Enasidenib is an oral isocitrate dehydrogenase-2 (IDH2) inhibitor approved for the treatment of adult patients with relapsed or refractory acute myelogenous leukemia (AML) with an IDH2 mutation as detected by an FDA-approved test. Enasidenib targets mutant IDH2 variants resulting in increased myeloid differentiation and mature myeloid cell counts in IDH2-mutated AML. Differentiation syndrome has been reported with enasidenib, this syndrome can be fatal if untreated. Corticosteroid therapy and hemodynamic monitoring are indicated if differentiation syndrome is suspected.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Moderate/High
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take enasidenib orally with or without food at approximately the same time each day.
-Swallow tablets whole; do not split, crush, or chew tablets.
-If a dose is missed, vomited, or not taken at the usual time, take the dose as soon as possible on the same day and return to the normal schedule the following day; do not take 2 doses to make up for the missed dose.
-Store tablets in the original container; keep the bottle tightly closed with the desiccant canister inside to protect the tablets from moisture.
Leukocytosis has been reported with enasidenib therapy. Monitor complete blood counts prior to starting enasidenib and then at least every 2 weeks for the first 3 months or longer during treatment. Start hydroxyurea per standard clinical practice in patients who have or develop a WBC count greater than 30 x 109 cells/L. Hold enasidenib therapy if leukocytosis is not improved with hydroxyurea; therapy may be resumed when the WBC count is less than 30 x 109 cells/L. Noninfectious leukocytosis occurred in 14% of patients with relapsed or refractory AML who received enasidenib in a clinical trial (n = 214); grade 3 or higher leukocytosis was reported in 7% of patients.
Differentiation syndrome with or without concomitant hyperleukocytosis has been reported with enasidenib therapy; this syndrome may be fatal if not treated. Monitor patients for signs and symptoms of differentiation syndrome. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg PO/IV every 12 hours) and closely monitor hemodynamic parameters. Taper corticosteroids after symptoms resolve. Interrupt enasidenib therapy if renal dysfunction and/or severe pulmonary symptoms requiring intubation or ventilator support persist after 48 hours of corticosteroid therapy. Resume enasidenib therapy when sign and symptoms of toxicity resolve to grade 2 or less. Differentiation syndrome occurred in 14% of patients with relapsed or refractory acute myelogenous leukemia who received enasidenib in a clinical trial (n = 214); grade 3 or higher differentiation syndrome was reported in 7% of patients. Adverse events associated with differentiation syndrome in the clinical trial included acute respiratory distress characterized by dyspnea and/or hypoxia (68%) and a need for supplemental oxygen (76%), pulmonary infiltrates/pulmonary toxicity (73%), pleural effusion (45%), pericardial effusion (18%), renal impairment/nephrotoxicity (70%), fever (36%), lymphadenopathy (33%), bone pain (27%), and peripheral edema with rapid weight gain (21%). Pulmonary edema and acute respiratory distress syndrome (ARDS) have been reported in less than 10% of patients. Hepatic, renal, and multi-organ dysfunction have also occurred. Hospitalization is recommended in patients who develop pulmonary toxicity and/or nephrotoxicity. Differentiation syndrome may occur as soon as 1 day and up to 5 months after starting enasidenib.
Tumor lysis syndrome (TLS) has been reported with enasidenib therapy. Monitor blood chemistries such as serum uric acid, serum electrolytes, and renal function (e.g., BUN/serum creatinine levels) prior to starting enasidenib and then at least every 2 weeks for the first 3 months or longer during treatment. Manage laboratory abnormalities promptly. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop severe TLS. TLS occurred in 6% of patients with relapsed or refractory AML who received enasidenib in a clinical trial (n = 214).
Hyperbilirubinemia has been reported with enasidenib therapy. Monitor liver function tests, including bilirubin levels, prior to starting enasidenib and periodically during treatment. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop severe hyperbilirubinemia. New or worsening total bilirubin level elevations occurred in 81% of patients with relapsed or refractory AML who received enasidenib in a clinical trial (n = 214); grade 3 or higher total bilirubin level elevations were reported in 15% of patients. Of patients who had increased total bilirubin levels of 2-times the upper limit of normal or higher, bilirubin elevations occurred in the first month of therapy in about one-third of patients (35%) and 89% of patients had no concomitant transaminase level elevations or other liver disorder adverse events.
Electrolyte abnormalities have been reported with enasidenib therapy. New or worsening decreased calcium level/hypocalcemia (74%; grade 3 or higher, 8%), decreased potassium level/hypokalemia (41%; grade 3 or higher, 15%), and decreased phosphorus level/hypophosphatemia (27%; grade 3 or higher, 8%) occurred in patients with relapsed or refractory AML who received enasidenib in a clinical trial (n = 214).
Nausea (50%; grade 3 or higher, 5%), diarrhea (43%; grade 3 or higher, 8%), vomiting (34%; grade 3 or higher, 2%), decreased appetite/anorexia (34%; grade 3 or higher, 4%), and dysgeusia (12%) occurred in patients with relapsed or refractory AML who received enasidenib in a clinical trial (n = 214).
Differentiation syndrome with or without concomitant hyperleukocytosis has been reported with enasidenib therapy; this syndrome may be fatal if not treated. Monitor patients for signs and symptoms of differentiation syndrome such as fever, cough, dyspnea, acute respiratory distress syndrome, pulmonary infiltrates, pleural effusion or pericardial effusion, rapid weight gain of more than 10 pounds within a week, peripheral edema, cervical, axillary, or inguinal lymphadenopathy, dizziness, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg PO/IV every 12 hours) and closely monitor hemodynamic parameters. Taper corticosteroids after symptoms resolve; premature corticosteroid discontinuation may lead to symptom recurrence. Interrupt enasidenib therapy if renal dysfunction and/or severe pulmonary symptoms requiring intubation or ventilator support persist after 48 hours of corticosteroid therapy. Resume enasidenib therapy when sign and symptoms of toxicity resolve to grade 2 or less. Hospitalization is recommended in patients who develop pulmonary toxicity and/or nephrotoxicity. Differentiation syndrome may occur as soon as 1 day and up to 5 months after starting enasidenib.
