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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    An oral Bruton’s tyrosine kinase (BTK) inhibitor
    Used in adult patients with mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, Waldenstrom macroglobulinemia, and chronic graft-versus-host disease
    Serious bleeding events have been reported

    COMMON BRAND NAMES

    Imbruvica

    HOW SUPPLIED

    Imbruvica Oral Cap: 70mg, 140mg
    Imbruvica Oral Tab: 140mg, 280mg, 420mg, 560mg

    DOSAGE & INDICATIONS

    For the treatment of mantle cell lymphoma (MCL).
    NOTE: Ibrutinib has been designated by the FDA as an orphan drug for the treatment of MCL.
    For the treatment of MCL in patients who have received at least 1 prior therapy.
    Oral dosage
    Adults

    560 mg orally once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. In a long-term follow-up analysis (median time of 26.7 months) of a multicenter, single-arm, phase 2 study (n = 111), the primary endpoint of investigator-assessed overall response rate was 68%, the median progression-free survival (PFS) time was 13 months, and the median overall survival (OS) time was 22.5 months in patients with recurrent mantle cell lymphoma (MCL) who had received at least 1 prior therapy (median of 3 prior therapies); the median of duration of ibrutinib therapy was 8.3 months in this study. Additionally, the estimated 24-month PFS and OS rates were 31% and 47%, respectively. In a multinational, randomized, phase 3 trial (the MCL3001 trial; n = 280), patients with relapsed or refractory MCL who had at least 1 prior rituximab-containing regimen (median of 2 prior regimens) received ibrutinib 560 mg/day PO (median duration of therapy, 14.4 months) or temsirolimus 175 mg IV on days 1, 8, 15 of the first cycle followed by 75 mg on days 1, 8, 15 repeated every 21 days (median duration of therapy, 3 months). At a median follow-up of 20 months, the median PFS time was significantly improved with ibrutinib compared with temsirolimus (14.6 months vs. 6.2 months; hazard ratio (HR) = 0.43; 95% CI, 0.32 to 0.58; p < 0.0001). The median OS time was not significantly different between treatment arms (median time not reached vs. 21.3 months; HR = 0.76; 95% CI, 0.53 to 1.09); however, 23% of patients in the temsirolimus arm crossed over to the ibrutinib arm in this study.

    For the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
    NOTE: Ibrutinib has been designated by the FDA as an orphan drug for the treatment of CLL and SLL.
    For the treatment of CLL or SLL in patients with or without a 17p deletion, as a single agent.
    Oral dosage
    Adults

    420 mg orally once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. At a median follow-up time of 9.4 months (range, 0.1 to 16.6 months), the median progression-free survival (PFS) time was significantly improved with continuous oral ibrutinib compared with up to 24 weeks of IV ofatumumab (median time not reached vs. 8.1 months; hazard ratio (HR) = 0.22; 95% CI, 0.15 to 0.32; p < 0.001) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; n = 18; 4.6%) who had received at least 1 prior treatment and were considered inappropriate candidates for purine analog treatment in a multinational, randomized, phase III trial (the RESONATE trial; n = 391). In the ibrutinib arm, patients had a median of 3 prior therapies (range, 1 to 12 therapies) and the median age was 67 years (range, 30 to 86 years). The 12-month overall survival (OS) rates were 90% and 79% in the ibrutinib and ofatumumab arms, respectively (HR = 0.39; 95% CI, 0.22 to 0.7; p = 0.001); additionally, 29% of patients in the ofatumumab arm crossed over to the ibrutinib arm after disease progression. In 127 high-risk patients with chromosome 17p13.1 deletions in this trial, the median PFS time was also significantly improved with ibrutinib compared with ofatumumab (median time not reached vs. 5.8 months; HR = 0.25; 95% CI, 0.14 to 0.45). The 12-month OS rate was not significantly different between treatment arms in this subgroup analysis. At a median follow-up time of 18.4 months, the median PFS time was significantly improved with ibrutinib (median duration of therapy, 17.4 months) compared with chlorambucil (median time not reached vs. 18.9 months; HR = 0.16; 95% CI, 0.09 to 0.28; p < 0.001) in patients with previously untreated CLL or SLL (n = 20; 7.4%) who were 65 years of age or older and did not have a 17p deletion in a multinational, randomized, phase III trial (the RESONATE-2 trial; n = 269). The median age of patients in the ibrutinib arm was 74 years (range, 65 to 89 years). The 24-month OS rates were 98% and 85% in the ibrutinib and chlorambucil arms, respectively (HR = 0.16; 95% CI, 0.05 to 0.56; p = 0.001); crossover from the chlorambucil arm to the ibrutinib arm after disease progression was permitted.

