CONTRAINDICATIONS / PRECAUTIONS
Anticoagulant therapy, bleeding, dental work, GI bleeding, hematuria, intracranial bleeding, surgery
Major bleeding events such as intracranial bleeding (e.g., subdural hematoma), GI bleeding, hematuria, and post-procedural hemorrhage have been reported with ibrutinib therapy; some cases were fatal. Monitor patients for signs and symptoms of bleeding. Patients receiving concomitant antiplatelet or anticoagulant therapy have an increased risk for major bleeding. Evaluate the risk/benefit of using concomitant antithrombotic therapy or for continuing ibrutinib therapy in patients scheduled to have surgery. Consider stopping ibrutinib for at least 3 to 7 days pre- and post-surgery depending on the type of surgery (e.g., dental work/procedures) and the risk of bleeding.[56410]
Anemia, neutropenia, thrombocytopenia
Severe myelosuppression including neutropenia, thrombocytopenia, and anemia has been reported in patients who received ibrutinib. Monitor complete blood counts monthly. A dosage adjustment or therapy discontinuation may be necessary in patients who develop hematologic toxicity.
Infection, progressive multifocal leukoencephalopathy
Serious infection including progressive multifocal leukoencephalopathy and Pneumocystis jirovecii pneumonia has been reported with ibrutinib therapy; some cases resulted in death. Evaluate patients for signs and symptoms of infection (e.g., fever) and treat promptly. Consider infection prophylaxis in patients at risk for opportunistic infections.[56410]
Hepatic disease
Avoid ibrutinib use in patients with B-cell malignancies who have baseline severe hepatic impairment (Child-Pugh class C) and in patients with chronic graft-versus-host who have a total bilirubin level more than 3 times the ULN at baseline (unless of non-hepatic origin or due to Gilbert syndrome). An initial dose reduction may be necessary in patients with hepatic disease. Obtain liver function tests at baseline and as clinically indicated; monitor patients closely for signs and symptoms of hepatotoxicity. Interrupt therapy, reduce the dose, and/or discontinue ibrutinib in patients who develop grade 3 or higher hepatotoxicity.
Atrial fibrillation, atrial flutter, cardiac arrhythmias, cardiac disease, diabetes mellitus, heart failure, hypertension, syncope, ventricular arrhythmias
Serious cardiac arrhythmias (e.g., atrial fibrillation, atrial flutter, and ventricular arrhythmias), heart failure, and sudden death have occurred in patients who received ibrutinib as indicated or for unapproved uses in clinical trials. Patients with acute infections or cardiac risk factors/comorbidities such as a history of cardiac disease, cardiac arrhythmias, diabetes mellitus, or hypertension are at increased risk of cardiotoxicity including sudden death. Monitor patients at baseline for a history of or signs and symptoms of cardiac disease including cardiac arrhythmias and heart failure; perform heart function tests (e.g., ECG, echocardiogram) in patients who develop symptoms of an arrhythmia (e.g., palpitations, lightheadedness, syncope, or chest pain) or new onset dyspnea. If the cardiac arrhythmia persists despite treatment, evaluate the risks and benefits of continuing treatment with ibrutinib. Monitor blood pressure; start or adjust anti-hypertensive medication during ibrutinib therapy as appropriate. A dosage adjustment or therapy discontinuation may be necessary in patients who develop hypertension, heart failure, or arrhythmias.[56410]
Tumor lysis syndrome (TLS)
Tumor lysis syndrome (TLS) has been reported infrequently in patients who received ibrutinib. Assess patient risk and institute prophylaxis measures (e.g., anti-hyperuricemic agents and hydration) in patients at high-risk for TLS; closely monitor these patients for signs of TLS (e.g., uric acid, serum electrolytes, renal function tests). Promptly treat TLS if it occurs. Patients with a high tumor burden are at greater risk for developing TLS.
Geriatric
Anemia, grade 3 or higher pneumonia, thrombocytopenia, hypertension, and atrial fibrillation occurred more often in geriatric patients compared with younger patients who received ibrutinib in clinical studies (n = 1,124). In these studies, 64% of patients were 65 years or older and 23% of patients were 75 years or older.[56410]
Pregnancy
Ibrutinib may cause fetal harm if administered during pregnancy based on data from animal studies. Females of reproductive potential should be advised to avoid becoming pregnant while receiving ibrutinib. If a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus. In reproductive animal studies in pregnant rats and rabbits, visceral malformations of the heart and major vessels, skeletal variations (i.e., fused sternebrae), and increased resorptions and post-implantation loss were observed following ibrutinib doses that resulted in drug exposure 2- to 20-times of that reported at clinical human doses (range, 420 to 560 mg daily). Additionally, decreased fetal weight was reported in pregnant rats who received ibrutinib doses that resulted in 6-times the drug exposure of the recommended dose for Mantle-cell lymphoma.
Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk
Counsel patients about the reproductive risk and contraception requirements during ibrutinib treatment. Pregnancy testing should be performed prior to starting ibrutinib in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 1 month after ibrutinib therapy. Women who become pregnant while receiving ibrutinib should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during ibrutinib therapy and for 1 month after therapy due to the risk of male-mediated teratogenicity.[56410]
Breast-feeding
It is not known if ibrutinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing children, women should discontinue breast-feeding during ibrutinib therapy and for 1 week after the last dose.[56410]
DRUG INTERACTIONS
Abciximab: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as abciximab may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Acetaminophen; Aspirin: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Adagrasib: (Major) Avoid concomitant use of ibrutinib and adagrasib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of adagrasib is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when adagrasib is discontinued. Ibrutinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with other strong CYP3A inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Alpelisib: (Major) Avoid coadministration of alpelisib with ibrutinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and ibrutinib is a BCRP inhibitor.
Amiodarone: (Major) If ibrutinib is coadministered with amiodarone, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dose if amiodarone is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Anagrelide: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as anagrelide may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Antithrombin III: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as antithrombin III may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Apalutamide: (Major) Avoid coadministration of ibrutinib with apalutamide due to decreased plasma concentrations of ibrutinib. Ibrutinib is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Apixaban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as apixaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Aprepitant, Fosaprepitant: (Major) If ibrutinib is coadministered with multi-day oral aprepitant, fosaprepitant, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dose if aprepitant, fosaprepitant is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Argatroban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as argatroban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Aspirin, ASA: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Caffeine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Carisoprodol: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Dipyridamole: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives. (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as dipyridamole may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Aspirin, ASA; Omeprazole: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Oxycodone: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Aspirin, ASA; Pravastatin: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Atazanavir: (Major) Avoid concomitant use of ibrutinib and atazanavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of ibrutinib and atazanavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Berotralstat: (Major) If coadministered with berotralstat, reduce the ibrutinib dose to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dose if berotralstat is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity; modify the ibrutinib dosage as recommended if toxicity occurs. Additionally, reduce the berotralstat dose to 110 mg PO once daily in patients taking ibrutinib. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Ibrutinib is a CYP3A4 substrate and P-gp and BCRP inhibitor; berotralstat is a P-gp and BCRP substrate and moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC values of ibrutinib was increased by 3-fold. Coadministration with another P-gp and BCRP inhibitor increased berotralstat exposure by 69%.
Betrixaban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as betrixaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Bexarotene: (Moderate) Use ibrutinib and bexarotene together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; bexarotene is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Bivalirudin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as bivalirudin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Carbamazepine: (Major) Avoid the concomitant use of ibrutinib and carbamazepine; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Ceritinib: (Major) Avoid concomitant use of ibrutinib and ceritinib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Chloramphenicol: (Major) Avoid concomitant use of ibrutinib and chloramphenicol; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of chloramphenicol is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when chloramphenicol is discontinued. Ibrutinib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
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.
Cilostazol: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as cilostazol may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Ciprofloxacin: (Major) If ibrutinib is coadministered with ciprofloxacin, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dose if ciprofloxacin is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Clarithromycin: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Clopidogrel: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as clopidogrel may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
Cobicistat: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Colchicine: (Major) Avoid the concurrent use of ibrutinib and colchicine; plasma concentrations of colchicine may increase resulting in serious and life-threatening toxicity. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; colchicine is a narrow therapeutic index drug and a P-gp substrate.
Conivaptan: (Major) If ibrutinib is coadministered with conivaptan, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if conivaptan is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Crizotinib: (Major) If ibrutinib is coadministered with crizotinib, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy.Resume ibrutinib at the previous dosage if crizotinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs Ibrutinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Cyclosporine: (Major) If ibrutinib is coadministered with cyclosporine, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if cyclosporine is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Monitor cyclosporine levels and observe patients for symptoms of cyclosporine toxicity. Ibrutinib is a 3A4 substrate and a P-glycoprotein (P-gp) inhibitor in vitro; cyclosporine is a CYP3A4 inhibitor and a P-gp substrate with a narrow therapeutic index. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Dabigatran: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as dabigatran may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Dabrafenib: (Major) The concomitant use of dabrafenib and ibrutinib may lead to decreased ibrutinib concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of ibrutinib efficacy. Dabrafenib is a moderate CYP3A4 inducer and ibrutinib is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%. Additionally, simulations using physiologically-based pharmacokinetic (PBPK) models suggest that moderate CYP3A4 inducers may decrease ibrutinib exposure up to 3-fold.