Hepatotoxicity (i.e., hyperbilirubinemia) has been reported with enasidenib therapy. Enasidenib may interfere with bilirubin metabolism through UGT1A1 inhibition; therefore, use enasidenib with caution in patients with pre-existing hepatic disease. Monitor liver function tests, including bilirubin levels, prior to starting enasidenib and periodically during treatment. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop severe hyperbilirubinemia.
Leukocytosis and tumor lysis syndrome (TLS) have been reported with enasidenib therapy; enasidenib may induce myeloid proliferation resulting in a rapid increase in white blood cell (WBC) count and/or a rapid reduction in tumor cells. Monitor complete blood counts and other blood chemistries such as serum uric acid, serum electrolytes, and renal function (e.g., BUN/serum creatinine levels) prior to starting enasidenib and then at least every 2 weeks for the first 3 months or longer during treatment. Start hydroxyurea per standard clinical practice in patients who have or develop a WBC count greater than 30 x 109 cells/L. Interrupt enasidenib therapy if leukocytosis is not improved with hydroxyurea. Resume enasidenib therapy when the WBC count is less than 30 x 109 cells/L. Manage other laboratory abnormalities promptly. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop severe TLS.
Enasidenib may cause fetal harm when administered during pregnancy, based on animal studies. Females of reproductive potential should avoid becoming pregnant while taking enasidenib. Discuss the potential hazard to the fetus if enasidenib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal birth weights and skeletal variations were observed when enasidenib was administered to pregnant rabbits during organogenesis at doses resulting in exposures of approximately 1.6-times the exposure in humans (at the recommended dose); postimplantation loss, resorptions, and decreased viable fetuses were also reported. Additionally, spontaneous abortion occurred in pregnant rabbits with enasidenib doses resulting in exposures approximately 0.1-times the exposure in humans.
Counsel patients about the reproductive risk and contraception requirements during enasidenib treatment. Pregnancy testing prior to starting enasidenib therapy is recommended for females of reproductive potential. These patients should avoid pregnancy and use effective nonhormonal contraception during therapy and for 2 months after the last enasidenib dose. Due to the risk of male-mediated teratogenicity, men with female partners of reproductive potential should avoid fathering a child and use effective contraception during and for 2 months after enasidenib therapy. Based on information from animal studies, infertility may occur in females or males of reproductive potential. It is not known if infertility is reversible.
It is not known if enasidenib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from enasidenib, women should discontinue breast-feeding during enasidenib therapy and for 2 months after the last dose.
For the treatment of acute myelogenous leukemia (AML):
The FDA has designated enasidenib as an orphan drug for the treatment of AML.
-for the treatment of relapsed or refractory AML with an isocitrate dehydrogenase-2 (IDH2) mutation:
NOTE: Evaluate patients for the presence of the IDH2 mutation in the blood or bone marrow using an FDA-approved detection test (www.fda.gov/CompanionDiagnostics).
Oral dosage:
Adults: 100 mg PO once daily until disease progression. Treat patients without disease progression for a minimum of 6 months to allow time for clinical response. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop toxicity. Treatment with enasidenib resulted in a complete remission (CR) or a CR with partial hematologic recovery (CRh) rate of 23% in patients with IDH2 (R140, 78%; R172, 22%)-mutated relapsed or refractory AML in a phase I/II trial (n = 199). In patients who achieved a CR/CRh, the median duration of response was 8.2 months, the median time to first response was 1.9 months (range, 0.5 to 7.5 months), and the median time to best response was 3.7 months (range, 0.6 to 11.2 months). Of the 157 patients who were dependent on red blood cell or platelet transfusions at baseline, 34% of patients became transfusion independent during any 56-day post baseline period. In this trial, patients (median age, 68 years; range, 19 to 100 years) had received a median of 2 prior therapies (range, 1 to 6 therapies); 13% of patients had undergone prior stem-cell transplantation.
Therapeutic Drug Monitoring:
Guidance for Treatment-Related Toxicity
Differentiation syndrome
Administer corticosteroid therapy (e.g., dexamethasone 10 mg PO/IV every 12 hours) if differentiation syndrome is suspected; closely monitor hemodynamic parameters. Interrupt enasidenib therapy if renal dysfunction and/or severe pulmonary symptoms requiring intubation or ventilator support persist after 48 hours of corticosteroid therapy. Resume enasidenib therapy when signs and symptoms of toxicity resolve to grade 2 or less. Taper corticosteroids after symptoms completely resolve.
Noninfectious leukocytosis (white blood cell (WBC) count greater than 30 x 109 cells/L)
Start hydroxyurea per standard clinical practice. Interrupt enasidenib therapy if leukocytosis is not improved with hydroxyurea. Resume enasidenib therapy at 100 mg PO once daily when the WBC count is less than 30 x 109 cells/L.
Other toxicity including tumor lysis syndrome
For grade 3 or higher toxicity, interrupt enasidenib therapy until toxicity resolves to grade 2 or less. Resume enasidenib therapy at 50 mg PO once daily; may increase to 100 mg PO once daily if the toxicity resolves to grade 1 or less. Discontinue enasidenib if grade 3 or higher toxicity recurs.
Maximum Dosage Limits:
-Adults
100 mg/day PO.
-Geriatric
100 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Treatment-related hepatic impairment: For a bilirubin level of greater than 3-times the upper limit of normal (ULN) that persists for 2 weeks or longer without elevated transaminases or other hepatic disorders, decrease the enasidenib dose to 50 mg PO once daily; may increase to 100 mg PO once daily if the bilirubin level decreases to 2-times the ULN or less.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Acetaminophen; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal or increased toxicity if coadministration with enasidenib is necessary. Consider adjusting the dose of hydrocodone as needed based on response. Avoid this combination when hydrocodone is being used for cough. Concomitant use may alter hydrocodone exposure although the net effect is unknown. Hydrocodone is a substrate of CYP3A and CYP2D6 and enasidenib is a weak CYP3A inducer and CYP2D6 inhibitor.
Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with enasidenib is necessary; consider increasing the dose of oxycodone as needed. If enasidenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and enasidenib is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Afatinib: (Moderate) If the concomitant use of enasidenib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of enasidenib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-gp substrate and enasidenib is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with enasidenib is necessary. If enasidenib is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a weak CYP3A inducer like enasidenib with alfentanil, a CYP3A substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Alosetron: (Major) Avoid coadministration of alosetron and enasidenib due to the potential for increased exposure and half-life of alosetron. Alosetron is a CYP1A2 substrate; enasidenib is a strong CYP1A2 inhibitor. Coadministration of another strong CYP1A2 inhibitor increased the mean alosetron AUC by about 6-fold and prolonged the half-life by 3-fold.
Alpelisib: (Major) Avoid coadministration of alpelisib with enasidenib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and enasidenib is a BCRP inhibitor.
Amitriptyline: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with enasidenib is necessary; a dose reduction of amitriptyline may be necessary. Concurrent use may increase the exposure of amitriptyline which is a CYP2D6 substrate; enasidenib is a weak CYP2D6 inhibitor.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp, BCRP, and OATP1B1/3 substrate; enasidenib is a P-gp, BCRP, and OATP1B1/3 inhibitor.
Amoxapine: (Major) Lower doses of amoxapine may be required during concurrent use of enasidenib due to the potential for increased amoxapine exposure. If enasidenib is discontinued, an increased dose of amoxapine may be necessary. Amoxapine is a CYP2D6 substrate; enasidenib is a CYP2D6 inhibitor.
Anagrelide: (Moderate) Monitor for cardiovascular events including QT prolongation, torsade de pointes (TdP), and vasodilation and titrate the anagrelide dose accordingly if concomitant use of enasidenib is necessary. Concomitant use may increase anagrelide exposure; anagrelide is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of enasidenib. Patients receiving both a CYP3A inhibitor plus enasidenib may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form and CYP3A inhibitor strength. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP2D6 and CYP3A substrate; enasidenib is a weak CYP2D6 inhibitor.
Asenapine: (Moderate) Monitor for increased asenapine-related adverse effects, such as extrapyramidal symptoms and QT prolongation, if concomitant use of enasidenib is necessary; dosage reduction of asenapine may be necessary. Concomitant use may increase the exposure of asenapine. Asenapine is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Aspirin, ASA; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with enasidenib is necessary; consider increasing the dose of oxycodone as needed. If enasidenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and enasidenib is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atogepant: (Major) Avoid concurrent use of atogepant and enasidenib due to unpredictable effects on atogepant. Concurrent use may alter atogepant exposure and decrease its efficacy and/or increase the risk of adverse effects. Atogepant is a CYP3A and OATP1B1/3 substrate and enasidenib is a OATP inhibitor and weak CYP3A inducer. The net effect on atogepant exposure is unknown. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration. Coadministration with a weak CYP3A inducer resulted in a 25% reduction in atogepant overall exposure and a 24% reduction in atogepant peak concentration.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp, BCRP, and OATP1B1/3 substrate; enasidenib is a P-gp, BCRP, and OATP1B1/3 inhibitor.
Avanafil: (Major) Coadministration of avanafil with enasidenib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and enasidenib is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of enasidenib 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 enasidenib is a CYP2C19 inhibitor.
Bendamustine: (Major) Consider the use of an alternative therapy if enasidenib treatment is needed in patients receiving bendamustine. Concomitant use of enasidenib may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with enasidenib is necessary; consider increasing the dose of benzhydrocodone as needed. If enasidenib is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate and enasidenib is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving enasidenib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving enasidenib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; enasidenib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Brincidofovir: (Moderate) Postpone the administration of enasidenib for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and enasidenib is necessary. Brincidofovir is an OATP1B1/3 substrate and enasidenib is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with enasidenib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with enasidenib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If enasidenib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and enasidenib is a CYP3A inducer.
Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with enasidenib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If enasidenib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A substrate and enasidenib is a CYP3A inducer.
Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor. (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor. (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Caffeine: (Major) Advise patients to avoid or minimize caffeine consumption during enasidenib treatment due to the risk for increased caffeine exposure which may increase the risk for caffeine-related adverse reactions, such as nervousness, irritability, insomnia, tachycardia, and tremor. Caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor. (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Caffeine; Sodium Benzoate: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of enasidenib; carbamazepine dose adjustments may be needed. Concomitant use may decrease carbamazepine concentrations. Carbamazepine is a CYP3A substrate and enasidenib is a CYP3A inducer.
Cariprazine: (Major) Coadministration of cariprazine with enasidenib is not recommended as the net effect of CYP3A induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A substrate and enasidenib is a weak CYP3A inducer. Coadministration of cariprazine with CYP3A inducers has not been evaluated.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with enasidenib is necessary; consider adjusting the dose of tramadol as needed. Tramadol is a CYP2D6 and CYP3A substrate and enasidenib is a CYP2D6 inhibitor and weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with enasidenib is necessary; a dose reduction of amitriptyline may be necessary. Concurrent use may increase the exposure of amitriptyline which is a CYP2D6 substrate; enasidenib is a weak CYP2D6 inhibitor.
Chlorpheniramine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal or increased toxicity if coadministration with enasidenib is necessary. Consider adjusting the dose of hydrocodone as needed based on response. Avoid this combination when hydrocodone is being used for cough. Concomitant use may alter hydrocodone exposure although the net effect is unknown. Hydrocodone is a substrate of CYP3A and CYP2D6 and enasidenib is a weak CYP3A inducer and CYP2D6 inhibitor.
Chlorpromazine: (Moderate) Monitor for an increase in chlorpromazine-related adverse reactions, including QT prolongation, anticholinergic effects, orthostasis, and somnolence, if coadministration with enasidenib is necessary. Concomitant use may increase chlorpromazine exposure. Chlorpromazine is a CYP2D6 substrate and enasidenib is a weak CYP2D6 inhibitor.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Citalopram: (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with enasidenib. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation. Citalopram is a sensitive CYP2C19 substrate; enasidenib is a weak inhibitor of CYP2C19.
Clomipramine: (Moderate) Monitor for an increase in clomipramine-related adverse reactions if concomitant use of enasidenib is necessary; a clomipramine dose reduction may be necessary. Concomitant use may increase clomipramine exposure; clomipramine is a CYP1A2 and CYP2D6 substrate and enasidenib is a strong CYP1A2 and weak CYP2D6 inhibitor.
Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of enasidenib. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; enasidenib is a CYP2C19 inhibitor.
Clozapine: (Moderate) Monitor for a reduction in clozapine efficacy or an increase in clozapine-related adverse effects if clozapine is coadministered with enasidenib; adjust the clozapine dose as necessary based on response. Concurrent use may alter clozapine exposure although the net effect is unknown. Clozapine is a CYP3A and CYP2D6 substrate and enasidenib is a weak CYP3A inducer and CYP2D6 inhibitor.
Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with enasidenib is necessary. In vitro, cobimetinib is a P-gp substrate; enasidenib is a P-gp inhibitor.
Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with enasidenib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If enasidenib is discontinued, consider a dose reduction of codeine and frequently monitor for signs of respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine and by CYP3A to norcodeine (norcodeine does not have analgesic properties); enasidenib is a weak CYP3A inducer. Concomitant use with enasidenib can increase norcodeine levels via increased CYP3A metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Colchicine: (Major) Avoid concomitant use of colchicine and enasidenib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, 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 the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Conjugated Estrogens: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Bazedoxifene: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Medroxyprogesterone: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with enasidenib is necessary. Concurrent use may alter cyclosporine exposure resulting in decreased efficacy or increased risk of adverse effects. Cyclosporine is CYP3A and P-gp substrate and enasidenib is a weak CYP3A inducer and P-gp inhibitor. The net effect on cyclosporine exposure is unknown.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with enasidenib is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-glycoprotein substrate and enasidenib is a P-gp inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desipramine: (Moderate) Monitor for an increase in desipramine-related adverse reactions if coadministration with enasidenib is necessary; a dose reduction of desipramine may be necessary. Concurrent use may increase the exposure of desipramine which is a CYP2D6 substrate; enasidenib is a weak CYP2D6 inhibitor.
Desogestrel; Ethinyl Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, and decreased efficacy if coadministration with enasidenib is necessary. Concurrent use may alter diazepam exposure although the net effect is unknown. Diazepam is a CYP2C19 and CYP3A substrate and enasidenib is a CYP2C19 inhibitor and weak CYP3A inducer.
Dienogest; Estradiol valerate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing enasidenib. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and enasidenib is a P-gp inhibitor. Coadministration of digoxin after multiple doses of enasidenib increased digoxin Cmax by 26% and AUC by 20%.
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Doravirine: (Minor) Concurrent administration of doravirine and enasidenib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; enasidenib is a weak CYP3A inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor. (Minor) Concurrent administration of doravirine and enasidenib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A substrate; enasidenib is a weak CYP3A inducer.
Doxepin: (Moderate) Monitor for an increase in doxepin-related adverse reactions if concomitant use of enasidenib is necessary. Concomitant use may increase doxepin exposure. Doxepin is metabolized by CYP2C19, CYP1A2, and CYP2D6 and enasidenib is a strong CYP1A2 and weak CYP2C19 and CYP2D6 inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of enasidenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Enasidenib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of enasidenib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Enasidenib is a P-gp inhibitor and doxorubicin is a P-gp substrate. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Drospirenone: (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Drospirenone; Estetrol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Drospirenone; Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Drospirenone; Ethinyl Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Duloxetine: (Major) Avoid coadministration of duloxetine with enasidenib due to the risk of increased duloxetine exposure and adverse effects. Duloxetine is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased duloxetine exposure by approximately 6-fold.
Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of enasidenib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and enasidenib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with enasidenib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of enasidenib. Increased concentrations of edoxaban may occur during concomitant use of enasidenib; monitor for increased adverse effects of edoxaban.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Elagolix: (Contraindicated) Coadministration of elagolix with enasidenib is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and enasidenib is a strong OATP1B1 inhibitor.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Coadministration of elagolix with enasidenib is contraindicated as concurrent use may increase elagolix exposure. Elagolix is a substrate of OATP1B1 and enasidenib is a strong OATP1B1 inhibitor. (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Elbasvir; Grazoprevir: (Contraindicated) Concomitant use of grazoprevir and enasidenib is contraindicated due to the potential for increased grazoprevir exposure. Grazoprevir is a substrate of OATP1B1/3; enasidenib is an inhibitor of OATP1B1/3.
Eliglustat: (Moderate) Monitor for an increase in the frequency and severity of eliglustat-related adverse effects if concomitant use with enasidenib is necessary. Concomitant use may increase eliglustat exposure. Eliglustat is a CYP2D6 substrate and enasidenib is a weak CYP2D6 inhibitor.
Eluxadoline: (Major) Reduce the dose of eluxadoline to 75 mg twice daily and monitor for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity) if coadministered with enasidenib. Coadministration may increase exposure of eluxadoline. Eluxadoline is an OATP1B1 substrate and enasidenib is a an OATP1B1 inhibitor. Coadministration with another OATP1B1 inhibitor increased the exposure of eluxadoline by 4.4-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Ergotamine; Caffeine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of enasidenib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor.
Esterified Estrogens: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination.
Esterified Estrogens; Methyltestosterone: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination.
Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Levonorgestrel: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Estradiol; Norethindrone: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Estradiol; Norgestimate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Estradiol; Progesterone: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Estrogens: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination.
Estropipate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination.
Ethinyl Estradiol; Norelgestromin: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Ethinyl Estradiol; Norgestrel: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Etonogestrel: (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Etonogestrel; Ethinyl Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with enasidenib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
Fenfluramine: (Major) Do not exceed a maximum dose of fenfluramine 20 mg per day if coadministered with enasidenib; for patients also receiving stiripentol plus clobazam, do not exceed a maximum dose of fenfluramine 17 mg per day. Concomitant use may increase fenfluramine plasma concentrations and the risk of adverse reactions. Fenfluramine is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased fenfluramine overall exposure by 102% and decreased norfenfluramine overall exposure by 22%.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of enasidenib is necessary. If enasidenib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A inducer like enasidenib with fentanyl, a CYP3A substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Fezolinetant: (Contraindicated) Concomitant use of fezolinetant and enasidenib is contraindicated due to the risk of increased fezolinetant exposure which may increase the risk of fezolinetant-related adverse effects. Fezolinetant is a CYP1A2 substrate; enasidenib is a strong CYP1A2 inhibitor. Concomitant use with another strong CYP1A2 inhibitor increased fezolinetant overall exposure by 840%.
