Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of acute myeloid leukemia (AML), relapsed or refractory myelodysplastic syndromes (MDS), and locally advanced or metastatic cholangiocarcinoma in adult patients with a susceptible IDH1 mutation as detected by an FDA-approved test. Differentiation syndrome has been reported with ivosidenib in patients with AML or MDS; this syndrome can be fatal if untreated. Corticosteroid therapy and hemodynamic monitoring are indicated if differentiation syndrome is suspected. Prolongation of the QTc interval has also occurred in patients treated with ivosidenib. Monitor ECGs and electrolytes, correcting any abnormalities as clinically appropriate.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take ivosidenib with or without food at approximately the same time each day; do not take with a high-fat meal.
-Swallow tablets whole; do not split, crush, or chew tablets.
-If a dose is missed or not taken at the usual time, take the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.
-If a dose is vomited, do not take another dose. Take the next dose at the regular time the next day.
Cough (14% to 32%; grade 3 or 4, less than 1%) and dyspnea (20% to 33%; grade 3 or 4, 9% or less) occurred in patients who received ivosidenib in clinical trials. Pleural effusion was reported in 13% (grade 3 or higher, 3%) of patients with relapsed or refractory acute myeloid leukemia (AML) who received ivosidenib in a clinical trial (n = 179). The term dyspnea included respiratory failure and hypoxia in patients with AML who received ivosidenib plus azacitidine.
QT prolongation on electrocardiogram (ECG) occurred in 10% to 26% (grade 3 or higher, 11% or less) of patients who received ivosidenib in clinical trials. Monitor ECGs at least once weekly for the first 3 weeks of therapy and then at least once monthly thereafter. Promptly correct any electrolyte abnormalities before or during therapy. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. The QTcF was greater than 500 milliseconds (msec) in 14% of patients with newly diagnosed AML who received ivosidenib plus azacitidine (n = 71) in a clinical trial; additionally, a QTcF greater than 60 msec increase from baseline was reported in 22% of patients in this trial. Following treatment with single-agent ivosidenib in patients with hematological malignancies (n = 265) or cholangiocarcinoma (n = 123), a QTc greater than 500 msec occurred in 9% and 2%, respectively, and a QTc greater than 60 msec increase from baseline occurred in 14% and 5%, respectively. One patient with a hematological malignancy developed ivosidenib-related ventricular fibrillation. The mean increase in QTc interval was 17 msec in patients with newly diagnosed or relapsed/refractory acute myeloid leukemia who received ivosidenib 500 mg in a cardiac electrophysiology study; the increase in QTc interval was concentration-dependent. A similar mean increase in QTc interval was observed in patients with relapsed or refractory myelodysplastic syndrome and in patients with solid tumors, including cholangiocarcinoma.
Electrolyte abnormalities have been reported with ivosidenib therapy in clinical trials. Monitor electrolytes prior to and during treatment; promptly correct any electrolyte abnormalities. Worsening hypophosphatemia/decreased phosphate level (21% to 41%; grade 3 or higher, 5% to 10%), hypomagnesemia/decreased magnesium level (25% to 38%), hypokalemia/decreased potassium level (43% or less; grade 3 or higher, 11% or less), hyponatremia/decreased sodium level (39% or less; grade 3 or higher, 5% or less), hypocalcemia/decreased calcium level (25% or less; grade 3 or higher, 4% or less), and hyperkalemia/increased potassium level (24% or less; grade 3 or higher, 3% or less) from baseline occurred in acute myeloid leukemia or myelodysplastic syndrome patients who received ivosidenib in clinical trials.
Hyperuricemia/increased uric acid level occurred in 29% (grade 3 or higher, 4%) of patients with newly diagnosed AML (n = 28) and 32% (grade 3 or higher, 6%) of patients with relapsed or refractory AML (n = 179) who received single-agent ivosidenib in a multicenter, nonrandomized trial. Additionally, tumor lysis syndrome (TLS) was reported in 8% of patients with relapsed/refractory AML; 6% of these patients experienced grade 3 or higher TLS.
Nephrotoxicity, specifically increased serum creatinine level, occurred in 29% of patients with newly diagnosed acute myeloid leukemia (AML; n = 28) and 23% (grade 3 or higher, 1%) of patients with relapsed or refractory AML (n = 179) who received single-agent ivosidenib in clinical trials. Additionally, worsening elevated serum creatinine level from baseline was reported in 95% (grade 3 or higher, 5%) of patients with relapsed or refractory myelodysplastic syndrome who received ivosidenib (n = 19) in a clinical trial.
Arthralgia (30% to 42%; grade 3 or 4, 4% to 16%) and myalgia (18% to 26%; grade 3 or 4, 4% or less) occurred in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received ivosidenib in clinical trials. In patients with AML or MDS, monitor blood creatine phosphokinase (CPK) weekly for the first month of therapy. The term arthralgia included back pain, flank pain, joint swelling, musculoskeletal stiffness, neck pain, and extremity pain; the term myalgia included muscular weakness, muscle cramps/spasms, musculoskeletal pain or discomfort, and musculoskeletal chest pain.
Guillain-Barre syndrome occurred in less than 0.8% of patients with hematologic malignancies who received ivosidenib in a nonrandomized clinical study (n = 265). Monitor patients for signs or symptoms of motor and/or sensory neuropathy (e.g., unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing). Permanently discontinue ivosidenib in patients who are diagnosed with Guillain-Barre syndrome. Headache (11% to 16%), dizziness (21% or less) and neuropathy (14% or less; grade 3 or 4, 1% or less) including peripheral neuropathy (11% or less) occurred in patients who received ivosidenib in clinical trials. The term neuropathy included ataxia, gait disturbance, paresthesias, motor and sensory peripheral neuropathy, sensory disturbance, lumbosacral plexopathy, Guillain-Barre syndrome, and burning sensation.
There was one case of progressive multifocal leukoencephalopathy (PML) reported in relapsed or refractory AML patients who received single-agent ivosidenib (n = 179) in nonrandomized trial.
Diarrhea (32% to 61%; grade 3 or 4, 7% or less), mucositis (21% to 28%; grade 3 or 4, 5% or less), constipation (16% to 21%; grade 3 or 4, 4% or less), decreased appetite/anorexia (18% to 39%; grade 3 or 4, 4% or less), nausea (16% to 41%; grade 3 or 4, 7% or less), vomiting (18% to 41%; grade 3 or 4, 4% or less), and abdominal pain (16% to 35%; grade 3 or 4, 1% to 4%) occurred in patients who received ivosidenib in clinical trials. Dyspepsia was reported in 11% of patients with newly diagnosed acute myeloid leukemia in a clinical trial (n = 28). The term mucositis included aphthous ulcer, esophageal pain, esophagitis, gingival pain, gingivitis, oral ulceration, mucosal inflammation, oral pain, oropharyngeal pain, proctalgia, and stomatitis.
Worsening elevated hepatic enzymes, including increased AST (27% to 37%; grade 3 or higher, 5% or less), ALT (14% to 21%; grade 3 or higher, 1% to 5%), and alkaline phosphatase (16% to 46%; grade 3 or higher, 1% or less) levels, and hyperbilirubinemia (16% to 30%; grade 3 or higher, 13% or less) from baseline were reported in patients who received ivosidenib in clinical trials. Ascites occurred in 23% (grade 3 or higher, 9%) of cholangiocarcinoma patients who received ivosidenib, while serious cases of cholestatic jaundice occurred in at least 2% of these patients.
Fatigue including asthenia occurred in 37% to 50% (grade 3 or 4, 3% to 14%) of patients who received ivosidenib in clinical trials.
New or worsening anemia/decreased hemoglobin level was reported in 40% to 60% (grade 3 or higher, 7% to 46%) of patients who received ivosidenib as monotherapy or in combination with azacitidine in clinical trials. Other hematological adverse events that worsened from baseline in patients with newly diagnosed AML who received ivosidenib in combination with azacitidine were decreased leukocyte count/leukopenia (65%; grade 3 or higher, 55%), decreased platelet count/thrombocytopenia (58%; grade 3 or higher, 42%), and decreased neutrophil count/neutropenia (25%; grade 3 or higher, 23%).
Rash (14% to 26%; grade 3 or 4, 4% or less) and pruritus (26% or less; grade 3 or 4, 4% or less) occurred in patients who received ivosidenib in clinical trials. The term rash included acneiform rash, maculopapular rash, urticaria, erythematous rash/erythema, pruritic rash, exfoliative dermatitis, and skin ulcer.
There were 2 cases of posterior reversible encephalopathy syndrome (PRES) reported in patients with AML who received single-agent ivosidenib in a nonrandomized trial.
Edema occurred in 43% of patients with newly diagnosed AML (n = 28) and 32% (grade 3 or higher, 1%) of patients with relapsed or refractory AML (n = 179) who received single-agent ivosidenib in a multicenter, nonrandomized trial. The term edema includes face edema or swelling, fluid overload, fluid retention, hypervolemia, and peripheral edema.