    For the treatment of CLL or SLL, in combination with bendamustine and rituximab.
    Oral dosage
    Adults

    420 mg orally once daily until disease progression in combination with bendamustine 70 mg/m2 IV over 30 minutes on days 2 and 3 of cycle 1 and on days 1 and 2 for cycles 2 to 6 and rituximab 375 mg/m2 IV on day 1 of cycle 1 and then 500 mg/m2 IV on day 1 for cycles 2 to 6. Treatment with bendamustine and rituximab is repeated every 28 days for up to 6 cycles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. At a median follow-up time of 17 months, the median progression-free survival (PFS) time was significantly improved with ibrutinib plus bendamustine and rituximab compared with placebo plus bendamustine and rituximab (median time not reached vs. 13.3 months; hazard ratio (HR) = 0.203; 95% CI, 0.15 to 0.276; p < 0.0001) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; n = 64; 11%) who had received at least 1 prior treatment including at least 2 cycles of a chemotherapy-containing regimen in a prespecified interim analysis of a multinational, randomized, double-blind, phase III trial (the HELIOS trial; n = 578). The 18-month PFS rates were 79% and 24% in the ibrutinib- and placebo-containing arms, respectively. There was no statistically significant difference in overall survival between treatment arms at the time of analysis; however, 31% of patients in the placebo arm crossed over to the ibrutinib arm after disease progression. Patients with a 17p deletion or who had a prior hematopoietic stem-cell transplant were excluded in this study. In the ibrutinib-containing arm, the median duration of therapy was 14.7 months and patients had a mean of 2 prior therapies (range, 1 to 11 therapies).

    For the treatment of Waldenstrom macroglobulinemia.
    Oral dosage
    Adults

    420 mg orally once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. A minor response (MR) (defined as a 25% or greater reduction in serum IgM levels) or better was achieved in 90.5% of previously treated patients with Waldenstrom macroglobulinemia who received ibrutinib (median duration of 19.1 months; range, 0.5 to 29.7 months) in a multi-center, single-arm trial (n = 63). Patients in this study had received a median of 2 prior therapies (range, 1 to 9 therapies); the MYD88L265P and CXCR4WHIM mutations were present in 89% and 34% of patients, respectively. Although no patients achieved a complete response, 36 patients (57%) had a partial response (PR) (defined as a 50% or greater reduction in serum IgM levels) and 10 patients (16%) had a very good partial response (defined as a 90% or greater reduction in serum IgM levels) resulting in a PR or better rate of 73%. The median times to MR and PR were 4 weeks and 8 weeks, respectively. In a subgroup analysis, a PR or better was achieved in 91.2% of patients with the MYD88L265P CXCR4WT genotype, 61.9% of patients with the MYD88L265P CXCR4WHIM genotype, and 28.6% of patients with the MYD88WTCXCR4WT genotype. The estimated 2-year progression-free survival and overall survival rates were 69.1% and 95.2%, respectively. Treatment with single-agent ibrutinib resulted in an overall response rate of 90% in a subpopulation of 31 patients with Waldenstrom macroglobulinemia from an ongoing randomized, placebo-controlled, phase III trial (the iNNOVATE trial) who were refractory to the most recent rituximab-containing therapy. The 18-month progression-free survival and overall survival rates were 86% and 97%, respectively. Patients (median age, 67 years; range, 58 to 75 years) in this analysis had previously received a median of 4 therapies (range, 2 to 6 therapies).