Flecainide: (Moderate) Monitor for an increase in flecainide-related adverse reactions, including QT prolongation, if coadministration with enasidenib is necessary. Flecainide is a CYP2D6 substrate and enasidenib is a weak CYP2D6 inhibitor. Plasma concentrations of flecainide may increase, especially in extensive CYP2D6 metabolizers.
Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with enasidenib. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and enasidenib is a weak CYP2D6 inhibitor.
Fluvastatin: (Moderate) Monitor for an increase in fluvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase fluvastatin exposure. Fluvastatin is a substrate of OATP1B3; enasidenib is an inhibitor of OATP1B3.
Fosphenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with fosphenytoin and enasidenib due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C19 substrate and enasidenib is a CYP2C19 inhibitor.
Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in glecaprevir-related adverse effects if coadministration with enasidenib is necessary. Concomitant use may increase glecaprevir exposure. Glecaprevir is a substrate of P-gp, BCRP, and OATP1B1/3 and enasidenib is a P-gp, BCRP, and OATP1B1/3 inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of enasidenib is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and BCRP and enasidenib is a P-gp and BCRP inhibitor.
Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with enasidenib is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; enasidenib is an OATP1B1/3 inhibitor.
Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with enasidenib is necessary. Concomitant use may increase glyburide exposure. Glyburide is a substrate of OATP1B1/3; enasidenib is an OATP1B1/3 inhibitor.
Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal or increased toxicity if coadministration with enasidenib is necessary. Consider adjusting the dose of hydrocodone as needed based on response. Avoid this combination when hydrocodone is being used for cough. Concomitant use may alter hydrocodone exposure although the net effect is unknown. Hydrocodone is a substrate of CYP3A and CYP2D6 and enasidenib is a weak CYP3A inducer and CYP2D6 inhibitor.
Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal or increased toxicity if coadministration with enasidenib is necessary. Consider adjusting the dose of hydrocodone as needed based on response. Avoid this combination when hydrocodone is being used for cough. Concomitant use may alter hydrocodone exposure although the net effect is unknown. Hydrocodone is a substrate of CYP3A and CYP2D6 and enasidenib is a weak CYP3A inducer and CYP2D6 inhibitor.
Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal or increased toxicity if coadministration with enasidenib is necessary. Consider adjusting the dose of hydrocodone as needed based on response. Avoid this combination when hydrocodone is being used for cough. Concomitant use may alter hydrocodone exposure although the net effect is unknown. Hydrocodone is a substrate of CYP3A and CYP2D6 and enasidenib is a weak CYP3A inducer and CYP2D6 inhibitor.
Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal or increased toxicity if coadministration with enasidenib is necessary. Consider adjusting the dose of hydrocodone as needed based on response. Avoid this combination when hydrocodone is being used for cough. Concomitant use may alter hydrocodone exposure although the net effect is unknown. Hydrocodone is a substrate of CYP3A and CYP2D6 and enasidenib is a weak CYP3A inducer and CYP2D6 inhibitor.
Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal or increased toxicity if coadministration with enasidenib is necessary. Consider adjusting the dose of hydrocodone as needed based on response. Avoid this combination when hydrocodone is being used for cough. Concomitant use may alter hydrocodone exposure although the net effect is unknown. Hydrocodone is a substrate of CYP3A and CYP2D6 and enasidenib is a weak CYP3A inducer and CYP2D6 inhibitor.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with enasidenib is necessary; consider increasing the dose of oxycodone as needed. If enasidenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and enasidenib is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Imipramine: (Moderate) Monitor for an increase in imipramine-related adverse reactions if coadministration with enasidenib is necessary; a dose reduction of imipramine may be necessary. Concurrent use may increase the exposure of imipramine which is a CYP2D6 substrate; enasidenib is a weak CYP2D6 inhibitor.
Isradipine: (Minor) Monitor for decreased efficacy of isradipine if coadministration with enasidenib is necessary. Concomitant use may decrease isradipine exposure. Isradipine is a CYP3A substrate and enasidenib is a weak CYP3A inducer.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with enasidenib is necessary. Lapatinib is a P-gp substrate and enasidenib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Major) Avoid coadministration of enasidenib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; enasidenib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and enasidenib is a P-gp inhibitor.
Letermovir: (Moderate) Monitor for an increase in letermovir-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase letermovir exposure. Letermovir is a substrate of OATP1B1/3; enasidenib is an OATP1B1/3 inhibitor.
Leuprolide; Norethindrone: (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Levonorgestrel: (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Levonorgestrel; Ethinyl Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with enasidenib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with enasidenib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with enasidenib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP1A2 substrate and enasidenib is a CYP1A2 inhibitor. Coadministration of another CYP1A2 inhibitor increased lidocaine exposure by 71%.
Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and enasidenib. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; enasidenib is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with enasidenib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with enasidenib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with enasidenib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and enasidenib is a weak CYP3A inducer.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a substrate of P-gp; enasidenib is an inhibitor of P-gp.
Lumateperone: (Major) Avoid coadministration of lumateperone and enasidenib as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A substrate; enasidenib is a weak CYP3A inducer.
Maprotiline: (Moderate) Monitor for an increase in maprotiline-related adverse reactions if coadministration with enasidenib is necessary; a dose reduction of maprotiline may be necessary. Concurrent use may increase exposure of maprotiline. Maprotiline is a CYP2D6 substrate and enasidenib is a CYP2D6 inhibitor.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
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 enasidenib therapy. Avoid initiation of enasidenib 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 enasidenib therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP2C19 substrate and enasidenib is a weak CYP2C19 inhibitor. Concomitant use with another weak CYP2C19 inhibitor in CYP2C19 normal and rapid metabolizers increased overall mavacamten exposure by 48%.
Meclizine: (Moderate) Monitor for meclizine-related adverse effects, such as drowsiness and anticholinergic effects, when coadministered with enasidenib. Concomitant use may increase the exposure to meclizine. Meclizine is a CYP2D6 substrate and enasidenib is a CYP2D6 inhibitor.