Dalteparin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as dalteparin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Danazol: (Major) If ibrutinib is coadministered with danazol, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy.Resume ibrutinib at the previous dosage if danazol is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Darunavir: (Major) Avoid concomitant use of ibrutinib and darunavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Darunavir; Cobicistat: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. (Major) Avoid concomitant use of ibrutinib and darunavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. (Major) Avoid concomitant use of ibrutinib and darunavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Delavirdine: (Major) Avoid concomitant use of ibrutinib and delavirdine; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Desirudin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as desirudin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Dexamethasone: (Moderate) Use ibrutinib and dexamethasone together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; dexamethasone is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Digoxin: (Moderate) Use ibrutinib and digoxin together with caution; plasma concentrations of digoxin may increase resulting in increased toxicity. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; digoxin is a P-gp substrate with a narrow therapeutic index. In addition, some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients.
Diltiazem: (Major) If ibrutinib is coadministered with diltiazem, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if diltiazem is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Dipyridamole: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as dipyridamole may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Dronedarone: (Major) If ibrutinib is coadministered with dronedarone, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if dronedarone is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Duvelisib: (Major) If ibrutinib is coadministered with duvelisib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if duvelisib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a sensitive CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Edoxaban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as edoxaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Efavirenz: (Moderate) Use ibrutinib and efavirenz together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use ibrutinib and efavirenz together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use ibrutinib and efavirenz together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Elbasvir; Grazoprevir: (Moderate) Administering ibrutinib with elbasvir; grazoprevir may result in elevated ibrutinib plasma concentrations. Ibrutinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Encorafenib: (Moderate) Coadministration of encorafenib with ibrutinib may result in increased toxicity or decreased efficacy of ibrutinib. Ibrutinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
Enoxaparin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as enoxaparin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Enzalutamide: (Major) Avoid coadministration of ibrutinib with enzalutamide due to decreased plasma concentrations of ibrutinib. Ibrutinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Eptifibatide: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as eptifibatide may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Erythromycin: (Major) If ibrutinib is coadministered with erythromycin, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if erythromycin is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of erythromycin, the AUC value of ibrutinib increased by 3-fold.
Eslicarbazepine: (Moderate) Use ibrutinib and eslicarbazepine together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Etravirine: (Moderate) Use ibrutinib and etravirine together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; etravirine is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ibrutinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate. Ibrutinib may inhibit P-gp. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Fedratinib: (Major) If ibrutinib is coadministered with fedratinib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if fedratinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the CAUC value of ibrutinib was increased by 3-fold.
Fluconazole: (Major) If ibrutinib is coadministered with fluconazole, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if fluconazole is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Flutamide: (Moderate) Use ibrutinib and flutamide together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; flutamide is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Fluvoxamine: (Major) If ibrutinib is coadministered with fluvoxamine, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if fluvoxamine is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Fondaparinux: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as fondaparinux may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Fosamprenavir: (Major) If ibrutinib is coadministered with fosamprenavir, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for a B-cell malignancy. Resume ibrutinib at the previous dose if fosamprenavir is discontinued. No initial ibrutinib dosage reduction is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A substrate; fosamprenavir is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Fosphenytoin: (Major) Avoid the concomitant use of ibrutinib and fosphenytoin; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during ibrutinib treatment due to the risk of increased ibrutinib exposure and adverse reactions. Ibrutinib is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
Heparin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as heparin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Idelalisib: (Major) Avoid concomitant use of ibrutinib and idelalisib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Imatinib: (Major) If ibrutinib is coadministered with imatinib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if imatinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib weas increased by 3-fold.
Indinavir: (Major) Avoid concomitant use of ibrutinib and indinavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Isavuconazonium: (Major) If ibrutinib is coadministered with isavuconazonium, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if isavuconazonium is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection);modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; isavuconazonium is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of ibrutinib and rifampin; significantly reduced ibrutinib plasma concentrations have occurred. Ibrutinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. When ibrutinib was administered with rifampin, the Cmax and AUC values of ibrutinib decreased by more than 13-fold and 10-fold, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of ibrutinib and rifampin; significantly reduced ibrutinib plasma concentrations have occurred. Ibrutinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. When ibrutinib was administered with rifampin, the Cmax and AUC values of ibrutinib decreased by more than 13-fold and 10-fold, respectively.