    For the treatment of non-Hodgkin's lymphoma (NHL).
    NOTE: Ibrutinib has been designated by the FDA as an orphan drug for the treatment of nodal, splenic, and mucosa-associated lymphoid tissue (MALT) marginal zone lymphoma.
    For the treatment of marginal zone lymphoma in patients who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.
    Oral dosage
    Adults

    560 mg orally once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. The overall response rate (ORR) was 46% in patients with relapsed or refractory marginal zone lymphoma who received ibrutinib in a single-arm, phase II trial (n = 63). The median time to response was 4.5 months (range, 2.3 to 16.4 months) and the median response duration had not been reached (range, 16.7 months to time not reached). In patients with mucosa-associated lymphoid tissue (n = 32), nodal (n = 17), and splenic (n = 14) subtypes, the ORR were 46.7%, 41.2%, and 50%, respectively. Patients (median age, 66 years; range, 30 to 92 years) had received a median of 2 prior treatments (range, 1 to 9 treatments).

    For the treatment of graft-versus-host disease (GVHD).
    NOTE: Ibrutinib has been designated by the FDA as an orphan drug for the treatment of chronic GVHD.
    For the treatment of chronic GVHD after failure of 1 or more lines of systemic therapy.
    Oral dosage
    Adults

    420 mg orally once daily until chronic GVHD progression or a recurrence of the underlying malignancy. Discontinue ibrutinib when a patient no longer requires therapy for chronic GVHD, based on a medical assessment. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. Treatment with ibrutinib resulted in a best overall response rate of 67% in patients with chronic GVHD who failed first-line corticosteroid therapy and required additional therapy in a multicenter, phase Ib/II trial (n = 42; study PCYC-1129-CA); the complete response (CR) rate was 21%. Additionally, 48% of patients had a sustained response rate, defined as a CR or partial response that lasted at least 20 weeks. The median time to response was 12.3 weeks (range, 4.1 to 42.1 weeks). In this trial, patients (median age, 56 years; range, 19 to 74 years) had received a median of 2 prior cGVHD treatments (range, 1 to 3 treatments).

    MAXIMUM DOSAGE

    Adults

    560 mg/day PO.

    Geriatric

    560 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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (Child-Pugh class A) at baseline: 140 mg/day PO.
    Moderate hepatic impairment (Child-Pugh class B) at baseline: 70 mg/day PO.
    Severe hepatic impairment (Child-Pugh class C) at baseline: Avoid use.

    Renal Impairment

    Specific guidelines for dosage adjustment in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Take ibrutinib with a glass of water at the same time each day. 
    Swallow whole; do not open, break, or chew the capsules or cut, crush, or chew the tablets.
    If a dose is missed, take as soon as possible on the same day; return to the normal schedule the following day. Do not take 2 doses at the same time.

    STORAGE

    Imbruvica:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Anticoagulant therapy, bleeding, dental work, GI bleeding, hematuria, intracranial bleeding, surgery

    Serious 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. Patients receiving concomitant antiplatelet or anticoagulant therapy may be at increased risk for bleeding; monitor these patients for signs of bleeding. Evaluate the risk/benefit of 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.

    Anemia, neutropenia, thrombocytopenia

    Severe hematologic toxicity including neutropenia, thrombocytopenia, and anemia have been reported in patients who received ibrutinib. Monitor complete blood counts monthly.

    Renal failure, renal impairment

    Ibrutinib has not been studied in patients with creatinine clearance less than 25 mL/min; therefore, use with caution in patients with severe renal impairment or who are on dialysis. Renal failure has been reported in patients with mantle cell lymphoma.

    Geriatric, 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. In clinical studies (n = 552), grade 3 or higher pneumonia has been reported more often with ibrutinib therapy in geriatric patients compared with younger patients. In these studies, 62% of patients were 65 years of age or older and 21% of patients were 75 years of age or older.