Medroxyprogesterone: (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Mefloquine: (Moderate) Monitor for a decrease in mefloquine efficacy and an increase in mefloquine-related adverse effects if concomitant use of enasidenib is necessary. Concomitant use may alter mefloquine exposure although the net effect is unknown. Mefloquine is a P-gp and CYP3A substrate and enasidenib is a P-gp inhibitor and weak CYP3A inducer.
Melatonin: (Moderate) Monitor for an increase in melatonin-related adverse reactions if concomitant use of enasidenib is necessary. Concomitant use may increase melatonin exposure; melatonin is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor.
Meperidine: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with enasidenib is necessary. Consider increasing the dose of meperidine as needed. If enasidenib is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP3A; enasidenib is a weak CYP3A inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal and increased toxicity if coadministration with enasidenib is necessary. Consider adjusting the dose of methadone as needed. Concomitant use may alter methadone exposure although the net effect is unknown. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; enasidenib is a weak CYP3A inducer and weak CYP2C19 and CYP2D6 inhibitor.
Metoprolol: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with enasidenib. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and enasidenib is a CYP2D6 inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with enasidenib. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and enasidenib is a CYP2D6 inhibitor.
Mexiletine: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with enasidenib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP1A2 and CYP2D6 substrate and enasidenib is a strong CYP1A2 and weak CYP2D6 inhibitor. Coadministration with another strong CYP1A2 inhibitor decreased the clearance of mexiletine by 38%.
Momelotinib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; enasidenib is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with enasidenib is necessary; decrease the dose of either drug as necessary. Morphine is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with enasidenib is necessary; decrease the dose of either drug as necessary. Morphine is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with enasidenib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; enasidenib is a P-gp inhibitor.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with enasidenib is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A substrate and enasidenib is a weak CYP3A inducer.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and enasidenib. Concurrent use may alter sirolimus exposure and decrease its efficacy or increase the risk of adverse effects. Sirolimus is a P-gp and CYP3A substrate and enasidenib is a P-gp inhibitor and weak CYP3A inducer. The net effect on sirolimus exposure is unknown.
Nimodipine: (Moderate) Monitor for decreased efficacy of nimodipine if coadministration with enasidenib is necessary as concomitant use may decrease plasma concentrations of nimodipine. Nimodipine is a CYP3A substrate and enasidenib is a weak CYP3A inducer.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of enasidenib is necessary. Concomitant use of nirmatrelvir and enasidenib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and enasidenib is a CYP3A inducer. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with enasidenib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and enasidenib is a weak CYP3A inducer.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with enasidenib as concurrent use may decrease nisoldipine exposure and efficacy. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A substrate and enasidenib is a CYP3A inducer. Coadministration with a strong CYP3A inducer lowered nisoldipine plasma concentrations to undetectable levels.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Norethindrone: (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Norethindrone; Ethinyl Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Norgestimate; Ethinyl Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Norgestrel: (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Nortriptyline: (Moderate) Monitor for an increase in nortriptyline-related adverse reactions if coadministration with enasidenib is necessary; a dose reduction of nortriptyline may be necessary. Concurrent use may increase the exposure of nortriptyline which is a CYP2D6 substrate; enasidenib is a weak CYP2D6 inhibitor.
Olanzapine: (Moderate) Monitor for olanzapine-related adverse effects, including QT prolongation, if concomitant use of enasidenib is necessary; an olanzapine dose reduction may be necessary. Concomitant use may increase olanzapine exposure; olanzapine is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor.
Olanzapine; Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with enasidenib. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and enasidenib is a weak CYP2D6 inhibitor. (Moderate) Monitor for olanzapine-related adverse effects, including QT prolongation, if concomitant use of enasidenib is necessary; an olanzapine dose reduction may be necessary. Concomitant use may increase olanzapine exposure; olanzapine is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor.
Olanzapine; Samidorphan: (Moderate) Monitor for olanzapine-related adverse effects, including QT prolongation, if concomitant use of enasidenib is necessary; an olanzapine dose reduction may be necessary. Concomitant use may increase olanzapine exposure; olanzapine is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with enasidenib is necessary; consider increasing the dose of oxycodone as needed. If enasidenib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A substrate and enasidenib is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with enasidenib is necessary due to the risk of decreased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A substrate and enasidenib is a weak CYP3A inducer.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with enasidenib is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and enasidenib is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Pazopanib: (Major) Avoid coadministration of pazopanib and enasidenib due to the potential for increased pazopanib exposure. Pazopanib is a P-gp and BCRP substrate; enasidenib is a P-gp and BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp or BCRP.
Perphenazine; Amitriptyline: (Moderate) Monitor for an increase in amitriptyline-related adverse reactions if coadministration with enasidenib is necessary; a dose reduction of amitriptyline may be necessary. Concurrent use may increase the exposure of amitriptyline which is a CYP2D6 substrate; enasidenib is a weak CYP2D6 inhibitor.
Phenytoin: (Moderate) Monitor phenytoin concentrations during concomitant therapy with enasidenib due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C19 substrate and enasidenib is a CYP2C19 inhibitor.
Pimozide: (Moderate) Monitor for pimozide-related adverse reactions, including QT prolongation and ventricular arrhythmias, if coadministered with enasidenib. Coadministration may result in elevated pimozide concentrations. Pimozide is metabolized primarily through CYP3A, and to a lesser extent CYP1A2 and CYP2D6; enasidenib is a strong CYP1A2 and weak CYP2D6 inhibitor.
Pirfenidone: (Major) Avoid concomitant use of pirfenidone and enasidenib due to the increased risk for pirfenidone-related adverse effects and exposure. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1; enasidenib is a strong CYP1A2 inhibitor and weak CYP2C19 inhibitor.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
Posaconazole: (Moderate) Monitor for an increase in posaconazole-related adverse reactions if coadministration with enasidenib is necessary. Posaconazole is a P-glycoprotein (P-gp) substrate; enasidenib is a P-gp inhibitor.
Pralsetinib: (Major) Avoid concomitant use of enasidenib 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 P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Pravastatin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase pravastatin exposure. Pravastatin is an OATP1B1/3 substrate; enasidenib is an OATP1B1/3 inhibitor.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and enasidenib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, 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 the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Progesterone: (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Progestins: (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with enasidenib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and enasidenib with a CYP3A inhibitor. Propafenone is a CYP1A2, CYP3A, and CYP2D6 substrate; enasidenib is a strong CYP1A2 and weak CYP2D6 inhibitor.