Fever occurred in 23% (grade 3 or higher, 1%) of patients with relapsed or refractory AML (n = 179) who received single-agent ivosidenib in a multicenter, nonrandomized trial.
Weight loss occurred in 11% of patients with newly diagnosed AML (n = 28) who received single-agent ivosidenib in a multicenter, nonrandomized trial.
Noninfectious leukocytosis has been reported with ivosidenib therapy. Monitor complete blood counts prior to starting ivosidenib and then at least once weekly for the first month, once every other week for the second month, and then once monthly during treatment thereafter. Start hydroxyurea per standard clinical practice in patients who have or develop a white blood cell (WBC) count greater than 25 x 109 cells/L or an absolute increase in total WBC count of greater than 15 x 109 cells/L from baseline. Taper hydroxyurea after symptoms resolve. Hold ivosidenib therapy if leukocytosis is not improved with hydroxyurea; therapy may be resumed when the leukocytosis resolves. Leukocytosis occurred in 13% to 38% (grade 3 or 4, 8% or less) of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received ivosidenib in clinical trials. Additionally, leukocytosis (13%) and increased lymphocyte count/lymphocytosis (24%; grade 3 or higher, 1%) were reported in patients with newly diagnosed AML who received ivosidenib in combination with azacitidine (n = 71) in a randomized trial. The term leukocytosis included hyperleukocytosis and increased WBC count.
Differentiation syndrome, associated with rapid proliferation and differentiation of myeloid cells, was reported in 11% to 25% (grade 3 or 4, 13% or less) of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received ivosidenib in clinical trials. This syndrome may occur with or without hyperleukocytosis. Fatal differentiation syndrome was reported in 3 patients (3%) with newly diagnosed AML who received ivosidenib in combination with azacitidine (n = 71) in a randomized trial. Monitor patients for signs and symptoms of differentiation syndrome. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg IV every 12 hours or PO/IV equivalent) and closely monitor hemodynamic parameters. Taper corticosteroids after symptoms resolve. Premature corticosteroid discontinuation may lead to symptom recurrence; therefore, administer corticosteroids for a minimum of 3 days. Interrupt ivosidenib therapy if severe signs and/or symptoms persist after 48 hours of corticosteroid therapy. Resume ivosidenib therapy when signs and symptoms resolve to grade 2 or less. This syndrome may be associated with peripheral edema, leukocytosis, fever, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and increased serum creatinine. Differentiation syndrome may occur as soon as 1 day and up to 3 months after starting ivosidenib.
Infection has been reported in patients treated with ivosidenib. In a randomized clinical trial, at least 2% of cholangiocarcinoma patients treated with single-agent ivosidenib developed serious cases of pneumonia.
Hyperglycemia/increased glucose level was reported in 56% (grade 3 or higher, 13%) of patients with newly diagnosed AML who received ivosidenib in combination with azacitidine (n = 71) in a randomized trial.
Hematoma was reported in 15% of patients with newly diagnosed AML who received ivosidenib in combination with azacitidine (n = 71) in a randomized trial. The term hematoma included eye hematoma, catheter-site/application-site/injection-site hematoma, oral mucosa hematoma, spontaneous hematoma, and periorbital hematoma.
Hypertension occurred in 16% (all grade 3 or 4) of patients with myelodysplastic syndrome who received single-agent ivosidenib (n = 19) and 13% (grade 3 or higher, 4%) of patients with newly diagnosed acute myeloid leukemia who received ivosidenib plus azacitidine (n = 71) in clinical trials. Chest pain (unspecified) including angina pectoris and non-cardiac chest pain (16%; grade 3 or 4, 3%) and hypotension (12%; grade 3 or 4, 4%) were reported in patients with relapsed or refractory AML who received ivosidenib (n = 179) in a clinical trial.
Insomnia was reported in 18% (grade 3 or higher, 1%) of patients with newly diagnosed AML who received ivosidenib in combination with azacitidine (n = 71) in a randomized trial.
Pulmonary embolism (3%) resulting in therapy discontinuation and fatal cerebral ischemia (n = 1) were reported in patients with newly diagnosed AML who received ivosidenib in combination with azacitidine (n = 71) in a randomized trial.
Worsening hypoalbuminemia/decreased albumin level from baseline was reported in 37% of patients with relapsed or refractory myelodysplastic syndrome who received ivosidenib (n = 19) in a clinical trial.
Leukocytosis and tumor lysis syndrome (TLS) have been reported with ivosidenib therapy in patients with AML and MDS; ivosidenib may induce myeloid proliferation resulting in a rapid increase in white blood cell (WBC) count and/or a rapid reduction in tumor cells. In patients with AML or MDS, monitor complete blood counts (CBC) and other blood chemistries such as serum uric acid, serum electrolytes, and renal function (e.g., BUN/serum creatinine levels) prior to starting ivosidenib and then at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Also monitor blood creatine phosphokinase (CPK) weekly for the first month of therapy in these patients. Start hydroxyurea per standard clinical practice in patients who have or develop a WBC count greater than 25 x 109 cells/L, or an absolute increase in total WBC of greater than 15 x 109 cells/L from baseline. Interrupt ivosidenib therapy if leukocytosis is not improved with hydroxyurea. Resume ivosidenib therapy when leukocytosis has resolved. Manage other laboratory abnormalities promptly. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop severe TLS.
Differentiation syndrome with or without concomitant noninfectious leukocytosis has been reported with ivosidenib therapy in patients with AML; this syndrome may be fatal if not treated. Monitor AML patients for signs and symptoms of differentiation syndrome such as fever, dyspnea, hypoxia, pulmonary infiltrates, pleural effusion or pericardial effusion, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg IV every 12 hours or PO/IV equivalent) and closely monitor hemodynamic parameters. Taper corticosteroids after symptoms resolve; premature corticosteroid discontinuation may lead to symptom recurrence. Interrupt ivosidenib therapy if severe signs and/or symptoms persist after 48 hours of corticosteroid therapy. Resume ivosidenib therapy when sign and symptoms resolve to grade 2 or less. Differentiation syndrome occurred as soon as 1 day and up to 3 months after starting ivosidenib.
QT prolongation and ventricular arrhythmias have been reported in clinical trial patients treated with ivosidenib. These trials excluded patients with a baseline QTc of 450 milliseconds or more, unless it was due to a pre-existing bundle branch block. Patients with AML were excluded for a history of uncontrolled or significant heart disease, while those with cholangiocarcinoma were excluded for other risk factors that increased the risk of QT prolongation or arrhythmic events (e.g., heart failure or hypokalemia). While both clinical trials also excluded patients with a personal or family history of long QT syndrome, more frequent monitoring may be necessary in patients with congenital long QT syndrome as this condition may increase the risk of QT prolongation. Obtain an ECG at baseline; monitor ECGs at least once weekly for the first 3 weeks of therapy, and then at least once monthly during therapy; also monitor electrolytes. Promptly manage any abnormalities. More frequent monitoring may be necessary in patients with congestive heart failure, electrolyte imbalance (e.g., hypomagnesemia, hypokalemia, hypocalcemia), or those who are taking medications known to prolong the QTc interval as these conditions may increase the risk of QT prolongation. Use ivosidenib with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, stress-related cardiomyopathy, myocardial infarction, stroke, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Guillain-Barre syndrome has been reported in patients treated with ivosidenib. Monitor patients for new onset of motor and/or sensory neuropathy including unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue ivosidenib therapy in patients who are diagnosed with Guillain-Barre syndrome.
Carefully consider the risks and potential benefits of ivosidenib in patients with severe hepatic disease/impairment (Child-Pugh class C); the pharmacokinetics and safety of ivosidenib in these patients are unknown. No initial dosage adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.
Carefully consider the risks and potential benefits of ivosidenib in patients with severe renal impairment (estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m2 using the MDRD equation) or renal disease requiring dialysis; the pharmacokinetics and safety of ivosidenib in these patients are unknown. No initial dosage adjustment is necessary in patients with mild or moderate renal impairment (eGFR of 30 mL/min/1.73m2 or greater).
Although there are no adequately controlled studies in pregnant females, ivosidenib can cause fetal harm when administered during pregnancy based on animal studies. Women who are pregnant or who become pregnant while receiving ivosidenib should be apprised of the potential hazard to the fetus. In animal embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with spontaneous abortions, decreased fetal weights, skeletal variations, and visceral variations at 2 to 3.9 times the steady-state clinical exposure based on AUC at the recommended human dose.
Counsel patients about the reproductive risk during ivosidenib treatment. Ivosidenib can be teratogenic if taken by the mother during pregnancy. Contraception requirements are advised. Females and males with female partners of reproductive potential should avoid pregnancy and use effective contraception during treatment with ivosidenib. It may also be advisable to continue contraception precautions for a time after discontinuation of ivosidenib therapy. Because coadministration of ivosidenib may decrease the concentrations of hormonal contraceptives, consider alternative (non-hormonal) methods of contraception in patients receiving ivosidenib. Females of reproductive potential should undergo pregnancy testing prior to initiation of ivosidenib. Women who become pregnant while receiving ivosidenib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of ivosidenib on human fertility / infertility, uterine atrophy was reported in female rats at non-tolerated dose levels of toxicity studies.