    Hepatic disease

    Avoid ibrutinib use in patients with severe hepatic impairment/hepatic disease (Child-Pugh class C). An initial dose reduction is recommended in patients with baseline mild or moderate hepatic impairment (Child-Pugh class A or B). 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, hypertension, syncope, ventricular arrhythmias

    Serious cardiac arrhythmias (e.g., atrial fibrillation, atrial flutter, and ventricular arrhythmias) have occurred in patients treated with ibrutinib; fatalities have been reported. Patients with acute infections or cardiac risk factors such as a history of cardiac disease, cardiac arrhythmias, or hypertension are at increased risk. Periodically monitor patients clinically for signs and symptoms of cardiac arrhythmias and perform an ECG 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; consider a dose reduction if ibrutinib is continued. Monitor patients for new onset or worsening hypertension; medically manage hypertension as clinically appropriate.

    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.

    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 at least 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 at least 1 month after therapy due to the risk of male-mediated teratogenicity.

    Breast-feeding

    No information is available regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 10.0-61.0
    infection / Delayed / 0-26.0
    thrombocytopenia / Delayed / 0-17.0
    new primary malignancy / Delayed / 3.0-16.0
    anemia / Delayed / 0-13.0
    fatigue / Early / 0-12.0
    visual impairment / Early / 11.0-11.0
    hypertension / Early / 4.0-8.0
    atrial flutter / Early / 0-7.0
    hypokalemia / Delayed / 0-7.0
    GI bleeding / Delayed / 0-6.0
    hematuria / Delayed / 0-6.0
    subdural hematoma / Early / 0-6.0
    intracranial bleeding / Delayed / 0-6.0
    sinusitis / Delayed / 0-6.0
    musculoskeletal pain / Early / 1.0-6.0
    fever / Early / 0-5.0
    rash / Early / 0-5.0
    headache / Early / 0-5.0
    dyspnea / Early / 0-4.0
    dehydration / Delayed / 4.0-4.0
    asthenia / Delayed / 0-4.0
    muscle cramps / Delayed / 0-3.0
    peripheral edema / Delayed / 0-3.0
    bleeding / Early / 0-2.0
    ecchymosis / Delayed / 0-2.0
    anorexia / Delayed / 2.0-2.0
    arthralgia / Delayed / 0-2.0
    cough / Delayed / 0-2.0
    hyperuricemia / Delayed / 0-2.0
    anxiety / Delayed / 0-2.0
    ventricular tachycardia / Early / 0-1.0
    ventricular fibrillation / Early / 0-1.0
    atrial fibrillation / Early / 5.0
    leukoencephalopathy / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    lymphocytosis / Delayed / 7.0-66.0
    hypoalbuminemia / Delayed / 0-14.0
    blurred vision / Early / 10.0-13.0
    hepatitis / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known

