of a moderate CYP3A4/CYP2D6 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 inhibition.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with berotralstat 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 berotralstat is discontinued, wait at least 3 half-lives of berotralstat before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Terbinafine: (Moderate) Monitor for an increase in terbinafine-related adverse reactions if coadministration with berotralstat is necessary. Terbinafine is a CYP2C9 and CYP3A substrate; berotralstat is a dual weak CYP2C9 and moderate CYP3A inhibitor. Coadministration with a moderate CYP2C9 and moderate CYP3A inhibitor increased the Cmax and AUC of terbinafine by 52% and 69%, respectively.
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with berotralstat; 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); berotralstat 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 berotralstat 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 berotralstat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Thioridazine: (Contraindicated) Coadministration of thioridazine and berotralstat is contraindicated due to the potential for increased thioridazine exposure. Increased plasma concentrations of thioridazine are expected to increase the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes type arrhythmias. Thioridazine is a CYP2D6 substrate and berotralstat is a CYP2D6 inhibitor.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with berotralstat. Coadministration may increase the exposure of ticagrelor. Ticagrelor is a sensitive substrate of CYP3A; berotralstat is a moderate inhibitor of CYP3A.
Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with berotralstat is necessary. Concurrent use may increase the exposure of tinidazole. Tinidazole is a CYP3A4 substrate and berotralstat is a moderate CYP3A inhibitor.
Tipranavir: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with berotralstat is necessary. Concomitant use may increase the plasma concentrations of tipranavir. Tipranavir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Tolvaptan: (Major) Avoid coadministration of berotralstat when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with berotralstat. 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 CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Tramadol: (Moderate) Concurrent use of tramadol with berotralstat may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A4; berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Tramadol; Acetaminophen: (Moderate) Concurrent use of tramadol with berotralstat may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A4; berotralstat is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with berotralstat. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with berotralstat and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Tricyclic antidepressants: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Trimipramine: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions if coadministration with berotralstat is necessary; a dose reduction of the antidepressant may be necessary. Concurrent use may increase exposure of tricyclic antidepressants (TCAs). TCAs are CYP2D6 substrates and berotralstat is a CYP2D6 inhibitor.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with berotralstat. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A substrate; berotralstat 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 berotralstat 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 CYP3A4/5; berotralstat is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 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 berotralstat due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of berotralstat. Venetoclax is a CYP3A substrate; berotralstat is a moderate CYP3A inhibitor.
Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with berotralstat. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with berotralstat is necessary. Vinblastine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with berotralstat is necessary. Vinorelbine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Voclosporin: (Major) Reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening if coadministered with berotralstat. Concomitant use may increase voclosporin exposure and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors is predicted to increase voclosporin exposure by 3-fold.
Voriconazole: (Moderate) Monitor for increased voriconazole-related adverse effects if coadministered with berotralstat as concurrent use may increase voriconazole exposure. Voriconazole is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased voriconazole exposure by 79%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with berotralstat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The active metabolite of warfarin, the S-enantiomer, is a CYP2C9 substrate and berotralstat is a CYP2C9 inhibitor. Additionally, the R-enantiomer of warfarin is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with berotralstat. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of berotralstat, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; berotralstat is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
Berotralstat is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. Berotralstat decreases plasma kallikrein activity to control excess bradykinin production in patients with hereditary angioedema (HAE). Bradykinin is a potent vasodilator that increases vascular permeability, resulting in the swelling and pain associated with HAE. Plasma kallikrein cleaves high-molecular-weight-kininogen (HMWK) to produce cleaved HMWK (cHMWK) and bradykinin. In patients with HAE due to C1-inhibitor deficiency or dysfunction, normal regulation of plasma kallikrein is not present.
Berotralstat is administered orally. Plasma protein binding is approximately 99%. It is metabolized by CYP2D6 and CYP3A4. Approximately 9% is excreted in the urine (3.4% unchanged) and 79% is excreted in feces. Elimination half-life is approximately 93 hours (range: 39 to 152 hours).
Affected cytochrome P450 isoenyzmes and drug transporters: CYP2D6, CYP2C9, CYP2C19, CYP3A4, P-gp, BCRP
Berotralstat is a substrate and moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CYP2C9 and CYP2C19. It is a substrate of P-glycoprotein (P-gp) and BCRP. At a dose of 300 mg/day, it is a P-gp inhibitor.
-Route-Specific Pharmacokinetics
Oral Route
Tmax of berotralstat when administered with food is 5 hours (range: 1 to 8 hours). Steady-state Cmax and AUC are 158 ng/mL and 2,770 ng/mL x hour, respectively, after administration of 150 mg/day. Cmax and AUC decreased to 97.8 ng/mL and 1,600 ng/mL x hour, respectively, with a dose of 110 mg/day. When given with a high-fat meal, no differences in Cmax and AUC were observed, but Tmax was delayed by 3 hours (2 hours vs. 5 hours).
-Special Populations
Hepatic Impairment
Cmax increased 27%, AUC decreased 5%, and half-life increased 22% in patients with severe hepatic impairment (Child-Pugh Class C) compared to patients with normal hepatic function in a single-dose pharmacokinetic study. Additionally, the percent of unbound berotralstat increased 2-fold from mean 1.2% to 2.4% in those with severe dysfunction. In patients with moderate impairment (Child-Pugh Class B), Cmax increased 77%, AUC increased 78%, and half-life increased 37%. Berotralstat pharmacokinetics were unchanged in patients with mild hepatic impairment (Child-Pugh Class A) compared to patients with normal hepatic function.
Renal Impairment
Cmax and AUC increased 47% and 14%, respectively, in patients with severe renal impairment (CrCl less than 30 mL/minute) compared to those with normal renal function (CrCl more than 90 mL/minute) in a single-dose pharmacokinetic study; however, no clinically relevant differences were observed. The pharmacokinetics of berotralstat have not been studied in patients with end-stage renal disease (CrCl less than 15 mL/minute, eGFR less than 15 mL/minute/m2, or those requiring hemodialysis).
Pediatrics
Based on population pharmacokinetic analyses, exposure at steady-state was approximately 20% higher in pediatric patients 12 to 17 years compared to adults; however, the higher exposure in adolescents is not considered to be clinically meaningful.
Geriatric
Age does not have a clinically meaningful impact on the systemic exposure of berotralstat based on population pharmacokinetic analyses that included patients 65 to 74 years (n = 25).