Due to the potential for serious adverse reactions in a nursing infant from ivosidenib, advise women to discontinue breast-feeding during treatment and for 1 month after the final dose. It is not known whether ivosidenib is present in human milk, although many drugs are excreted in human milk.
For the treatment of acute myelogenous leukemia (AML):
NOTE: Ivosidenib is designated as an orphan drug by the FDA for this indication.
NOTE: Evaluate patients for the presence of the isocitrate dehydrogenase-1 (IDH1) mutation using an FDA-approved detection test (www.fda.gov/CompanionDiagnostics).
-for the treatment of relapsed or refractory AML with an isocitrate dehydrogenase-1 (IDH1) mutation, as monotherapy:
Oral dosage:
Adults: 500 mg orally 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The overall response rate was 39.1% in patients with relapsed or refractory IDH1 mutation-positive AML (n = 179) who received ivosidenib in a multicenter, phase 1/2 trial; the complete remission (CR) or CR with partial hematologic recovery rate in these patients was 30.2%. The median duration of response was 6.5 months. At a median follow-up time of 14.8 months (range, 0.2 to 30.3 months), the median overall survival time was 8.8 months.
-for the treatment of newly diagnosed AML with an IDH1 mutation in patients who are 75 years of age or older or who have comorbidities that preclude use of intensive induction chemotherapy, as monotherapy:
Oral dosage:
Adults: 500 mg orally 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The overall response rate was 55.9% in patients with previously untreated IDH1 mutation-positive AML (n = 34; median age, 77 years; range, 64 to 87 years) who received ivosidenib in a multicenter, phase 1/2 trial; the complete remission (CR) or CR with partial hematologic recovery rate in these patients was 35.3%. The median duration of response was 9.2 months.
-for the treatment of newly diagnosed AML with an IDH1 mutation in patients who are 75 years of age or older or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine:
Oral dosage:
Adults: 500 mg orally once daily until disease progression, in combination with azacitidine. Azacitidine (75 mg/m2 subcutaneously or IV) may be administered once daily on days 1 to 7, every 28 days; alternatively, azacitidine may be administered once daily on days 1 to 5 and days 8 to 9, every 28 days. Therapy interruption, dose reduction, or drug discontinuation may be necessary in patients who develop toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind phase 3 clinical trial, patients with newly diagnosed, IDH1-positive AML who were 75 years or older or had comorbidities precluding the use of intensive induction chemotherapy were randomized to treatment with azacitidine plus ivosidenib (n = 72) or azacitidine plus placebo (n = 74). The primary endpoint of event-free survival duration was the same in each group (0.03 months). However, a secondary endpoint of complete remission (CR) was significantly higher in the ivosidenib group compared with the placebo group (34% vs. 11%), for a median duration not estimable versus 11 months, respectively; the rate of CR plus CR with partial hematologic recovery (CR+CRh) was also significantly higher in the ivosidenib arm (37% vs. 13%). Treatment with azacitidine plus ivosidenib significantly improved another secondary endpoint of median overall survival compared with azacitidine plus placebo (24 months vs. 7.9 months).
For the treatment of cholangiocarcinoma:
NOTE: Ivosidenib is designated as an orphan drug by the FDA for this indication.
NOTE: Evaluate patients for the presence of the isocitrate dehydrogenase-1 (IDH1) mutation using an FDA-approved detection test (www.fda.gov/CompanionDiagnostics).
-for the treatment of previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation:
Oral dosage:
Adults: 500 mg orally once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, double-blind clinical trial (ClarIDHy), treatment with ivosidenib significantly improved progression-free survival compared with placebo in previously treated patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation. The objective response rate was 2.4% (3 partial responses) vs. 0%, respectively; stable disease occurred in 50.8% of patients treated with ivosidenib compared with 27.9% of those who received placebo. Median overall survival was not significantly improved in the ivosidenib group (10.3 months vs. 7.5 months); however, 70% of patients randomized to placebo crossed over to receive ivosidenib after radiographic disease progression.
For the treatment of myelodysplastic syndrome (MDS):
NOTE: Ivosidenib is designated as an orphan drug by the FDA for this indication.
NOTE: Evaluate patients for the presence of the isocitrate dehydrogenase-1 (IDH1) mutation using an FDA-approved detection test (www.fda.gov/CompanionDiagnostics).
-for the treatment of relapsed or refractory MDS:
Oral dosage:
Adults: 500 mg orally 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. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The overall remission rate was 38.9% (all complete responses) in patients with IDH1 mutation-positive relapsed or refractory MDS who received ivosidenib in a multicenter trial (n =18). At a median follow-up time of 27.1 (range, 3.7 to 88.7) months, the median time to response was 1.9 (range, 1 to 5.6) months and the median duration of response was not estimable (range, 1.9 to more than 80.8 months). During any 56-day post baseline period, 6 of 9 patients (67%) who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline became independent of RBC and platelet transfusions and 7 of 9 patients (78%) who were transfusion independent at baseline remained transfusion independent. One patient received a stem-cell transplant following ivosidenib therapy.
Therapeutic Drug Monitoring:
DOSAGE ADJUSTMENTS FOR TREATMENT-RELATED TOXICITY:
Differentiation Syndrome
-Administer corticosteroid therapy (e.g., dexamethasone 10 mg IV every 12 hours or equivalent PO/IV corticosteroid) if differentiation syndrome is suspected; closely monitor hemodynamic parameters. Interrupt ivosidenib therapy if severe signs and/or symptoms persist after 48 hours of corticosteroid therapy. Taper corticosteroids after a minimum of 3 days after symptoms completely have resolved; symptoms may recur with premature discontinuation of corticosteroids. Resume ivosidenib therapy when signs and symptoms of toxicity resolve to grade 2 or less.
Guillain-Barre Syndrome
-Permanently discontinue ivosidenib.
Noninfectious Leukocytosis
-White blood cell (WBC) count greater than 25 x 109 cells/L, or an absolute increase in total WBC of greater than 15 x 109 cells/L from baseline: Start hydroxyurea per standard clinical practice, and leukapheresis if clinically indicated. Interrupt ivosidenib therapy if leukocytosis is not improved with hydroxyurea. Resume ivosidenib therapy at 500 mg PO once daily when leukocytosis has resolved. Taper hydroxyurea after symptoms completely have resolved; symptoms may recur with premature discontinuation of hydroxyurea.
QT Prolongation
-QTc interval 481 to 500 msec: Interrupt ivosidenib therapy. Monitor and supplement electrolyte levels as clinically indicated. When the QTc interval returns to 480 msec or less, resume ivosidenib at 500 mg PO once daily. Monitor ECG at least weekly for 2 weeks following resolution of QTc prolongation.
-QTc interval more than 500 msec: Interrupt ivosidenib therapy. Monitor and supplement electrolyte levels as clinically indicated. When the QTc interval returns to 480 msec or less or within 30 msec of baseline, restart ivosidenib at 250 mg PO once daily. Monitor ECG at least weekly for 2 weeks following resolution of QTc prolongation. Consider re-escalating the dose of ivosidenib to 500 mg PO once daily if an alternative etiology for QTc prolongation can be identified.
-QTc interval prolongation with life-threatening arrhythmia: Permanently discontinue ivosidenib.
Other Grade 3 or Higher Treatment-Related Toxicity
-AML monotherapy or MDS patients: Hold ivosidenib therapy. When the toxicity resolves to grade 2 or less, resume ivosidenib at 250 mg PO once daily. Consider re-escalating to 500 mg PO once daily if the toxicity resolves to grade 1 or less. Discontinue ivosidenib therapy if grade 3 or higher toxicity recurs.
-AML in combination with azacitidine and cholangiocarcinoma patients: Hold ivosidenib therapy. When the toxicity resolves to grade 1 or less, or baseline, resume ivosidenib without a dose reduction for grade 3 toxicity or at 250 mg PO once daily for grade 4 toxicity. If grade 3 toxicity recurs a second time, reduce the dose if ivosidenib to 250 mg once daily, resuming a dose of 500mg daily upon resolution. Discontinue ivosidenib if grade 3 toxicity recurs a third time or grade 4 toxicity recurs a second time.
Maximum Dosage Limits:
-Adults
500 mg/day PO.
-Geriatric
500 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.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: No dosage adjustments are needed.
Severe hepatic impairment (Child-Pugh class C): The effect of severe hepatic impairment on this drug is unknown.
Patients with Renal Impairment Dosing
eGFR 30 mL/minute/1.73 m2 or more: No dosage adjustments are needed.
eGFR less than 30 mL/minute/1.73 m2: The effect of severe renal impairment or renal impairment requiring dialysis on this drug is unknown.