    Mild

    dizziness / Early / 11.0-20.0
    epistaxis / Delayed / 11.0-19.0
    xerophthalmia / Early / 0-17.0
    petechiae / Delayed / 11.0-16.0
    pruritus / Rapid / 0-14.0
    gastroesophageal reflux / Delayed / 13.0-13.0
    arthropathy / Delayed / 13.0-13.0
    lacrimation / Early / 0-13.0
    chills / Rapid / 12.0-12.0
    syncope / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    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.
    Amiodarone: (Major) If coadministered with amiodarone, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if amiodarone is discontinued. 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. Ibrutinib is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid the 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; clarithromycin is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the 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; clarithromycin is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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.
    Aprepitant, Fosaprepitant: (Major) If coadministered with aprepitant, fosaprepitant, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if aprepitant, fosaprepitant is discontinued. 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. Ibrutinib is a CYP3A4 substrate; aprepitant, fosaprepitant is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    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; Dihydrocodeine: (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; 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: (Severe) Atazanavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; atazanavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Atazanavir; Cobicistat: (Severe) Atazanavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; atazanavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly. (Major) Avoid the 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; cobicistat is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    Belladonna Alkaloids; Ergotamine; 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.
    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.
    Boceprevir: (Severe) Do not use ibrutinib concomitantly with boceprevir; boceprevir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events. Significantly increased ibrutinib levels may occur. Consider the use of alternate agents. Ibrutinib is a CYP3A4 substrate; boceprevir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Bosentan: (Moderate) Use ibrutinib and bosentan 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; bosentan is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Brigatinib: (Moderate) Use ibrutinib and brigatinib 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; brigatinib is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    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) If coadministered with ceritinib, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if ceritinib is discontinued. 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. Ibrutinib is a CYP3A4 substrate; ceritinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Chloramphenicol: (Major) Avoid the 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; chloramphenicol is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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.
    Cimetidine: (Major) If coadministered with cimetidine, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if cimetidine is discontinued. 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. Ibrutinib is a CYP3A4 substrate; cimetidine is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ciprofloxacin: (Major) If coadministered with ciprofloxacin, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if ciprofloxacin is discontinued. 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. Ibrutinib is a CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Clarithromycin: (Major) Avoid the 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; clarithromycin is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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 the 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; cobicistat is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the 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; cobicistat is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the 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; cobicistat is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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) Avoid the concomitant use of ibrutinib and conivaptan; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Treatment with ibrutinib should be initiated no sooner than 1 week after the infusion of conivaptan is completed. Ibrutinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Crizotinib: (Major) If coadministered with crizotinib, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if crizotinib is discontinued. 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. Ibrutinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Cyclosporine: (Major) The concomitant use of ibrutinib and cyclosporine may result in increased plasma concentrations of ibrutinib or cyclosporine. If coadministered with cyclosporine, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if cyclosporine is discontinued. 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. 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 Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    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 74%. Additionally, simulations using physiologically-based pharmacokinetic (PBPK) models suggest that moderate CYP3A4 inducers may decrease ibrutinib exposure up to 3-fold.
    Dalfopristin; Quinupristin: (Major) Avoid the concomitant use of ibrutinib and dalfopristin; quinupristin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of dalfopristin; quinupristin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when dalfopristin; quinupristin is discontinued. Ibrutinib is a CYP3A4 substrate; dalfopristin; quinupristin is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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.
    Danaparoid: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as danaparoid 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 coadministered with danazol, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if danazol is discontinued. 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. Ibrutinib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Darunavir: (Severe) Darunavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; darunavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Darunavir; Cobicistat: (Severe) Darunavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; darunavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly. (Major) Avoid the 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; cobicistat is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Severe) Ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Delavirdine: (Severe) Delavirdine is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; delavirdine is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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) Avoid the concomitant use of ibrutinib and diltiazem; ibrutinib exposure may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate, and pharmacokinetic simulations predict a 4.9-fold increase in the mean geometric AUC of ibrutinib when it is administered with diltiazem. Although much data suggests that diltiazem is a moderate CYP3A4 inhibitor, the manufacturer of ibrutinib classifies diltiazem as a strong CYP3A4 inhibitor and recommends against coadministration.