Itraconazole: (Major) Avoid ibrutinib use during and for 2 weeks after discontinuation of itraconazole treatment. If short-term use of itraconazole is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when itraconazole is discontinued. Taking these drugs together may result in increased ibrutinib plasma concentrations, resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ivosidenib: (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.
Ketoconazole: (Major) Avoid concomitant use of ibrutinib and ketoconazole; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of ketoconazole is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when ketoconazole is discontinued. Ibrutinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of ketoconazole, the Cmax and AUC values of ibrutinib increased by 29-fold and 24-fold, respectively.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ibrutinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ibrutinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Major) If ibrutinib is coadministered with oral lefamulin, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if oral lefamulin is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Lenacapavir: (Major) If ibrutinib is coadministered with lenacapavir, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for a B-cell malignancy. Resume ibrutinib at the previous dose if lenacapavir is discontinued. No initial ibrutinib dosage reduction is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A substrate; lenacapavir is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Lepirudin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as lepirudin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ibrutinib; monitor for potential reduction in efficacy. Ibrutinib is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ibrutinib; monitor for potential reduction in efficacy. Ibrutinib is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Major) If ibrutinib is coadministered with letermovir, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if letermovir is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Avoid coadministration in patients also receiving cyclosporine, because the magnitude of the interaction may be increased. Ibrutinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold. A strong CYP3A4 inhibitor increased the Cmax and AUC of ibrutinib by 29- and 24-fold, respectively.
Levoketoconazole: (Major) Avoid concomitant use of ibrutinib and ketoconazole; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of ketoconazole is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when ketoconazole is discontinued. Ibrutinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of ketoconazole, the Cmax and AUC values of ibrutinib increased by 29-fold and 24-fold, respectively.
Lonafarnib: (Major) Avoid concomitant use of ibrutinib and lonafarnib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ibrutinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and ibrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ibrutinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and ibrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of ibrutinib and lumacaftor; ivacaftor; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Methotrexate: (Moderate) Use ibrutinib and methotrexate together with caution; plasma concentrations of methotrexate may increase resulting in increased toxicity. Ibrutinib is a BCRP inhibitor in vitro; methotrexate is a BCRP substrate with a narrow therapeutic index.
Mifepristone: (Major) Avoid concomitant use of ibrutinib and chronic mifepristone therapy; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mitotane: (Major) Avoid the concomitant use of ibrutinib and mitotane; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Modafinil: (Moderate) Use ibrutinib and modafinil together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; modafinil is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Nafcillin: (Moderate) Use ibrutinib and nafcillin together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; nafcillin is a moderate CYP3A inducer. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that moderate CYP3A4 inducers may decrease ibrutinib exposure up to 3-fold.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with ibrutinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and ibrutinib is a P-gp inhibitor.
Nefazodone: (Major) Avoid concomitant use of ibrutinib and nefazodone; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Nelfinavir: (Major) Avoid concomitant use of ibrutinib and nelfinavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Netupitant, Fosnetupitant; Palonosetron: (Major) If ibrutinib is coadministered with netupitant, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if netupitant is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Nilotinib: (Major) If ibrutinib is coadministered with nilotinib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if nilotinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Use ibrutinib and rifabutin together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Pazopanib: (Moderate) Use ibrutinib and pazopanib together with caution; plasma concentrations of ibrutinib or pazopanib may be increased. Monitor patients for symptoms of ibrutinib or pazopanib toxicity if these agents are used together. Ibrutinib is a 3A4 substrate and a P-glycoprotein (P-gp) inhibitor and breast cancer resistance protein (BCRP) inhibitor in vitro; pazopanib is a weak 3A4 inhibitor and a P-gp and BCRP substrate.
Phenobarbital: (Major) Avoid the concomitant use of ibrutinib and phenobarbital; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of ibrutinib and phenobarbital; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Phenytoin: (Major) Avoid the concomitant use of ibrutinib and phenytoin; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Posaconazole: (Major) Reduce the initial ibrutinib dosage to 140 mg/day PO in patients receiving ibrutinib for a B-cell malignancy or 280 mg/day PO in patients aged 12 years or older receiving ibrutinib for chronic graft-versus-host disease (cGVHD) if coadministered with posaconazole oral suspension 100 mg/day to 400 mg/day. Reduce the initial ibrutinib dosage to 70 mg/day PO in patients with a B-cell malignancy or 140 mg/day PO in patients aged 12 years and older with cGVHD if coadministered with posaconazole oral suspension 600 mg/day to 800 mg/day or posaconazole 300 mg (delayed-release tablets or IV) once daily. In patients aged 1 to 11 years receiving ibrutinib for cGVHD, reduce the initial ibrutinib dose to 80 mg/m2 per day PO if coadministered with any dosage of posaconazole. Resume ibrutinib at the previous dose if posaconazole is discontinued. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interrupt or modify ibrutinib therapy as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Simulations under fed conditions suggest that coadministration with posaconazole may increase ibrutinib exposure by 3- to 10-fold.