Propranolol: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of enasidenib as concurrent use may increase propranolol exposure. Propranolol is a CYP1A2 and CYP2D6 substrate and enasidenib is a strong CYP1A2 and weak CYP2D6 inhibitor.
Protriptyline: (Moderate) Monitor for an increase in protriptyline-related adverse reactions if coadministration with enasidenib is necessary; a dose reduction of protriptyline may be necessary. Concurrent use may increase the exposure of protriptyline which is a CYP2D6 substrate; enasidenib is a weak CYP2D6 inhibitor.
Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with enasidenib is necessary. Ramelteon is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased ramelteon exposure by 190-fold.
Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with enasidenib is necessary; a dose adjustment of ranolazine may be necessary. Ranolazine is a P-gp substrate. Enasidenib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates.
Rasagiline: (Major) Do not exceed a rasagiline dose of 0.5 mg once daily when coadministered with enasidenib. Coadministration may result in increased rasagiline concentrations. Rasagiline is primarily metabolized by CYP1A2; enasidenib is a strong CYP1A2 inhibitor. When rasagiline was administered with a strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
Relugolix: (Major) Avoid concomitant use of relugolix and oral enasidenib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer enasidenib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and enasidenib is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination. (Major) Avoid concomitant use of relugolix and oral enasidenib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer enasidenib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and enasidenib is a P-gp inhibitor.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with enasidenib due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a P-gp substrate and enasidenib is a P-gp inhibitor.
Resmetirom: (Major) Avoid concomitant use of resmetirom and enasidenib due to the risk for increased resmetirom exposure which may increase the risk for resmetirom-related adverse effects. Resmetirom is an OATP1B1/3 substrate and enasidenib is an OATP1B1/3 inhibitor.
Revefenacin: (Major) Avoid concomitant use of revefenacin and enasidenib. Concomitant use may increase exposure to the active metabolite of revefenacin and the risk for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; enasidenib is an inhibitor of OATP1B1 and OATP1B3.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Riluzole: (Moderate) Coadministration of riluzole with enasidenib may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely. Riluzole is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with enasidenib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and enasidenib is a P-gp inhibitor.
Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with enasidenib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and enasidenib is a weak CYP3A inducer.
Ropinirole: (Moderate) Concomitant use of ropinirole and enasidenib may increase the exposure of ropinirole. A dose adjustment of ropinirole may be needed when therapy with enasidenib is initiated or discontinued. Ropinirole is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased ropinirole exposure by 84%.
Ropivacaine: (Moderate) Use caution when ropivacaine is coadministered with enasidenib. Concomitant use may lead to increased ropivacaine concentrations. Ropivacaine is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor decreased the clearance of ropivacaine by 70%.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporters OATP1B1/3 and BCRP and enasidenib is an OATP1B1/3 and BCRP inhibitor. Coadministration of rosuvastatin after multiple doses of enasidenib increased rosuvastatin Cmax by 366% and AUC by 244%.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a substrate of the drug transporters OATP1B1/3 and BCRP and enasidenib is an OATP1B1/3 and BCRP inhibitor. Coadministration of rosuvastatin after multiple doses of enasidenib increased rosuvastatin Cmax by 366% and AUC by 244%.
Saquinavir: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with enasidenib is necessary. Saquinavir is a P-glycoprotein (P-gp) substrate; enasidenib is a P-gp inhibitor.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Segesterone Acetate; Ethinyl Estradiol: (Major) Advise patients taking estrogen hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens containing a minimum of 30 mcg of ethinyl estradiol or equivalent may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase estrogen elimination. (Major) Advise patients taking progestin hormones for contraception to consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for 2 months following discontinuation of enasidenib. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on enasidenib, with dose adjustments made based on clinical efficacy. Progestins are CYP3A substrates and enasidenib is a CYP3A inducer. Concurrent administration may increase progestin elimination.
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with enasidenib is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A substrate and enasidenib is a weak CYP3A inducer. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A inducers.
Silodosin: (Major) Avoid coadministration of silodosin and enasidenib due to the potential for increased silodosin exposure. In vitro data indicate that silodosin is a P-glycoprotein substrate; enasidenib is a P-gp inhibitor.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp and OATP1B1 substrate; enasidenib is a P-gp and OATP1B1 inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of enasidenib. Concurrent use may alter sirolimus exposure and decrease its efficacy or increase the risk of adverse effects. Sirolimus is a P-gp and CYP3A substrate and enasidenib is a P-gp inhibitor and weak CYP3A inducer. The net effect on sirolimus exposure is unknown.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and enasidenib. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and enasidenib is an OATP1B3 inhibitor.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of voxilaprevir and enasidenib due to the potential for increased voxilaprevir exposure. Voxilaprevir is a substrate for the drug transporter OATP1B13; enasidenib is an OATP1B1/3 inhibitor.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if enasidenib must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with enasidenib is necessary; consider increasing the dose of sufentanil injection as needed. If enasidenib is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs of respiratory depression and sedation. Sufentanil is a CYP3A substrate and enasidenib is a weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with enasidenib is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; enasidenib is a weak CYP3A inducer.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of enasidenib is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate; enasidenib is a P-gp and BCRP inhibitor.
Tasimelteon: (Major) Avoid coadministration of tasimelteon with enasidenib due to the potential for a large increase in tasimelteon exposure and greater risk of adverse reactions. Tasimelteon is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased tasimelteon exposure by 7-fold.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with enasidenib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with enasidenib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Theophylline, Aminophylline: (Moderate) Monitor theophylline concentrations and watch for an increase in theophylline-related adverse reactions if coadministration with enasidenib is necessary; a theophylline dose reduction may be necessary. Theophylline is a CYP1A2 substrate with a narrow therapeutic index and enasidenib is a CYP1A2 inhibitor.
Thioridazine: (Contraindicated) Coadministration of thioridazine and enasidenib 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 enasidenib is a weak CYP2D6 inhibitor.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with enasidenib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and enasidenib is a P-gp inhibitor.
Tipranavir: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-glycoprotein (P-gp) substrate; enasidenib is a P-gp inhibitor.
Tizanidine: (Contraindicated) Concomitant use of tizanidine and enasidenib is contraindicated due to the risk of tizanidine toxicity, including clinically significant hypotension, bradycardia, and sedation. Tizanidine is a CYP1A2 substrate and enasidenib is a strong CYP1A2 inhibitor. Coadministration with other strong CYP1A2 inhibitors increased the exposure of tizanidine by 10 and 33-fold.
Topotecan: (Major) Avoid coadministration of enasidenib with oral topotecan due to increased topotecan exposure; enasidenib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and BCRP and enasidenib is a P-gp and BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with enasidenib is necessary; consider adjusting the dose of tramadol as needed. Tramadol is a CYP2D6 and CYP3A substrate and enasidenib is a CYP2D6 inhibitor and weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with enasidenib is necessary; consider adjusting the dose of tramadol as needed. Tramadol is a CYP2D6 and CYP3A substrate and enasidenib is a CYP2D6 inhibitor and weak CYP3A inducer. Concomitant use with CYP3A inducers can decrease tramadol levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Trimipramine: (Moderate) Monitor for an increase in trimipramine-related adverse reactions if coadministration with enasidenib is necessary; a dose reduction of trimipramine may be necessary. Concurrent use may increase the exposure of trimipramine which is a CYP2D6 substrate; enasidenib is a weak CYP2D6 inhibitor.
Ubrogepant: (Major) Avoid concurrent use of ubrogepant and enasidenib due to the risk for unpredictable effects on ubrogepant concentrations. Concurrent use may alter ubrogepant exposure and decrease its efficacy or increase the risk of adverse effects. Ubrogepant is a CYP3A, P-gp, and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor and weak CYP3A inducer. The net effect on ubrogepant exposure is unknown.
Ulipristal: (Major) Avoid coadministration of ulipristal with enasidenib. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal. Ulipristal is a substrate of CYP3A and enasidenib is a CYP3A inducer.
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 enasidenib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of enasidenib. Venetoclax is a P-gp substrate and enasidenib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of enasidenib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of enasidenib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and enasidenib is a P-gp inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with enasidenib is necessary as concurrent use may alter the exposure of warfarin leading to increased bleeding risk or reduced efficacy. The R-enantiomer of warfarin is a CYP1A2 and CYP3A substrate and enasidenib is a CYP1A2 inhibitor and CYP3A inducer. 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. The net effect on warfarin exposure is unknown.
Zavegepant: (Major) Avoid concomitant use of zavegepant and enasidenib. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and enasidenib is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Enasidenib is an oral isocitrate dehydrogenase-2 (IDH2) inhibitor that targets the mutant IDH2 variants including R140Q, R172S, and R172K; IDH2 inhibition decreases levels of the oncologic metabolite, 2-hydroxyglutarate (2-HG), and causes increased myeloid differentiation, increased mature myeloid cell count, and reduced blast counts in IDH2-mutated acute myelogenous leukemia. In vitro, enasidenib inhibits the mutant IDH2 enzyme at approximately 40-fold lower concentrations than the wild-type enzyme.
Enasidenib is administered orally. In vitro, enasidenib and its metabolite (AGI-16903) are 98.5% and 96.6% bound to human plasma proteins, respectively. Following oral administration of enasidenib, the mean volume of distribution (Vd) was 55.8 L (coefficient of variance (CV), 29%), the terminal half-life was 7.9 days, and the mean total body clearance was 0.7 L/hour (CV, 62.5%). Following a radiolabeled dose of enasidenib, 89% of the dose was eliminated in the feces and 11% of the dose was eliminated in the urine; unchanged drug accounted for 34% and 0.4% of the radioactivity recovered in the feces and urine, respectively. Additionally, 89% of the radioactivity in the circulation was enasidenib; 10% of the radioactivity in the circulation was the N-dealkylated metabolite, AGI-16903.
Affected cytochrome P450 isoenzymes and transporters: OATP1B1, OATP1B3, BCRP, P-gp
In vitro, enasidenib is metabolized by multiple CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and UDP-glucuronosyl transferases (UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). AGI-16903 is metabolized by CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9; it is also a substrate of P-glycoprotein and breast cancer resistance protein (BCRP). In vitro studies suggest that enasidenib inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, P-gp, BCRP, organic anion transporter (OAT)-1, OAT family members 1B1 (OATP1B1) and OATP1B3, and organic cat anion transporter (OCT)-2 and induces CYP2B6 and CYP3A4. In vitro, AGI-16903 inhibits CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, BCRP, OAT1, OAT3, OATP1B1, and OCT2. P-gp substrates with a narrow therapeutic index and OATP1B1, OATP1B3, and BCRP substrates may require a dosage reduction and increased monitoring for toxicity if coadministered with enasidenib.
-Route-Specific Pharmacokinetics
Oral Route
Following a single oral 100-mg dose, the absolute bioavailability of enasidenib is approximately 57% and the median time to peak concentration (Tmax) is 4 hours. Following enasidenib 100 mg PO daily, the Cmax level was 13.1 mcg/mL (coefficient of variance (CV), 45%) at steady state (achieved within 29 days). The AUC values increase proportionally over a dosage range of 50 mg to 450 mg daily. Accumulation is approximately 10-fold when administered once daily.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (defined as a total bilirubin level less than or equal to 1-time the upper limit of normal (ULN) and AST level greater than the ULN OR a total bilirubin level greater than 1- to 1.5-times the ULN and any AST level) had no clinically significant impact on the pharmacokinetic parameters of enasidenib.
Renal Impairment
Mild or moderate renal impairment (defined as a creatinine clearance of 30 mL/min or greater) had no clinically significant impact on the pharmacokinetic parameters of enasidenib.
Geriatric
Age (range, 19 to 100 years) had no clinically significant impact on the pharmacokinetic parameters of enasidenib.
Gender Differences
Sex had no clinically significant impact on the pharmacokinetic parameters of enasidenib.
Ethnic Differences
Race (Caucasian, Black, or Asian ethnicity) had no clinically significant impact on the pharmacokinetic parameters of enasidenib.
Obesity
Body weight (range, 39 kg to 136 kg) or body surface area had no clinically significant impact on the pharmacokinetic parameters of enasidenib.