    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 coadministered with dronedarone, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if dronedarone is discontinued. 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. Ibrutinib is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    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: (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.
    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 coadministered with erythromycin, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if erythromycin is discontinued. 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. Ibrutinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of erythromycin, the Cmax and AUC values of ibrutinib increased by 3.4-fold and 3-fold, respectively.
    Erythromycin; Sulfisoxazole: (Major) If coadministered with erythromycin, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if erythromycin is discontinued. 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. Ibrutinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of erythromycin, the Cmax and AUC values of ibrutinib increased by 3.4-fold and 3-fold, respectively.
    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.
    Fentanyl: (Moderate) Use ibrutinib and fentanyl together with caution; plasma concentrations of fentanyl may increase resulting in increased toxicity. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; fentanyl is a P-gp substrate with a narrow therapeutic index.
    Fluconazole: (Major) If coadministered with fluconazole, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if fluconazole is discontinued. 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. Ibrutinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    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 coadministered with fluvoxamine, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if fluvoxamine is discontinued. 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. Ibrutinib is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    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: (Severe) Fosamprenavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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 the concomitant use of ibrutinib and grapefruit, grapefruit juice, or Seville oranges during ibrutinib therapy. ibrutinib expsoure may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate; grapefruit and Seville oranges are strong and/or moderate CYP3A4 inhibitors. When ibrutinib was administered with multiple doses of strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Griseofulvin: (Moderate) Use ibrutinib and griseofulvin 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; griseofulvin is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    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 the 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; idelalisib is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Imatinib: (Major) If coadministered with imatinib, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if imatinib is discontinued. 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. Ibrutinib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Indinavir: (Major) Avoid the 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; indinavir is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Isavuconazonium: (Major) If coadministered with isavuconazonium, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if isavuconazonium is discontinued. 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. Ibrutinib is a CYP3A4 substrate; isavuconazonium is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Isoniazid, INH: (Major) If coadministered with isoniazid, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if isoniazid is discontinued. 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. Ibrutinib is a CYP3A4 substrate; isoniazid is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    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. (Major) If coadministered with isoniazid, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if isoniazid is discontinued. 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. Ibrutinib is a CYP3A4 substrate; isoniazid is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-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. (Major) If coadministered with isoniazid, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if isoniazid is discontinued. 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. Ibrutinib is a CYP3A4 substrate; isoniazid is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-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). When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Ketoconazole: (Major) Avoid the concomitant use of ibrutinib and ketoconazole; ibrutinib plasma concentrations are increased and severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection) may occur. If short-term use (i.e., 7 days or less) of ketoconazole is necessary, hold ibrutinib therapy until after ketoconazole is discontinued. Ibrutinib is a CYP3A4 substrate; 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.
    Lapatinib: (Moderate) Consider an ibrutinib dose reduction if ibrutinib and lapatinib are coadministered; increased ibrutinib levels may occur. Monitor patients for signs and symptoms of ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a sensitive CYP3A4 substrate; lapatinib is a weak CYP3A4 inhibitor (in vivo). Coadministration of lapatinib with a sensitive CYP3A4 substrate (given IV or PO) increased the AUC value of the CYP3A4 substrate by 22% after IV administration and by 45% after oral administration.
    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 coadministered with letermovir, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if letermovir is discontinued. 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. 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 Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively. A strong CYP3A4 inhibitor increased the Cmax and AUC of ibrutinib by 29- and 24-fold, respectively.
    Loperamide: (Moderate) Use ibrutinib and loperamide together with caution; plasma concentrations of loperamide may increase resulting in increased toxicity. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects (e.g., depressed respiratory ventilation) and cardiac toxicities (e.g., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest). Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; loperamide is a P-gp substrate.
    Loperamide; Simethicone: (Moderate) Use ibrutinib and loperamide together with caution; plasma concentrations of loperamide may increase resulting in increased toxicity. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects (e.g., depressed respiratory ventilation) and cardiac toxicities (e.g., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest). Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; loperamide is a P-gp substrate.
    Lopinavir; Ritonavir: (Severe) Lopinavir; ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; lopinavir; ritonavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly. (Severe) Ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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, RU-486: (Major) If coadministered with mifepristone, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if mifepristone is discontinued. 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. Ibrutinib is a CYP3A4 substrate; mifepristone is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    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.