*non-FDA-approved indication
Acalabrutinib: (Moderate) Monitor for loss of acalabrutinib efficacy if coadministration with ivosidenib is necessary; a dosage increase of acalabrutinib may be needed. Acalabrutinib is a sensitive CYP3A4 substrate. Ivosidenib is a CYP3A4 inducer and may reduce acalabrutinib exposure.
Adagrasib: (Major) Avoid coadministration of ivosidenib with adagrasib due to the potential for increased ivosidenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, reduce the dose of ivosidenib to 250 mg PO once daily and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. If adagrasib is discontinued, wait at least 5 half-lives of adagrasib before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Albuterol; Budesonide: (Moderate) Monitor for loss of efficacy of budesonide during coadministration of ivosidenib; a budesonide dose adjustment may be necessary. Budesonide is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased budesonide concentrations.
Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with ivosidenib is necessary. If ivosidenib is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like ivosidenib with alfentanil, a sensitive CYP3A4 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.
Alfuzosin: (Major) Avoid coadministration of ivosidenib with alfuzosin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Alfuzosin may prolong the QT interval in a dose-dependent manner.
Amiodarone: (Major) Concomitant use of amiodarone and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Avoid coadministration of ivosidenib with amisulpride due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Amisulpride causes dose- and concentration- dependent QT prolongation.
Amlodipine; Celecoxib: (Moderate) Monitor for loss of efficacy of celecoxib during coadministration of ivosidenib; a celecoxib dose adjustment may be necessary. Celecoxib is a sensitive substrate of CYP2C9; ivosidenib may induce CYP2C9 leading to decreased celecoxib concentrations.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of ivosidenib with clarithromycin due to increased plasma concentrations of ivosidenib and additive QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If clarithromycin is discontinued, wait at least 5 half-lives of clarithromycin before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Anagrelide: (Major) Avoid coadministration of ivosidenib with anagrelide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
Apalutamide: (Major) Avoid coadministration of ivosidenib with apalutamide due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Apomorphine: (Major) Avoid coadministration of ivosidenib with apomorphine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of ivosidenib with aprepitant/fosaprepitant due to decreased plasma concentrations of aprepitant/fosaprepitant and increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate; monitor for loss of aprepitant/fosaprepitant efficacy. Ivosidenib is a CYP3A4 substrate and a CYP3A4 inducer. Aprepitant/fosaprepitant is a sensitive CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Aripiprazole: (Major) Avoid coadministration of ivosidenib with aripiprazole due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
Arsenic Trioxide: (Major) Avoid coadministration of ivosidenib with arsenic trioxide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use.
Artemether; Lumefantrine: (Major) Avoid coadministration of ivosidenib with artemether; lumefantrine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Artemether; lumefantrine is associated with prolongation of the QT interval.
Asenapine: (Major) Avoid coadministration of ivosidenib with asenapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Asenapine has been associated with QT prolongation.
Atazanavir: (Contraindicated) Atazanavir, with or without ritonavir, is contraindicated for use with ivosidenib. Concurrent administration may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduced antiretroviral efficacy and development of viral resistance. In addition, coadministration could result in increased ivosidenib concentrations, resulting in serious adverse reactions such as QT prolongation.
Atazanavir; Cobicistat: (Contraindicated) Atazanavir, with or without ritonavir, is contraindicated for use with ivosidenib. Concurrent administration may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduced antiretroviral efficacy and development of viral resistance. In addition, coadministration could result in increased ivosidenib concentrations, resulting in serious adverse reactions such as QT prolongation. (Major) Avoid coadministration of ivosidenib with cobicistat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If cobicistat is discontinued, wait at least 5 half-lives of cobicistat before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Atogepant: (Major) Avoid use of atogepant and ivosidenib when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with ivosidenib. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and ivosidenib is a weak CYP3A inducer. Coadministration with a weak CYP3A inducer resulted in a 25% reduction in atogepant overall exposure and a 24% reduction in atogepant peak concentration.
Atomoxetine: (Major) Avoid coadministration of ivosidenib with atomoxetine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
Avanafil: (Major) Coadministration of avanafil with ivosidenib is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and ivosidenib is a CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Azithromycin: (Major) Avoid coadministration of azithromycin with ivosidenib due to an increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
Bedaquiline: (Major) Avoid coadministration of ivosidenib with bedaquiline due to an increased risk of QT prolongation. If concomitant use is unavoidable, obtain serum electrolyte concentrations and a baseline ECG; correct any electrolyte abnormalities as clinically appropriate. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Bedaquiline has been reported to prolong the QT interval.
Berotralstat: (Major) Avoid coadministration of ivosidenib with berotralstat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bosutinib: (Moderate) Monitor for loss of efficacy of bosutinib during coadministration of ivosidenib; a bosutinib dose adjustment may be necessary. Bosutinib is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased bosutinib concentrations.
Budesonide: (Moderate) Monitor for loss of efficacy of budesonide during coadministration of ivosidenib; a budesonide dose adjustment may be necessary. Budesonide is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased budesonide concentrations.
Budesonide; Formoterol: (Moderate) Monitor for loss of efficacy of budesonide during coadministration of ivosidenib; a budesonide dose adjustment may be necessary. Budesonide is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased budesonide concentrations.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for loss of efficacy of budesonide during coadministration of ivosidenib; a budesonide dose adjustment may be necessary. Budesonide is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased budesonide concentrations.
Buprenorphine: (Major) Avoid coadministration of ivosidenib with buprenorphine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Buprenorphine; Naloxone: (Major) Avoid coadministration of ivosidenib with buprenorphine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
Bupropion: (Moderate) Monitor for loss of efficacy of bupropion during coadministration of ivosidenib. A bupropion dose increase may be necessary; do not exceed the maximum recommended dose. Bupropion is a sensitive substrate of CYP2B6; ivosidenib may induce CYP2B6 leading to decreased bupropion concentrations.
Bupropion; Naltrexone: (Moderate) Monitor for loss of efficacy of bupropion during coadministration of ivosidenib. A bupropion dose increase may be necessary; do not exceed the maximum recommended dose. Bupropion is a sensitive substrate of CYP2B6; ivosidenib may induce CYP2B6 leading to decreased bupropion concentrations.
Buspirone: (Moderate) Monitor for loss of efficacy of buspirone during coadministration of ivosidenib; a buspirone dose adjustment may be necessary. Buspirone is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased buspirone concentrations.
Cabotegravir; Rilpivirine: (Major) Avoid coadministration of ivosidenib with rilpivirine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Carbamazepine: (Major) Avoid coadministration of ivosidenib with carbamazepine due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Celecoxib: (Moderate) Monitor for loss of efficacy of celecoxib during coadministration of ivosidenib; a celecoxib dose adjustment may be necessary. Celecoxib is a sensitive substrate of CYP2C9; ivosidenib may induce CYP2C9 leading to decreased celecoxib concentrations.
Celecoxib; Tramadol: (Moderate) Monitor for loss of efficacy of celecoxib during coadministration of ivosidenib; a celecoxib dose adjustment may be necessary. Celecoxib is a sensitive substrate of CYP2C9; ivosidenib may induce CYP2C9 leading to decreased celecoxib concentrations.
Ceritinib: (Major) Avoid coadministration of ivosidenib with ceritinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ceritinib is discontinued, wait at least 5 half-lives of ceritinib before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Chloramphenicol: (Major) Avoid coadministration of ivosidenib with chloramphenicol due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If chloramphenicol is discontinued, wait at least 5 half-lives of chloramphenicol before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Chloroquine: (Major) Avoid coadministration of chloroquine with ivosidenib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses.
Chlorpromazine: (Major) Avoid coadministration of ivosidenib with chlorpromazine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
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.
Ciprofloxacin: (Major) Avoid coadministration of ivosidenib with ciprofloxacin due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Ciprofloxacin is a moderate CYP3A4 inhibitor; rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Cisapride: (Contraindicated) Coadministration of ivosidenib with cisapride is contraindicated due to an increased risk of QT prolongation. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride.
Citalopram: (Major) Avoid coadministration of ivosidenib with citalopram due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Citalopram causes dose-dependent QT interval prolongation.
Clarithromycin: (Major) Avoid coadministration of ivosidenib with clarithromycin due to increased plasma concentrations of ivosidenib and additive QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If clarithromycin is discontinued, wait at least 5 half-lives of clarithromycin before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Clofazimine: (Major) Concomitant use of clofazimine and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clozapine: (Major) Avoid coadministration of ivosidenib with clozapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Cobicistat: (Major) Avoid coadministration of ivosidenib with cobicistat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If cobicistat is discontinued, wait at least 5 half-lives of cobicistat before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Cobimetinib: (Moderate) Monitor for loss of efficacy of cobimetinib during coadministration of ivosidenib; a cobimetinib dose adjustment may be necessary. Cobimetinib is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased cobimetinib concentrations.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Codeine; Promethazine: (Major) Concomitant use of promethazine and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Conivaptan: (Major) Avoid coadministration of ivosidenib with conivaptan due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is necessary, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the ivosidenib overall exposure 152-190%.
Conjugated Estrogens; Medroxyprogesterone: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Crizotinib: (Major) Avoid coadministration of ivosidenib with crizotinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Cyclosporine: (Major) Avoid coadministration of ivosidenib with cyclosporine due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and cyclosporine is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Danazol: (Major) Avoid coadministration of ivosidenib with danazol due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and danazol is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Darunavir: (Major) Avoid coadministration of ivosidenib with darunavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation; darunavir exposure may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of darunavir. If darunavir is discontinued, wait at least 5 half-lives of darunavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer. Darunavir is a strong CYP3A4 inhibitor and sensitive substrate. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Darunavir; Cobicistat: (Major) Avoid coadministration of ivosidenib with cobicistat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If cobicistat is discontinued, wait at least 5 half-lives of cobicistat before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. (Major) Avoid coadministration of ivosidenib with darunavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation; darunavir exposure may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of darunavir. If darunavir is discontinued, wait at least 5 half-lives of darunavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer. Darunavir is a strong CYP3A4 inhibitor and sensitive substrate. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of ivosidenib with cobicistat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If cobicistat is discontinued, wait at least 5 half-lives of cobicistat before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. (Major) Avoid coadministration of ivosidenib with darunavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation; darunavir exposure may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of darunavir. If darunavir is discontinued, wait at least 5 half-lives of darunavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer. Darunavir is a strong CYP3A4 inhibitor and sensitive substrate. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Dasatinib: (Major) Avoid coadministration of ivosidenib with dasatinib due to an increased risk of QT prolongation; dasatinib exposure may also decrease. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Monitor for loss of efficacy of dasatinib. Ivosidenib is a CYP3A4 inducer that has been associated with prolongation of the QTc interval and ventricular arrhythmias. Dasatinib is a sensitive CYP3A4 substrate; in vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Major) Avoid coadministration of ivosidenib with degarelix due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Avoid coadministration of ivosidenib with delavirdine due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If delavirdine is discontinued, wait at least 5 half-lives of delavirdine before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
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.
Desflurane: (Major) Avoid coadministration of ivosidenib with halogenated anesthetics due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Halogenated anesthetics can prolong the QT interval.
Desogestrel; Ethinyl Estradiol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Deutetrabenazine: (Major) Avoid coadministration of ivosidenib with deutetrabenazine if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Bupropion: (Moderate) Monitor for loss of efficacy of bupropion during coadministration of ivosidenib. A bupropion dose increase may be necessary; do not exceed the maximum recommended dose. Bupropion is a sensitive substrate of CYP2B6; ivosidenib may induce CYP2B6 leading to decreased bupropion concentrations.
Dextromethorphan; Quinidine: (Major) Avoid coadministration of ivosidenib with quinidine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
Dienogest; Estradiol valerate: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Diltiazem: (Major) Avoid coadministration of ivosidenib with diltiazem due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and diltiazem is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Disopyramide: (Major) Avoid coadministration of ivosidenib with disopyramide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP).
Dofetilide: (Major) Avoid coadministration of ivosidenib with dofetilide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Dolasetron: (Major) Avoid coadministration of ivosidenib with dolasetron due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Major) Avoid coadministration of ivosidenib with rilpivirine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil: (Major) Avoid coadministration of ivosidenib with donepezil due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Donepezil; Memantine: (Major) Avoid coadministration of ivosidenib with donepezil due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Dronedarone: (Contraindicated) Coadministration of dronedarone and ivosidenib is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. Ivosidenib has been associated with QTc prolongation and ventricular arrhythmias. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Avoid coadministration of ivosidenib with droperidol due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
Drospirenone: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Drospirenone; Estetrol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Drospirenone; Estradiol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Drospirenone; Ethinyl Estradiol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Duvelisib: (Major) Avoid coadministration of ivosidenib with duvelisib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and duvelisib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Efavirenz: (Major) Avoid coadministration of ivosidenib with efavirenz due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ivosidenib with efavirenz due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ivosidenib with efavirenz due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QTc prolongation has been observed with the use of efavirenz.
Elagolix; Estradiol; Norethindrone acetate: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Eletriptan: (Moderate) Monitor for loss of efficacy of eletriptan during coadministration of ivosidenib; a eletriptan dose adjustment may be necessary. Eletriptan is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased eletriptan concentrations.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for loss of efficacy of ivacaftor during coadministration of ivosidenib; a ivacaftor dose adjustment may be necessary. Ivacaftor is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ivacaftor concentrations.
Eliglustat: (Major) Avoid coadministration of ivosidenib with eliglustat due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of ivosidenib with cobicistat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If cobicistat is discontinued, wait at least 5 half-lives of cobicistat before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ivosidenib with cobicistat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If cobicistat is discontinued, wait at least 5 half-lives of cobicistat before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of ivosidenib with rilpivirine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ivosidenib with rilpivirine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Encorafenib: (Major) Avoid concurrent use of encorafenib with ivosidenib due to the risk for decreased ivosidenib exposure and efficacy and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ivosidenib is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Concurrent use of a strong CYP3A inducer is predicted to decrease ivosidenib exposure by 33%.
Entrectinib: (Major) Avoid coadministration of ivosidenib with entrectinib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Entrectinib has been associated with QT prolongation.
Enzalutamide: (Major) Avoid coadministration of ivosidenib with enzalutamide due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Eribulin: (Major) Avoid coadministration of ivosidenib with eribulin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Eribulin has been associated with QT prolongation.
Erythromycin: (Major) Avoid coadministration of ivosidenib with erythromycin due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Erythromycin is a moderate CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Escitalopram: (Major) Avoid coadministration of ivosidenib with escitalopram due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP).
Estradiol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Estradiol; Levonorgestrel: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Estradiol; Norethindrone: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Estradiol; Norgestimate: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Ethinyl Estradiol; Norelgestromin: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Ethinyl Estradiol; Norgestrel: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Etonogestrel: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Etonogestrel; Ethinyl Estradiol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Etrasimod: (Major) Concomitant use of etrasimod and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Ezetimibe; Simvastatin: (Moderate) Monitor for loss of efficacy of simvastatin during coadministration of ivosidenib; a simvastatin dose adjustment may be necessary. Simvastatin is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased simvastatin concentrations.
Fedratinib: (Major) Avoid coadministration of ivosidenib with fedratinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and fedratinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Felodipine: (Moderate) Monitor for loss of efficacy of felodipine during coadministration of ivosidenib; a felodipine dose adjustment may be necessary. Felodipine is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased felodipine concentrations.
Fexinidazole: (Major) Concomitant use of fexinidazole and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fingolimod: (Major) Avoid coadministration of ivosidenib with fingolimod due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Avoid coadministration of ivosidenib with flecainide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Fluconazole: (Major) Avoid coadministration of ivosidenib with fluconazole due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Fluconazole is a moderate CYP3A4 inhibitor that has also been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with fluconazole is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of fluconazole with ivosidenib are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control. Additive QT prolongation may also occur.
Fluoxetine: (Major) Avoid coadministration of ivosidenib with fluoxetine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
Fluphenazine: (Minor) Coadministration of ivosidenib with fluphenazine may increase the risk of QT prolongation. If concomitant use is necessary, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Fluvoxamine: (Major) Avoid coadministration of ivosidenib with fluvoxamine due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Fluvoxamine is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported during fluvoxamine post-marketing use. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Fosamprenavir: (Major) Avoid coadministration of ivosidenib with fosamprenavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Foscarnet: (Major) Avoid coadministration of ivosidenib with foscarnet due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
Fosphenytoin: (Major) Avoid coadministration of ivosidenib with fosphenytoin due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Fostemsavir: (Major) Avoid coadministration of ivosidenib with fostemsavir if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) Avoid coadministration of ivosidenib with gemifloxacin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of ivosidenib with gemtuzumab due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) Avoid coadministration of ivosidenib with gilteritinib if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Gilteritinib has also been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with ivosidenib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Monitor electrolytes and correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
Goserelin: (Major) Avoid coadministration of ivosidenib with goserelin if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Androgen deprivation therapy (i.e., goserelin) also may prolong the QT/QTc interval.
Granisetron: (Major) Avoid coadministration of ivosidenib with granisetron due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Granisetron has been associated with QT prolongation.
Grapefruit juice: (Major) Advise patients to avoid grapefruit juice while taking ivosidenib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation or other toxicities. Ivosidenib is a CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Halogenated Anesthetics: (Major) Avoid coadministration of ivosidenib with halogenated anesthetics due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Halogenated anesthetics can prolong the QT interval.
Haloperidol: (Major) Avoid coadministration of ivosidenib with haloperidol due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Major) Avoid coadministration of ivosidenib with histrelin if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Androgen deprivation therapy (i.e., histrelin) also may prolong the QT/QTc interval.
Hydroxychloroquine: (Major) Avoid coadministration of ivosidenib and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Dose reduce or interrupt ivosidenib therapy if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Hydroxychloroquine also prolongs the QT interval.
Hydroxyzine: (Major) Avoid coadministration of ivosidenib with hydroxyzine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP).
Ibrutinib: (Moderate) Monitor for loss of efficacy of ibrutinib during coadministration of ivosidenib; an ibrutinib dose adjustment may be necessary. Ibrutinib is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ibrutinib concentrations.
Ibutilide: (Major) Avoid coadministration of ivosidenib with ibutilide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Ibutilide administration can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idelalisib: (Major) Avoid coadministration of ivosidenib with idelalisib if possible due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If idelalisib is discontinued, wait at least 5 half-lives of idelalisib before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Iloperidone: (Major) Avoid coadministration of ivosidenib with iloperidone due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Iloperidone has been associated with QT prolongation.
Imatinib: (Major) Avoid coadministration of ivosidenib with imatinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Indinavir: (Major) Avoid coadministration of ivosidenib with indinavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation; indinavir exposure may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of indinavir. If indinavir is discontinued, wait at least 5 half-lives of indinavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer; indinavir is a strong CYP3A4 inhibitor and sensitive substrate. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of ivosidenib with inotuzumab due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Inotuzumab has been associated with QT interval prolongation.
Isavuconazonium: (Major) Avoid coadministration of ivosidenib with isavuconazonium due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation; isavuconazonium exposure may also decrease. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of isavuconazonium. Ivosidenib is a CYP3A4 substrate and inducer; isavuconazole, the active moiety of isavuconazonium, is a moderate CYP3A4 inhibitor and sensitive substrate. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Isoflurane: (Major) Avoid coadministration of ivosidenib with halogenated anesthetics due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Halogenated anesthetics can prolong the QT interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of ivosidenib with rifampin due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin is predicted to decrease ivosidenib exposure at steady-state by 33%.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of ivosidenib with rifampin due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin is predicted to decrease ivosidenib exposure at steady-state by 33%.
Itraconazole: (Major) Do not coadminister ivosidenib with itraconazole due to decreased exposure to itraconazole and loss of antifungal efficacy. Additionally, ivosidenib exposure may increase which increases the risk of QT prolongation. If a patient has received itraconazole, reduce the initial dose of ivosidenib to 250 mg PO once daily and wait at least 5 half-lives of itraconazole after stopping therapy before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer, and has been associated with QTc prolongation as well as ventricular arrhythmias. Itraconazole is a CYP3A4 substrate and strong inhibitor that has also been associated with QT prolongation. Coadministration with itraconazole increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. Because ivosidenib induces CYP3A4, it is also expected to decrease steady-state exposure to CYP3A4 substrates, such as itraconazole, to a clinically relevant extent.
Ivacaftor: (Moderate) Monitor for loss of efficacy of ivacaftor during coadministration of ivosidenib; a ivacaftor dose adjustment may be necessary. Ivacaftor is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ivacaftor concentrations.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and ivosidenib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. If coadministered, decreased ketoconazole exposure and loss of antifungal efficacy may occur. Additionally, concomitant use may increase the exposure of ivosidenib, further increasing the risk for adverse effects. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ketoconazole is discontinued, wait at least 5 half-lives of ketoconazole before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. Because ivosidenib induces CYP3A4, it is also expected to decrease steady-state exposure to CYP3A4 substrates, such as ketoconazole, to a clinically relevant extent.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of ivosidenib with clarithromycin due to increased plasma concentrations of ivosidenib and additive QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If clarithromycin is discontinued, wait at least 5 half-lives of clarithromycin before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Lapatinib: (Major) Avoid coadministration of ivosidenib with lapatinib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience.
Lefamulin: (Major) Avoid coadministration of lefamulin with ivosidenib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs and electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib.
Lenacapavir: (Major) Avoid coadministration of ivosidenib with lenacapavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling. Multiple doses of the moderate CYP3A inhibitor are predicted to increase the ivosidenib steady-state AUC to 190% of control.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with ivosidenib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval and ventricular arrhythmias have also been reported in patients treated with ivosidenib.
Letermovir: (Major) Avoid coadministration of ivosidenib with letermovir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. In patients receiving the combination of letermovir and cyclosporine who require ivosidenib therapy, reduce the dose of ivosidenib to 250 mg PO once daily. If letermovir or cyclosporine is discontinued, wait at least 5 half-lives of letermovir or cyclosporine before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor; however, when letermovir is combined with cyclosporine the effect may be similar to a strong CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control. Coadministration with a strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Leuprolide: (Major) Avoid coadministration of ivosidenib with leuprolide if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Androgen deprivation therapy (i.e., leuprolide) also may prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of ivosidenib with leuprolide if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Androgen deprivation therapy (i.e., leuprolide) also may prolong the QT/QTc interval. (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Levofloxacin: (Major) Concomitant use of levofloxacin and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and ivosidenib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. If coadministered, decreased ketoconazole exposure and loss of antifungal efficacy may occur. Additionally, concomitant use may increase the exposure of ivosidenib, further increasing the risk for adverse effects. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ketoconazole is discontinued, wait at least 5 half-lives of ketoconazole before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. Because ivosidenib induces CYP3A4, it is also expected to decrease steady-state exposure to CYP3A4 substrates, such as ketoconazole, to a clinically relevant extent.
Levonorgestrel: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Levonorgestrel; Ethinyl Estradiol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Lithium: (Major) Avoid coadministration of ivosidenib with lithium due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Lithium has also been associated with QT prolongation.
Lofexidine: (Major) Avoid coadministration of ivosidenib with lofexidine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Lofexidine prolongs the QT interval.
Lomitapide: (Moderate) Monitor for loss of efficacy of lomitapide during coadministration of ivosidenib; a lomitapide dose adjustment may be necessary. Lomitapide is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased lomitapide concentrations.
Lonafarnib: (Major) Avoid coadministration of ivosidenib with lonafarnib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If lonafarnib is discontinued, wait at least 5 half-lives of lonafarnib before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Loperamide: (Major) Avoid coadministration of ivosidenib with loperamide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Major) Avoid coadministration of ivosidenib with loperamide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of ivosidenib with ritonavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ritonavir is discontinued, wait at least 5 half-lives of ritonavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. (Major) Avoid coadministration of lopinavir with ivosidenib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Interrupt or dose reduce ivosidenib if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Lopinavir is associated with QT prolongation.
Lovastatin: (Moderate) Monitor for loss of efficacy of lovastatin during coadministration of ivosidenib; a lovastatin dose adjustment may be necessary. Lovastatin is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased lovastatin concentrations.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ivosidenib with lumacaftor; ivacaftor due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%. (Moderate) Monitor for loss of efficacy of ivacaftor during coadministration of ivosidenib; a ivacaftor dose adjustment may be necessary. Ivacaftor is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ivacaftor concentrations.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ivosidenib with lumacaftor; ivacaftor due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Lumateperone: (Major) Avoid coadministration of lumateperone and ivosidenib as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A substrate; ivosidenib is a weak CYP3A inducer.
Lurasidone: (Moderate) Monitor for loss of efficacy of lurasidone during coadministration of ivosidenib; a lurasidone dose adjustment may be necessary. Lurasidone is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased lurasidone concentrations.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as ivosidenib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib.
Maprotiline: (Major) Avoid coadministration of ivosidenib with maprotiline due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Medroxyprogesterone: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Mefloquine: (Major) Avoid coadministration of ivosidenib with mefloquine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Metformin; Repaglinide: (Moderate) Monitor for loss of efficacy of repaglinide during coadministration of ivosidenib. A repaglinide dose increase may be necessary. Repaglinide is a sensitive substrate of CYP2C8; ivosidenib may induce CYP2C8 leading to decreased repaglinide concentrations.
Methadone: (Major) Avoid coadministration of ivosidenib with methadone due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
Metronidazole: (Major) Concomitant use of metronidazole and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Moderate) Monitor for loss of efficacy of midazolam during coadministration of ivosidenib; a midazolam dose adjustment may be necessary. Midazolam is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased midazolam concentrations.
Midostaurin: (Major) Avoid coadministration of ivosidenib with midostaurin due to an increased risk of QT prolongation; midostaurin exposure may also be decreased. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of midostaurin. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation was reported in patients who received midostaurin in clinical trials.
Mifepristone: (Major) Avoid coadministration of ivosidenib with mifepristone due to increased plasma concentrations of ivosidenib and additive QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If mifepristone is discontinued, wait at least 5 half-lives of mifepristone before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Mifepristone is a strong CYP3A4 inhibitor associated with dose-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Mirtazapine: (Major) Concomitant use of ivosidenib and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mitotane: (Major) Avoid coadministration of ivosidenib with mitotane due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Mobocertinib: (Major) Concomitant use of mobocertinib and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Moxifloxacin: (Major) Avoid coadministration of ivosidenib with moxifloxacin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Quinolones have been associated with a risk of QT prolongation. Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Naloxegol: (Moderate) Monitor for loss of efficacy of naloxegol during coadministration of ivosidenib; a naloxegol dose adjustment may be necessary. Naloxegol is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased naloxegol concentrations.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with ivosidenib. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and ivosidenib is a weak CYP3A inducer.
Nefazodone: (Major) Avoid coadministration of ivosidenib with nefazodone if possible due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If nefazodone is discontinued, wait at least 5 half-lives of nefazodone before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Nelfinavir: (Major) Avoid coadministration of ivosidenib with nelfinavir if possible due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If nelfinavir is discontinued, wait at least 5 half-lives of nelfinavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of ivosidenib with netupitant due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Nilotinib: (Major) Avoid coadministration of ivosidenib with nilotinib due to increased plasma concentrations of ivosidenib and QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of ivosidenib with ritonavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ritonavir is discontinued, wait at least 5 half-lives of ritonavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of ivosidenib is necessary. Concomitant use of nirmatrelvir and ivosidenib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and ivosidenib is a weak CYP3A inducer.
Nirogacestat: (Major) Avoid coadministration of ivosidenib with nirogacestat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling. Multiple doses of the moderate CYP3A inhibitor are predicted to increase the ivosidenib steady-state AUC to 190% of control.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with ivosidenib due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a sensitive CYP3A4 substrate and ivosidenib is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Norethindrone: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Norethindrone; Ethinyl Estradiol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Norgestimate; Ethinyl Estradiol: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Norgestrel: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Ofloxacin: (Major) Concomitant use of ofloxacin and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Avoid coadministration of ivosidenib with olanzapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) Avoid coadministration of ivosidenib with fluoxetine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. (Major) Avoid coadministration of ivosidenib with olanzapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Major) Avoid coadministration of ivosidenib with olanzapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ondansetron: (Major) Concomitant use of ondansetron and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Oral Contraceptives: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Osilodrostat: (Major) Avoid coadministration of ivosidenib with osilodrostat due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of ivosidenib with osimertinib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib and/or osimertinib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
Oxaliplatin: (Major) Avoid coadministration of ivosidenib with oxaliplatin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation and ventricular arrhythmias, including fatal torsade de pointes, have been reported with oxaliplatin use in postmarketing experience.
Ozanimod: (Major) Avoid coadministration of ivosidenib with ozanimod if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with torsade de pointes in patients with bradycardia.
Pacritinib: (Major) Concomitant use of pacritinib and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Avoid coadministration of ivosidenib with paliperidone if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as needed. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
Panobinostat: (Major) Avoid coadministration of ivosidenib with panobinostat due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation has been reported with panobinostat.
Pasireotide: (Major) Avoid coadministration of ivosidenib with pasireotide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of ivosidenib with pazopanib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Pazopanib has been reported to prolong the QT interval.
Pentamidine: (Major) Avoid coadministration of ivosidenib with pentamidine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Systemic pentamidine has been associated with QT prolongation.
Perphenazine: (Minor) Coadministration of ivosidenib with perphenazine may increase the risk of QT prolongation. If concomitant use is necessary, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Perphenazine; Amitriptyline: (Minor) Coadministration of ivosidenib with perphenazine may increase the risk of QT prolongation. If concomitant use is necessary, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Phenobarbital: (Major) Avoid coadministration of ivosidenib with phenobarbital due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of ivosidenib with phenobarbital due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Phenytoin: (Major) Avoid coadministration of ivosidenib with phenytoin due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Pimavanserin: (Major) Avoid coadministration of ivosidenib with pimavanserin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Pimavanserin may also cause QT prolongation.
Pimozide: (Contraindicated) Coadministration of ivosidenib with pimozide is contraindicated due to an increased risk of QT prolongation. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Pitolisant: (Major) Avoid coadministration of ivosidenib with pitolisant due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Pitolisant prolongs the QT interval.
Ponesimod: (Major) Avoid coadministration of ivosidenib with ponesimod if possible due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
Posaconazole: (Major) Avoid coadministration of ivosidenib with posaconazole due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If posaconazole is discontinued, wait at least 5 half-lives of posaconazole before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Posaconazole is a strong CYP3A4 inhibitor associated with QT prolongation, as well as rare cases of torsade de pointes. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. Additive QT prolongation may also occur.
Primaquine: (Major) Avoid coadministration of ivosidenib with primaquine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Primaquine may also cause QT interval prolongation.
Primidone: (Major) Avoid coadministration of ivosidenib with primidone due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Procainamide: (Major) Avoid coadministration of ivosidenib with procainamide due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Prochlorperazine: (Minor) Coadministration of ivosidenib with prochlorperazine may increase the risk of QT prolongation. If concomitant use is necessary, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Promethazine: (Major) Concomitant use of promethazine and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quetiapine: (Major) Avoid coadministration of ivosidenib with quetiapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Additionally, monitor for loss of efficacy of quetiapine during coadministration of ivosidenib; a quetiapine dose adjustment may be necessary. Quetiapine is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased quetiapine concentrations. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
Quinidine: (Major) Avoid coadministration of ivosidenib with quinidine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
Quinine: (Major) Avoid coadministration of ivosidenib with quinine due to increased plasma concentrations of ivosidenib and QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Quinine is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Quizartinib: (Major) Concomitant use of quizartinib and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Major) Avoid coadministration of ivosidenib with ranolazine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Relugolix: (Major) Avoid coadministration of ivosidenib with relugolix if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of ivosidenib with relugolix if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Repaglinide: (Moderate) Monitor for loss of efficacy of repaglinide during coadministration of ivosidenib. A repaglinide dose increase may be necessary. Repaglinide is a sensitive substrate of CYP2C8; ivosidenib may induce CYP2C8 leading to decreased repaglinide concentrations.
Ribociclib: (Major) Avoid coadministration of ivosidenib with ribociclib due to an increased risk of QT prolongation; increased exposure to ivosidenib may also occur. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Coadministration with another strong CYP3A4 inhibitor increased single dose ivosidenib exposure to 269% of control.
Ribociclib; Letrozole: (Major) Avoid coadministration of ivosidenib with ribociclib due to an increased risk of QT prolongation; increased exposure to ivosidenib may also occur. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Coadministration with another strong CYP3A4 inhibitor increased single dose ivosidenib exposure to 269% of control.
Rifampin: (Major) Avoid coadministration of ivosidenib with rifampin due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin is predicted to decrease ivosidenib exposure at steady-state by 33%.
Rifapentine: (Major) Avoid coadministration of ivosidenib with rifapentine due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Rilpivirine: (Major) Avoid coadministration of ivosidenib with rilpivirine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Risperidone: (Major) Avoid coadministration of ivosidenib with risperidone due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes. Reports of QT prolongation and torsade de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
Ritlecitinib: (Major) Avoid coadministration of ivosidenib with ritlecitinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling. Multiple doses of the moderate CYP3A inhibitor are predicted to increase the ivosidenib steady-state AUC to 190% of control.
Ritonavir: (Major) Avoid coadministration of ivosidenib with ritonavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ritonavir is discontinued, wait at least 5 half-lives of ritonavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Romidepsin: (Major) Avoid coadministration of ivosidenib with romidepsin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Romidepsin has been reported to prolong the QT interval.
Saquinavir: (Major) Avoid coadministration of ivosidenib with saquinavir due to increased plasma concentrations of ivosidenib and additive QT prolongation; exposure to saquinavir may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of saquinavir. If saquinavir is discontinued, wait at least 5 half-lives of saquinavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Saquinavir boosted with ritonavir is a strong CYP3A4 and increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
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) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Selpercatinib: (Major) Avoid coadministration of ivosidenib with selpercatinib if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
Sertraline: (Major) Concomitant use of sertraline and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Avoid coadministration of ivosidenib with halogenated anesthetics due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Halogenated anesthetics can prolong the QT interval.
Sildenafil: (Moderate) Monitor for loss of efficacy of sildenafil during coadministration of ivosidenib; a sildenafil dose adjustment may be necessary. Sildenafil is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased sildenafil concentrations.
Simvastatin: (Moderate) Monitor for loss of efficacy of simvastatin during coadministration of ivosidenib; a simvastatin dose adjustment may be necessary. Simvastatin is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased simvastatin concentrations.
Siponimod: (Major) Avoid coadministration of siponimod and ivosidenib due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of ivosidenib. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and ivosidenib is a weak CYP3A inducer.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) Avoid coadministration of ivosidenib with solifenacin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with ivosidenib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib.
Sotalol: (Major) Concomitant use of sotalol and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of ivosidenib with St. John's Wort due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Sunitinib: (Major) Avoid coadministration of ivosidenib with sunitinib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Sunitinib can also prolong the QT interval.
Tacrolimus: (Major) Avoid coadministration of ivosidenib with tacrolimus due to an increased risk of QT prolongation; tacrolimus exposure may also decrease. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of tacrolimus. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Ivosidenib is a CYP3A4 inducer that has been associated with prolongation of the QTc interval and ventricular arrhythmias. Tacrolimus also causes QT prolongation and is a sensitive CYP3A4 substrate.
Tamoxifen: (Major) Concomitant use of tamoxifen and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Telavancin: (Major) Avoid coadministration of ivosidenib with telavancin due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Telavancin has been associated with QT prolongation.
Tetrabenazine: (Major) Avoid coadministration of ivosidenib with tetrabenazine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Tezacaftor; Ivacaftor: (Moderate) Monitor for loss of efficacy of ivacaftor during coadministration of ivosidenib; a ivacaftor dose adjustment may be necessary. Ivacaftor is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ivacaftor concentrations.
Thioridazine: (Contraindicated) Coadministration of ivosidenib with thioridazine is contraindicated due to an increased risk of QT prolongation. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Ticagrelor: (Moderate) Monitor for loss of efficacy of ticagrelor during coadministration of ivosidenib; a ticagrelor dose adjustment may be necessary. Ticagrelor is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ticagrelor concentrations.
Tipranavir: (Major) Avoid coadministration of ivosidenib with tipranavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation; tipranavir exposure may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of tipranavir. If tipranavir is discontinued, wait at least 5 half-lives of tipranavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer. Tipranavir is a strong CYP3A4 inhibitor and sensitive substrate. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Tolterodine: (Major) Avoid coadministration of ivosidenib with tolterodine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of ivosidenib with toremifene due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
Trandolapril; Verapamil: (Major) Avoid coadministration of ivosidenib with verapamil due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Trazodone: (Major) Concomitant use of trazodone and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triazolam: (Moderate) Monitor for loss of efficacy of triazolam during coadministration of ivosidenib; a triazolam dose adjustment may be necessary. Triazolam is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased triazolam concentrations.
Triclabendazole: (Major) Concomitant use of triclabendazole and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) Coadministration of ivosidenib with trifluoperazine may increase the risk of QT prolongation. Monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Triptorelin: (Major) Avoid coadministration of ivosidenib with triptorelin if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Androgen deprivation therapy (i.e., triptorelin) also may prolong the QT/QTc interval.
Tucatinib: (Major) Avoid coadministration of ivosidenib with tucatinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If tucatinib is discontinued, wait at least 5 half-lives of tucatinib before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ulipristal: (Major) Consider alternative methods of contraception in patients receiving ivosidenib. Coadministration may decrease the concentrations of hormonal contraceptives.
Vandetanib: (Major) Avoid coadministration of vandetanib with ivosidenib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption of therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Prolongation of the QTc interval and ventricular arrhythmias have also been reported in patients treated with ivosidenib.
Vardenafil: (Major) Concomitant use of vardenafil and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vemurafenib: (Major) Avoid coadministration of ivosidenib with vemurafenib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib and/or vandetanib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Vemurafenib has also been associated with QT prolongation.
Venlafaxine: (Major) Concomitant use of venlafaxine and ivosidenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Major) Avoid coadministration of ivosidenib with verapamil due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and verapamil is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Voclosporin: (Major) Avoid concomitant use of ivosidenib and voclosporin due to the risk of additive QT prolongation. If concomitant use is necessary, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of ivosidenib with clarithromycin due to increased plasma concentrations of ivosidenib and additive QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If clarithromycin is discontinued, wait at least 5 half-lives of clarithromycin before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Clarithromycin is a strong CYP3A4 inhibitor associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Voriconazole: (Major) Avoid coadministration of ivosidenib with voriconazole due to increased plasma concentrations of ivosidenib and additive QT prolongation and risk of decreased voriconazole exposure and loss of antifungal efficacy. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If voriconazole is discontinued, wait at least 5 half-lives of voriconazole before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Voriconazole is a strong CYP3A4 associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. Because ivosidenib induces CYP3A4, it is also expected to decrease steady-state exposure to CYP3A4 substrates, such as voriconazole, to a clinically relevant extent.
Vorinostat: (Major) Avoid coadministration of ivosidenib with vorinostat due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Vorinostat has been associated with a risk of QT prolongation.
Voxelotor: (Major) Avoid coadministration of ivosidenib with voxelotor due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with ivosidenib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Ivosidenib is a weak CYP2C9/CYP3A4 inducer and the enantiomers of warfarin are substrates of CYP2C9/CYP3A4.
Ziprasidone: (Major) Avoid coadministration of ivosidenib with ziprasidone due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.
Ivosidenib is an oral isocitrate dehydrogenase-1 (IDH1) inhibitor that targets the mutant IDH1 variants including R132H and R132C substitutions; in AML patients, susceptible IDH1 mutations are those that lead to increased levels of the oncologic metabolite, 2-hydroxyglutarate (2-HG). IDH1 inhibition decreases levels of 2-HG, and causes increased myeloid differentiation, increased mature myeloid cell count, and reduced blast counts in IDH1-mutated acute myelogenous leukemia. In vitro, ivosidenib inhibits selected IDH1 R132 mutants at much lower concentrations than the wild-type enzyme. Ivosidenib also reduced 2-HG levels in a patient-derived xenograft intrahepatic cholangiocarcinoma mouse model with IDH1 R132C. Multiple daily doses of ivosidenib decreased plasma 2-HG concentrations in patients with hematologic malignancies and cholangiocarcinoma to levels similar to those observed at baseline in healthy subjects. In bone marrow of patients with hematologic malignancies and in tumor biopsy of patients with cholangiocarcinoma, mean 2-HG concentrations were reduced by 93.1% (CV, 11.1%) and 82.2% (CV, 32.4%), respectively.
Ivosidenib is administered orally. In vitro, ivosidenib is 92% to 96% protein bound. After oral administration of a single dose of radiolabeled ivosidenib to healthy subjects, 77% of ivosidenib was eliminated in the feces (67% unchanged), and 17% in the urine (10% unchanged); over 92% of the total dose radioactivity was recovered in the plasma. In patients with AML, MDS, and cholangiocarcinoma, the steady-state volumes of distribution ranged from 403 to 706 L, apparent clearances ranged from 4.6 to 6.1 L/hour, and terminal half-lives ranged from 58 to 129 hours. Ivosidenib is metabolized via CYP3A4 (major) and N-dealkylation and hydrolytic (minor) pathways.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4 and CYP2C9
Ivosidenib is a substrate and inducer of CYP3A4. In vitro, it is a substrate of P-glycoprotein (P-gp), an inhibitor of OAT3 and P-gp, and an inducer of CYP2B6, CYP2C8, and CYP2C9.
-Route-Specific Pharmacokinetics
Oral Route
Steady-state pharmacokinetic values were similar in patients with AML or MDS and lower in patients with cholangiocarcinoma. The steady-state Cmax values were 5,820 to 6,551 nanograms (ng)/mL and 4,799 ng/mL in patients with AML/MDS and cholangiocarcinoma, respectively; the steady-state AUC values were 103,770 to 106,326 ng x hour/mL and 86,382 ng x hour/mL, respectively. The median Tmax was reached at 2 or 3 hours. Steady-state plasma concentrations were reached within 14 days.
Effects of food: In heathy subjects, administration of a single oral dose of ivosidenib with a high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories) increased the Cmax and AUC values by 1.98-fold and 1.24-fold, respectively, compared with the fasted state. Ivosidenib should not be administered with a high-fat meal.
-Special Populations
Hepatic Impairment
Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment does not have a clinically significant impact on the pharmacokinetic (PK) parameters of ivosidenib. The PK parameters of ivosidenib in patients with severe hepatic impairment (Child-Pugh class C) are unknown.
Renal Impairment
Mild or moderate renal impairment (i.e., eGFR 30 mL/minute/1.73 m2 or more, MDRD) does not have a clinically significant impact on the pharmacokinetic (PK) parameters of ivosidenib. The PK parameters of ivosidenib in patients with severe renal impairment (eGFR less than 30 mL/minute/1.73 m2, MDRD) or renal impairment requiring dialysis are unknown.
Geriatric
Age (18 to 89 years) does not have a clinically significant impact on the pharmacokinetic parameters of ivosidenib.
Gender Differences
Sex does not have a clinically significant impact on the pharmacokinetic parameters of ivosidenib.
Ethnic Differences
Race (White, Asian, Black or African American) does not have a clinically significant impact on the pharmacokinetic parameters of ivosidenib.
Obesity
Body weight (38 kg to 150 kg) does not have a clinically significant impact on the pharmacokinetic parameters of ivosidenib.
Other
Performance Status
ECOG performance status does not have a clinically significant impact on the pharmacokinetic parameters of ivosidenib.