Prasugrel: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as prasugrel may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Primidone: (Major) Avoid the concomitant use of ibrutinib and primidone; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Probenecid; Colchicine: (Major) Avoid the concurrent use of ibrutinib and colchicine; plasma concentrations of colchicine may increase resulting in serious and life-threatening toxicity. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; colchicine is a narrow therapeutic index drug and a P-gp substrate.
Relugolix: (Major) Avoid concomitant use of relugolix and oral ibrutinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ibrutinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate and ibrutinib is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral ibrutinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ibrutinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate and ibrutinib is a P-gp inhibitor.
Ribociclib: (Major) Avoid concomitant use of ibrutinib and ribociclib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ribociclib; Letrozole: (Major) Avoid concomitant use of ibrutinib and ribociclib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Rifabutin: (Moderate) Use ibrutinib and rifabutin together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
Rifampin: (Major) Avoid the concomitant use of ibrutinib and rifampin; significantly reduced ibrutinib plasma concentrations have occurred. Ibrutinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. When ibrutinib was administered with rifampin, the Cmax and AUC values of ibrutinib decreased by more than 13-fold and 10-fold, respectively.
Rifapentine: (Major) Avoid concurrent use of ibrutinib with rifapentine due to decreased plasma concentrations of ibrutinib. Ibrutinib is a sensitive CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ibrutinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ibrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with ibrutinib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and ibrutinib is a P-gp inhibitor.
Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Rivaroxaban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as rivaroxaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Saquinavir: (Major) Avoid concomitant use of ibrutinib and saquinavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
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.
Sirolimus: (Major) Avoid coadministration of sirolimus with ibrutinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and ibrutinib is a P-gp inhibitor.
St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of ibrutinib and St. John's Wort; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Stiripentol: (Moderate) Consider a dose adjustment of ibrutinib when coadministered with stiripentol. Coadministration may alter plasma concentrations of ibrutinib resulting in an increased risk of adverse reactions and/or decreased efficacy. Ibrutinib is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Talazoparib: (Major) Avoid coadministration of ibrutinib with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP and P-glycoprotein (P-gp) substrate; ibrutinib is a BCRP and P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with ibrutinib is necessary. Temsirolimus is a P-glycoprotein (P-gp) substrate and ibrutinib is a P-gp inhibitor. Concomitant use may lead to increased concentrations of temsirolimus.
Ticagrelor: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as ticagrelor may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Ticlopidine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as ticlopidine may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Tipranavir: (Major) Avoid concomitant use of ibrutinib and tipranavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Tirofiban: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as tirofiban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Topotecan: (Major) Avoid coadministration of ibrutinib with oral topotecan due to increased topotecan exposure; ibrutinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); ibrutinib is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
Trandolapril; Verapamil: (Major) If ibrutinib is coadministered with verapamil, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if verapamil is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Tucatinib: (Major) Avoid concomitant use of ibrutinib and tucatinib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with ibrutinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP and P-gp drug transporters; ibrutinib is a BCRP and P-gp inhibitor.
Verapamil: (Major) If ibrutinib is coadministered with verapamil, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if verapamil is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Voriconazole: (Major) If ibrutinib is coadministered with voriconazole 200 mg twice daily, reduce the initial ibrutinib dosage to 140 mg/day PO in patients receiving ibrutinib for a B-cell malignancy or 280 mg/day PO in patients aged 12 years and older receiving ibrutinib for chronic graft-versus-host disease (cGVHD). If ibrutinib is coadministered with voriconazole suspension 9 mg/kg (max dose of 350 mg) twice daily, reduce the initial ibrutinib dosage to 160 mg/m2 per day PO in patients aged 1 to 11 years receiving ibrutinib for cGVHD. Resume ibrutinib at the previous dose if voriconazole is discontinued. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with multiple doses of voriconazole increased steady-state ibrutinib exposure by 5.7-fold.
Voxelotor: (Major) If ibrutinib is coadministered with voxelotor, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for a B-cell malignancy. Resume ibrutinib at the previous dose if voxelotor is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration with multiple doses of another moderate CYP3A4 inhibitor increased steady-state ibrutinib exposure by 3-fold.
Warfarin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as warfarin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.