    Nefazodone: (Major) Avoid the 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; nefazodone is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Nelfinavir: (Major) Avoid the 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; nelfinavir is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Netupitant; Palonosetron: (Major) If coadministered with netupitant, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if netupitant is discontinued. 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. Ibrutinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Nevirapine: (Moderate) Use ibrutinib and nevirapine 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; nevirapine is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Nicardipine: (Major) If coadministered with nicardipine, initiate ibrutinib therapy at a reduced dose of 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease; monitor patients more frequently for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate; nicardipine is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Nilotinib: (Major) If coadministered with nilotinib, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if nilotinib is discontinued. 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. Ibrutinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ombitasvir; Paritaprevir; Ritonavir: (Severe) Ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Oxcarbazepine: (Moderate) Use ibrutinib and oxcarbazepine 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; oxcarbazepine is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    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.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    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) If coadministered with posaconazole oral suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 280 mg/day PO for the treatment of chronic graft-versus-host disease (GVHD). If coadministered with posaconazole oral suspension 200 mg 3 times daily or 400 mg twice daily or posaconazole 300 mg delayed-release tablets or IV once daily, reduce the ibrutinib dose to 70 mg/day PO for the treatment of B-cell malignancy or 140 mg/day PO for the treatment of chronic GVHD. Resume ibrutinib at the previous dose if posaconazole is discontinued. 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. Ibrutinib is a CYP3A4 substrate; 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.
    Quinine: (Major) If coadministered with quinine, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if quinine is discontinued. 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. Ibrutinib is a CYP3A4 substrate; quinine is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ribociclib: (Major) If coadministered with ribociclib, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if ribociclib is discontinued. 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. Ibrutinib is a CYP3A4 substrate; ribociclib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ribociclib; Letrozole: (Major) If coadministered with ribociclib, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if ribociclib is discontinued. 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. Ibrutinib is a CYP3A4 substrate; ribociclib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    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: (Moderate) Use ibrutinib and rifapentine 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; rifapentine is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Ritonavir: (Severe) Ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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 the 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; saquinavir boosted with ritonavir is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Sirolimus: (Moderate) Use ibrutinib and sirolimus together with caution; plasma concentrations of sirolimus may increase resulting in increased toxicity. Monitor sirolimus levels and adjust the dose as necessary. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; sirolimus is a P-gp substrate with a narrow therapeutic index.
    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.
    Streptogramins: (Major) Avoid the concomitant use of ibrutinib and dalfopristin; quinupristin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of dalfopristin; quinupristin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when dalfopristin; quinupristin is discontinued. Ibrutinib is a CYP3A4 substrate; dalfopristin; quinupristin is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Telaprevir: (Major) Avoid the concomitant use of ibrutinib and telaprevir; significantly increased ibrutinib levels may occur. Chronic use of telaprevir is not recommended; consider an alternate agent with less CYP3A4 inhibition. Ibrutinib is a CYP3A4 substrate; telaprevir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Telithromycin: (Major) Avoid the concomitant use of ibrutinib and telithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of telithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when telithromycin is discontinued. Ibrutinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ibrutinib is necessary, as the systemic exposure of ibrutinib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of ibrutinib. Ibrutinib is primarily metabolized by CYP3A4. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    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.
    Tinzaparin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as tinzaparin 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: (Severe) Tipranavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events, such as ibrutinib. Significantly increased ibrutinib levels may occur. Ibrutinib is a CYP3A4 substrate; tipranavir is a strong CYP3A inhibitor. When ibrutinib was administered with multiple doses of other strong CYP3A4 inhibitors, the Cmax and AUC values of ibrutinib were increased significantly.
    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.
    Tolvaptan: (Moderate) Use ibrutinib and tolvaptan together with caution; plasma concentrations of tolvaptan may increase resulting in increased toxicity. Coadministration may necessitate a decrease in tolvaptan dose. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; tolvaptan is a P-gp substrate and inhibitor.
    Topotecan: (Major) Avoid the concurrent use of ibrutinib and topotecan capsules; plasma concentrations of topotecan may increase resulting in increased toxicity. If coadministration is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. Use ibrutinib and intravenous (IV) topotecan together with caution. Ibrutinib is a P-glycoprotein (P-gp) inhibitor and breast cancer resistance protein (BCRP) inhibitor in vitro; topotecan is a P-gp and BCRP substrate. P-gp inhibitors have less of an effect on IV topotecan.
    Trandolapril; Verapamil: (Major) If coadministered with verapamil, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if verapamil is discontinued. 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. Ibrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Verapamil: (Major) If coadministered with verapamil, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if verapamil is discontinued. 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. Ibrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Voriconazole: (Major) If coadministered with voriconazole 200 mg twice daily, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 280 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if posaconazole is discontinued. 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. Ibrutinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with multiple doses of voriconazole increased steady-state ibrutinib Cmax and AUC values by 6.7-fold and 5.7-fold, respectively.
    Warfarin: (Moderate) The concomitant use of ibrutinib and aanticoagulant 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.

    PREGNANCY AND LACTATION

    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.

    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 at least 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 at least 1 month after therapy due to the risk of male-mediated teratogenicity.

    MECHANISM OF ACTION

    Ibrutinib (PCI-32765), a member of the Tec kinase family, selectively and irreversibly inhibits Bruton’s tyrosine kinase (BTK). BTK is a signaling molecule early within the B-cell antigen receptor (BCR) signaling cascade. Signaling from BCR regulates several pro-survival mechanisms of B-cells, including proliferation, differentiation, apoptosis, and cell migration. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity and inhibition of malignant B-cell proliferation and survival. In vitro, ibrutinib also inhibits cell migration and substrate adhesion.

    PHARMACOKINETICS

    Ibrutinib is administered orally. It is highly and reversibly bound to plasma proteins (97.3%) in vitro. The volume of distribution (Vd) is 683 liters (L), the apparent Vd at steady state is approximately 10,000 L, the apparent oral clearance is approximately 2,000 L/hour, and the half-life is 4 to 6 hours. Ibrutinib is metabolized to several metabolites, including the active metabolite PCI-45227. This dihydrodiol metabolite has activity that is about 15 times lower than that of ibrutinib; the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8:1. Ibrutinib and it’s metabolites are eliminated primarily via feces. In healthy subjects, about 80% and 10% of the radioactivity was excreted in the feces and urine, respectively, within 168 hours of radiolabeled [14C]-ibrutinib administration. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in feces; there was no unchanged ibrutinib found in urine. In patients with recurrent B-cell lymphoma, the Bruton’s tyrosine kinase (BTK) active site was over 90% occupied in peripheral blood mononuclear cells up to 24 hours after ibrutinib administration at doses of 2.5 mg/kg/day or higher (175 mg/day or higher for average weight of 70 kg).
     
    Affected cytochrome P450 isoenzymes or transporters: CYP3A4, P-gp, BCRP
    Ibrutinib is metabolized primarily by CYP3A and to a lesser extent by CYP2D6 (minor pathway). Avoid the concomitant use of ibrutinib with strong CYP3A inhibitors and inducers. If ibrutinib is administered with a moderate CYP3A inhibitor, reduce the ibrutinib dose and monitor patients closely for signs of ibrutinib toxicity. The AUC value of ibrutinib decreased by 3-fold in simulations evaluating the coadministration of ibrutinib and efavirenz (a moderate CYP3A4 inducer); dose adjustment or monitoring guidance is not available in patients receiving concomitant ibrutinib and a moderate CYP3A4 inducer. Ibrutinib and its active metabolite, PCI-45227, are not likely to inhibit any major cytochrome P450 isoenzymes at clinical doses; in vitro, both are weak inducers of CYP450 isoenzymes. In vitro, ibrutinib is an inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters; it is not a substrate for these transporters. Systemic ibrutinib may inhibit BCRP and P-gp at clinical doses; therefore, blood concentrations of narrow therapeutic index P-gp or BCRP substrates (e.g., digoxin, methotrexate) may be increased.

    Oral Route

    The absolute bioavailability of oral ibrutinib was 2.9% (90% CI, 2.1% to 3.9%) in healthy subjects under fasting conditions. Maximum concentrations are reached at a median Tmax of 1 to 2 hours. Exposure increases in a dose-proportional manner up to 840 mg in patients with B-cell malignancies. Following ibrutinib 420 mg/day, the mean steady-state AUC values were 708 (coefficient of variance (CV), 71%), 324 (CV, 48%), and 1,159 (CV, 50%) nanograms (ng)/mL x hour, in patients with chronic lymphocytic lymphoma/small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and chronic graft-versus-host disease, respectively. Following ibrutinib 560 mg/day, the mean steady-state AUC values were 865 (CV, 69%) and 978 (CV, 82%) ng/mL x hour, in patients with mantle cell lymphoma and marginal zone lymphoma, respectively.
    Effects of Food: Administering ibrutinib with a high-fat and high-calorie meal results in decreased apparent oral clearance (from approximately 2,000 L/hour to 1,000 L/hour), decrease IV clearance (from 76 L/hour to 62 L/hour), a 2- to 4-fold increase in Cmax, and a 2-fold increase in AUC when compared with the fasted state. A high-fat and high-calorie meal consisted of 800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat.