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    Small Molecule Antineoplastic Bruton's Tyrosine Kinase (BTK) 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, and Waldenstrom macroglobulinemia and in adults and pediatric patients aged 1 year and older with chronic graft-versus-host disease
    Serious bleeding events have been reported

    COMMON BRAND NAMES

    Imbruvica

    HOW SUPPLIED

    Ibrutinib Oral Susp: 1mL, 70mg
    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.[56410] 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 less than 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 3 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.[57371] At a follow-up time of 63 months, the median PFS time for the ibrutinib arm was 44.1 months.[56410] At a median follow-up time of 60 months (range, 0.1 to 66 months), the median PFS (median not reached vs. 15 months; HR = 0.146; 95% CI, 0.098 to 0.218) and OS (median not reached in either arm; HR = 0.45; 95% CI, 0.266 to 0.761) times were significantly improved with ibrutinib (median duration of therapy, 57 months) compared with chlorambucil 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 3 trial (the RESONATE-2 trial; n = 269). The median age of patients in the ibrutinib arm was 74 years (range, 65 to 89 years).

    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. Consider administering ibrutinib before rituximab on days these agents are given on the same day. 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 less than 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 3 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 CLL or SLL, in combination with obinutuzumab.
    Oral dosage
    Adults

    420 mg orally once daily until disease progression in combination with obinutuzumab 100 mg IV on day 1, 900 mg IV on day 2, then 1,000 mg IV on days 8 and 15 in cycle 1; give obinutuzumab 1,000 mg IV on day 1 repeated every 28 days on cycles 2 to 6. Consider administering ibrutinib before obinutuzumab on days these agents are given on the same day. 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.[56410] At a median follow-up time of 31.3 months, the median progression-free survival (PFS) time was significantly improved with ibrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab (median time not reached vs. 19 months; hazard ratio (HR) = 0.23; 95% CI, 0.15 to 0.37; p less than 0.0001) in patients with previously untreated CLL or SLL (n = 15; 7%) in a multinational, randomized, phase 3 trial (the iLLUMINATE trial; n = 229). The estimated 30-month PFS rates were 79% and 31% in the ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab arms, respectively. There was no statistically significant difference in overall survival between treatment arms at the time of analysis. In the ibrutinib-containing arm, the median duration of therapy was 29.3 months. Eligible patients were either 65 years or older or had certain coexisting conditions that made them unsuitable for fludarabine-based chemoimmunotherapy.[63904]

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

    420 mg orally once daily until disease progression in combination with rituximab; rituximab therapy started after 28 days of ibrutinib therapy in a randomized trial (the E1912 trial). Consider administering ibrutinib before rituximab on days these agents are given on the same day. 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 the E1912 trial, patients received rituximab starting after 28 days of ibrutinib therapy as follows: 50 mg/m2 IV on day 1 and 325 mg/m2 IV on day 2 of the first rituximab cycle followed by 500 mg/m2 on day 1 only for 5 additional cycles of therapy. Rituximab was repeated every 28 days for total of 6 cycles. [64595]

    For the treatment of Waldenstrom macroglobulinemia.
    For the treatment of Waldenstrom macroglobulinemia, 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. 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 3 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 Waldenstrom macroglobulinemia, in combination with rituximab.
    Oral dosage
    Adults

    420 mg orally once daily until disease progression in combination with rituximab 375 mg/m2 IV weekly on weeks 1, 2, 3, and 4 and 17, 18, 19, and 20 (for a total of 8 doses). Consider administering ibrutinib before rituximab on days these agents are given on the same day. 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.[56410]

    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).

    Adolescents and Children aged 12 years

    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 an overall response rate through week 25 of 60% in patients with moderate to severe chronic GVHD who required additional therapy after failure of at least 1 prior line of systemic therapy in a dose-finding, phase 1/2 trial (n = 47); the complete response rate was 4%. The median duration of response was 5.3 months. Additionally, the median time from first response to death or new systemic therapies for cGVHD was 14.8 months. In this trial, patients (median age, 13 years; range, 1 to 19 years) had received a median of 2 prior cGVHD treatments (range, 1 to 12 treatments).

    Children 1 to 11 years

    240 mg/m2 (maximum dose, 420 mg) orally once daily until chronic GVHD progression or a recurrence of the underlying malignancy. For BSA greater than 1.6 m2, give 420 mg orally once daily. For BSA less than 1.6 m2, administer ibrutinib per the following dose recommendations:
    BSA more than 0.3 to 0.4 m2: 1.2 mL (84 mg) oral suspension; BSA more than 0.4 to 0.5 m2: 1.5 mL (105 mg) oral suspension; BSA more than 0.5 to 0.6 m2: 1.9 mL (133 mg) oral suspension; BSA more than 0.6 to 0.7 m2: 2.2 mL (154 mg) oral suspension;BSA more than 0.7 to 0.8 m2: 210 mg tablet or capsule OR 2.6 mL (182 mg) oral suspension;BSA more than 0.8 to 0.9 m2: 210 mg tablet or capsule OR 2.9 mL (203 mg) oral suspension;BSA more than 0.9 to 1 m2: 210 mg tablet or capsule OR 3.3 mL (231 mg) oral suspension;BSA more than 1 to 1.1 m2: 280 mg tablet or capsule OR 3.6 mL (252 mg) oral suspension;BSA more than 1.1 to 1.2 m2: 280 mg tablet or capsule OR 4 mL (280 mg) oral suspension;BSA more than 1.2 to 1.3 m2: 280 mg tablet or capsule OR 4.3 mL (301 mg) oral suspension;BSA more than 1.3 to 1.4 m2: 350 mg tablet or capsule OR 4.6 mL (322 mg) oral suspension;BSA more than 1.4 to 1.5 m2: 350 mg tablet or capsule OR 5 mL (350 mg) oral suspension; andBSA more than 1.5 to 1.6 m2: 350 mg tablet or capsule OR 5.3 mL (371 mg) oral suspension.
    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 an overall response rate through week 25 of 60% in patients with moderate to severe chronic GVHD who required additional therapy after failure of at least 1 prior line of systemic therapy in a dose-finding, phase 1/2 trial (n = 47); the complete response (CR) rate was 4%. The median duration of response was 5.3 months. Additionally, the median time from first response to death or new systemic therapies for cGVHD was 14.8 months. In this trial, patients (median age, 13 years; range, 1 to 19 years) had received a median of 2 prior cGVHD treatments (range, 1 to 12 treatments).

    MAXIMUM DOSAGE

    Adults

    560 mg/day PO.

    Geriatric

    560 mg/day PO.

    Adolescents

    420 mg/day PO.

    Children

    12 years: 420 mg/day PO.1 to 11 years: 240 mg/m2 (Max of 420 mg) per day PO.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Patients with B-cell malignancies:
    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.
    Patients with graft-versus-host disease:
    Total bilirubin level more than 1.5 to 3 times the ULN at baseline (unless of non-hepatic origin or due to Gilbert syndrome): 12 years and older, 140 mg/day PO; 1 to less than 12 years of age, 80 mg/m2 per day PO.Total bilirubin level more than 3 times the ULN at baseline (unless of non-hepatic origin or due to Gilbert syndrome): Avoid use.

    Renal Impairment

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

    ADMINISTRATION

    Emetic Risk
    Minimal/Low
    Administer prn antiemetics as necessary.

    Oral Administration

    Take ibrutinib at the same time each day.
    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.

    Oral Solid Formulations

    Swallow whole with a glass of water.
    Do not open, break, or chew the capsules or cut, crush, or chew the tablets.

    Oral Liquid Formulations

    Read the manufacturer's Instructions for Use prior to preparing and administering ibrutinib oral suspension.
    Shake bottle well prior to administration.
    Use the provided oral syringe to draw up the dose; more than 1 syringe may be needed to give the full dose.
    Do not use the provided oral syringe for other patients or with other medications.
    Store the opened bottle between 2 and 25 degrees C (36 and 77 degrees F); do not freeze.
    Dispose of any unused medication within 60 days after first opening of the bottle; also throw away any used or unused syringes at the same time.

    STORAGE

    Imbruvica:
    - Discard any unused product 60 days after first opening bottle
    - Dispense in original container or USP equivalent tight container
    - Do not freeze
    - See package insert for detailed storage information
    - Store between 36 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

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

    Major bleeding events such as intracranial bleeding (e.g., subdural hematoma), GI bleeding, hematuria, and post-procedural hemorrhage have been reported with ibrutinib therapy; some cases were fatal. Monitor patients for signs and symptoms of bleeding. Patients receiving concomitant antiplatelet or anticoagulant therapy have an increased risk for major bleeding. Evaluate the risk/benefit of using concomitant antithrombotic therapy or for continuing ibrutinib therapy in patients scheduled to have surgery. Consider stopping ibrutinib for at least 3 to 7 days pre- and post-surgery depending on the type of surgery (e.g., dental work/procedures) and the risk of bleeding.[56410]

    Anemia, neutropenia, thrombocytopenia

    Severe myelosuppression including neutropenia, thrombocytopenia, and anemia has been reported in patients who received ibrutinib. Monitor complete blood counts monthly. A dosage adjustment or therapy discontinuation may be necessary in patients who develop hematologic toxicity.

    Infection, progressive multifocal leukoencephalopathy

    Serious infection including progressive multifocal leukoencephalopathy and Pneumocystis jirovecii pneumonia has been reported with ibrutinib therapy; some cases resulted in death. Evaluate patients for signs and symptoms of infection (e.g., fever) and treat promptly. Consider infection prophylaxis in patients at risk for opportunistic infections.[56410]

    Hepatic disease

    Avoid ibrutinib use in patients with B-cell malignancies who have baseline severe hepatic impairment (Child-Pugh class C) and in patients with chronic graft-versus-host who have a total bilirubin level more than 3 times the ULN at baseline (unless of non-hepatic origin or due to Gilbert syndrome). An initial dose reduction may be necessary in patients with hepatic disease. Obtain liver function tests at baseline and as clinically indicated; monitor patients closely for signs and symptoms of hepatotoxicity. Interrupt therapy, reduce the dose, and/or discontinue ibrutinib in patients who develop grade 3 or higher hepatotoxicity.

    Atrial fibrillation, atrial flutter, cardiac arrhythmias, cardiac disease, diabetes mellitus, heart failure, hypertension, syncope, ventricular arrhythmias

    Serious cardiac arrhythmias (e.g., atrial fibrillation, atrial flutter, and ventricular arrhythmias), heart failure, and sudden death have occurred in patients who received ibrutinib as indicated or for unapproved uses in clinical trials. Patients with acute infections or cardiac risk factors/comorbidities such as a history of cardiac disease, cardiac arrhythmias, diabetes mellitus, or hypertension are at increased risk of cardiotoxicity including sudden death. Monitor patients at baseline for a history of or signs and symptoms of cardiac disease including cardiac arrhythmias and heart failure; perform heart function tests (e.g., ECG, echocardiogram) in patients who develop symptoms of an arrhythmia (e.g., palpitations, lightheadedness, syncope, or chest pain) or new onset dyspnea. If the cardiac arrhythmia persists despite treatment, evaluate the risks and benefits of continuing treatment with ibrutinib. Monitor blood pressure; start or adjust anti-hypertensive medication during ibrutinib therapy as appropriate. A dosage adjustment or therapy discontinuation may be necessary in patients who develop hypertension, heart failure, or arrhythmias.[56410]

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has been reported infrequently in patients who received ibrutinib. Assess patient risk and institute prophylaxis measures (e.g., anti-hyperuricemic agents and hydration) in patients at high-risk for TLS; closely monitor these patients for signs of TLS (e.g., uric acid, serum electrolytes, renal function tests). Promptly treat TLS if it occurs. Patients with a high tumor burden are at greater risk for developing TLS.

    Geriatric

    Anemia, grade 3 or higher pneumonia, thrombocytopenia, hypertension, and atrial fibrillation occurred more often in geriatric patients compared with younger patients who received ibrutinib in clinical studies (n = 1,124). In these studies, 64% of patients were 65 years or older and 23% of patients were 75 years or older.[56410]

    Pregnancy

    Ibrutinib may cause fetal harm if administered during pregnancy based on data from animal studies. Females of reproductive potential should be advised to avoid becoming pregnant while receiving ibrutinib. If a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus. In reproductive animal studies in pregnant rats and rabbits, visceral malformations of the heart and major vessels, skeletal variations (i.e., fused sternebrae), and increased resorptions and post-implantation loss were observed following ibrutinib doses that resulted in drug exposure 2- to 20-times of that reported at clinical human doses (range, 420 to 560 mg daily). Additionally, decreased fetal weight was reported in pregnant rats who received ibrutinib doses that resulted in 6-times the drug exposure of the recommended dose for Mantle-cell lymphoma.

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ibrutinib treatment. Pregnancy testing should be performed prior to starting ibrutinib in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 1 month after ibrutinib therapy. Women who become pregnant while receiving ibrutinib should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during ibrutinib therapy and for 1 month after therapy due to the risk of male-mediated teratogenicity.[56410]

    Breast-feeding

    It is not known if ibrutinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing children, women should discontinue breast-feeding during ibrutinib therapy and for 1 week after the last dose.[56410]

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 6.0-61.0
    infection / Delayed / 0-21.0
    thrombocytopenia / Delayed / 0-19.0
    anemia / Delayed / 0-13.0
    fatigue / Early / 0-12.0
    fever / Early / 0-11.0
    visual impairment / Early / 11.0-11.0
    hypertension / Early / 4.0-11.0
    new primary malignancy / Delayed / 10.0-10.0
    osteonecrosis / Delayed / 0-9.0
    atrial fibrillation / Early / 8.4-8.4
    atrial flutter / Early / 8.4-8.4
    hypokalemia / Delayed / 0-7.0
    sinusitis / Delayed / 0-6.0
    skin cancer / Delayed / 0-6.0
    musculoskeletal pain / Early / 0-6.0
    asthenia / Delayed / 0-6.0
    arthralgia / Delayed / 0-5.0
    dyspnea / Early / 0-5.0
    rash / Early / 0-5.0
    headache / Early / 0-5.0
    dehydration / Delayed / 4.0-4.0
    bleeding / Early / 0-3.0
    hematuria / Delayed / 0-3.0
    subdural hematoma / Early / 0-3.0
    intracranial bleeding / Delayed / 0-3.0
    GI bleeding / Delayed / 0-3.0
    muscle cramps / Delayed / 0-3.0
    peripheral edema / Delayed / 0-3.0
    elevated hepatic enzymes / Delayed / 0-3.0
    ecchymosis / Delayed / 0-2.0
    anorexia / Delayed / 0-2.0
    cough / Delayed / 0-2.0
    hyperuricemia / Delayed / 0-2.0
    hyperbilirubinemia / Delayed / 0-2.0
    anxiety / Delayed / 0-2.0
    infusion-related reactions / Rapid / 0-2.0
    heart failure / Delayed / 1.7-1.7
    ventricular tachycardia / Early / 1.0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    dizziness / Early / 0-1.0
    insomnia / Early / 0-1.0
    stroke / Early / 0-1.0
    leukoencephalopathy / Delayed / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    cirrhosis / Delayed / 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
    conjunctivitis / Delayed / 0-11.0
    sinus tachycardia / Rapid / 0-11.0
    hypogammaglobulinemia / Delayed / 0-11.0
    interstitial lung disease / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known

    Mild

    xerophthalmia / Early / 0-17.0
    petechiae / Delayed / 11.0-16.0
    pruritus / Rapid / 0-14.0
    lacrimation / Early / 0-13.0
    chills / Rapid / 0-12.0
    influenza / Delayed / 0-12.0
    pharyngitis / Delayed / 0-12.0
    gastroesophageal reflux / Delayed / 0-12.0
    epistaxis / Delayed / 11.0-11.0
    weight loss / Delayed / 0-10.0
    panniculitis / Delayed / Incidence not known
    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.
    Acetaminophen; Aspirin: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Alpelisib: (Major) Avoid coadministration of alpelisib with ibrutinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and ibrutinib is a BCRP inhibitor.
    Amiodarone: (Major) If ibrutinib is coadministered with amiodarone, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dose if amiodarone is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Anagrelide: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as anagrelide may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Antithrombin III: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as antithrombin III may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Apalutamide: (Major) Avoid coadministration of ibrutinib with apalutamide due to decreased plasma concentrations of ibrutinib. Ibrutinib is a sensitive CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Apixaban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as apixaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Aprepitant, Fosaprepitant: (Major) If ibrutinib is coadministered with multi-day oral aprepitant, fosaprepitant, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dose if aprepitant, fosaprepitant is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Argatroban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as argatroban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Aspirin, ASA: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Caffeine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Caffeine; 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; Caffeine; Orphenadrine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Carisoprodol: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Dipyridamole: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives. (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as dipyridamole may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Aspirin, ASA; Omeprazole: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Oxycodone: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Aspirin, ASA; Pravastatin: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
    Atazanavir: (Major) Avoid concomitant use of ibrutinib and atazanavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Atazanavir; Cobicistat: (Major) Avoid concomitant use of ibrutinib and atazanavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    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.
    Berotralstat: (Major) If coadministered with berotralstat, reduce the ibrutinib dose to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dose if berotralstat is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity; modify the ibrutinib dosage as recommended if toxicity occurs. Additionally, reduce the berotralstat dose to 110 mg PO once daily in patients taking ibrutinib. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Ibrutinib is a CYP3A4 substrate and P-gp and BCRP inhibitor; berotralstat is a P-gp and BCRP substrate and moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC values of ibrutinib was increased by 3-fold. Coadministration with another P-gp and BCRP inhibitor increased berotralstat exposure by 69%.
    Betrixaban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as betrixaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Bexarotene: (Moderate) Use ibrutinib and bexarotene together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; bexarotene is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Bivalirudin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as bivalirudin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Boceprevir: (Contraindicated) 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.
    Carbamazepine: (Major) Avoid the concomitant use of ibrutinib and carbamazepine; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Ceritinib: (Major) Avoid concomitant use of ibrutinib and ceritinib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Chloramphenicol: (Major) Avoid concomitant use of ibrutinib and chloramphenicol; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of chloramphenicol is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when chloramphenicol is discontinued. Ibrutinib is a CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Cilostazol: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as cilostazol may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Ciprofloxacin: (Major) If ibrutinib is coadministered with ciprofloxacin, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dose if ciprofloxacin is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Clarithromycin: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Clopidogrel: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as clopidogrel may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cobicistat: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Colchicine: (Major) Avoid the concurrent use of ibrutinib and colchicine; plasma concentrations of colchicine may increase resulting in serious and life-threatening toxicity. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; colchicine is a narrow therapeutic index drug and a P-gp substrate.
    Conivaptan: (Major) If ibrutinib is coadministered with conivaptan, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if conivaptan is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Crizotinib: (Major) If ibrutinib is coadministered with crizotinib, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy.Resume ibrutinib at the previous dosage if crizotinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs Ibrutinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Cyclosporine: (Major) If ibrutinib is coadministered with cyclosporine, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if cyclosporine is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Monitor cyclosporine levels and observe patients for symptoms of cyclosporine toxicity. Ibrutinib is a 3A4 substrate and a P-glycoprotein (P-gp) inhibitor in vitro; cyclosporine is a CYP3A4 inhibitor and a P-gp substrate with a narrow therapeutic index. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Dabigatran: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as dabigatran may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Dabrafenib: (Major) The concomitant use of dabrafenib and ibrutinib may lead to decreased ibrutinib concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of ibrutinib efficacy. Dabrafenib is a moderate CYP3A4 inducer and ibrutinib is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%. Additionally, simulations using physiologically-based pharmacokinetic (PBPK) models suggest that moderate CYP3A4 inducers may decrease ibrutinib exposure up to 3-fold.
    Dalteparin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as dalteparin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    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 ibrutinib is coadministered with danazol, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy.Resume ibrutinib at the previous dosage if danazol is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Darunavir: (Major) Avoid concomitant use of ibrutinib and darunavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Darunavir; Cobicistat: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. (Major) Avoid concomitant use of ibrutinib and darunavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. (Major) Avoid concomitant use of ibrutinib and darunavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Delavirdine: (Major) Avoid concomitant use of ibrutinib and delavirdine; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and delavirdine is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Desirudin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as desirudin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Dexamethasone: (Moderate) Use ibrutinib and dexamethasone together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; dexamethasone is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Digoxin: (Moderate) Use ibrutinib and digoxin together with caution; plasma concentrations of digoxin may increase resulting in increased toxicity. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; digoxin is a P-gp substrate with a narrow therapeutic index. In addition, some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients.
    Diltiazem: (Major) If ibrutinib is coadministered with diltiazem, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if diltiazem is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Dipyridamole: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as dipyridamole may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Dronedarone: (Major) If ibrutinib is coadministered with dronedarone, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if dronedarone is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Duvelisib: (Major) If ibrutinib is coadministered with duvelisib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if duvelisib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a sensitive CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Edoxaban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as edoxaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Efavirenz: (Moderate) Use ibrutinib and efavirenz together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use ibrutinib and efavirenz together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use ibrutinib and efavirenz together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Elbasvir; Grazoprevir: (Moderate) Administering ibrutinib with elbasvir; grazoprevir may result in elevated ibrutinib plasma concentrations. Ibrutinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Encorafenib: (Moderate) Coadministration of encorafenib with ibrutinib may result in increased toxicity or decreased efficacy of ibrutinib. Ibrutinib is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Enoxaparin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as enoxaparin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Enzalutamide: (Major) Avoid coadministration of ibrutinib with enzalutamide due to decreased plasma concentrations of ibrutinib. Ibrutinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Eptifibatide: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as eptifibatide may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Erythromycin: (Major) If ibrutinib is coadministered with erythromycin, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if erythromycin is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of erythromycin, the AUC value of ibrutinib increased by 3-fold.
    Erythromycin; Sulfisoxazole: (Major) If ibrutinib is coadministered with erythromycin, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if erythromycin is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of erythromycin, the AUC value of ibrutinib increased by 3-fold.
    Eslicarbazepine: (Moderate) Use ibrutinib and eslicarbazepine together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Etravirine: (Moderate) Use ibrutinib and etravirine together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; etravirine is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ibrutinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate. Ibrutinib may inhibit P-gp. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Fedratinib: (Major) If ibrutinib is coadministered with fedratinib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if fedratinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the CAUC value of ibrutinib was increased by 3-fold.
    Fluconazole: (Major) If ibrutinib is coadministered with fluconazole, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if fluconazole is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Flutamide: (Moderate) Use ibrutinib and flutamide together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; flutamide is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Fluvoxamine: (Major) If ibrutinib is coadministered with fluvoxamine, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if fluvoxamine is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Fondaparinux: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as fondaparinux may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Fosamprenavir: (Major) Avoid concomitant use of ibrutinib and fosamprenavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Fosphenytoin: (Major) Avoid the concomitant use of ibrutinib and fosphenytoin; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during ibrutinib treatment due to the risk of increased ibrutinib exposure and adverse reactions. Ibrutinib is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
    Heparin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as heparin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Idelalisib: (Major) Avoid concomitant use of ibrutinib and idelalisib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and idelalisib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Imatinib: (Major) If ibrutinib is coadministered with imatinib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if imatinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib weas increased by 3-fold.
    Indinavir: (Major) Avoid concomitant use of ibrutinib and indinavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and indinavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Isavuconazonium: (Major) If ibrutinib is coadministered with isavuconazonium, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if isavuconazonium is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection);modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; isavuconazonium is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of ibrutinib and rifampin; significantly reduced ibrutinib plasma concentrations have occurred. Ibrutinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. When ibrutinib was administered with rifampin, the Cmax and AUC values of ibrutinib decreased by more than 13-fold and 10-fold, respectively.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of ibrutinib and rifampin; significantly reduced ibrutinib plasma concentrations have occurred. Ibrutinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. When ibrutinib was administered with rifampin, the Cmax and AUC values of ibrutinib decreased by more than 13-fold and 10-fold, respectively.
    Itraconazole: (Major) Avoid ibrutinib use during and for 2 weeks after discontinuation of itraconazole treatment. If short-term use of itraconazole is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when itraconazole is discontinued. Taking these drugs together may result in increased ibrutinib plasma concentrations, resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and itraconazole is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Ivosidenib: (Moderate) Monitor for loss of efficacy of ibrutinib during coadministration of ivosidenib; an ibrutinib dose adjustment may be necessary. Ibrutinib is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ibrutinib concentrations.
    Ketoconazole: (Major) Avoid concomitant use of ibrutinib and ketoconazole; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of ketoconazole is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when ketoconazole is discontinued. Ibrutinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of ketoconazole, the Cmax and AUC values of ibrutinib increased by 29-fold and 24-fold, respectively.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with ibrutinib is necessary. Lapatinib is a P-glycoprotein (P-gp) substrate and ibrutinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Lefamulin: (Major) If ibrutinib is coadministered with oral lefamulin, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if oral lefamulin is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Lepirudin: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as lepirudin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ibrutinib; monitor for potential reduction in efficacy. Ibrutinib is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of ibrutinib; monitor for potential reduction in efficacy. Ibrutinib is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Letermovir: (Major) If ibrutinib is coadministered with letermovir, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if letermovir is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Avoid coadministration in patients also receiving cyclosporine, because the magnitude of the interaction may be increased. Ibrutinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold. A strong CYP3A4 inhibitor increased the Cmax and AUC of ibrutinib by 29- and 24-fold, respectively.
    Levoketoconazole: (Major) Avoid concomitant use of ibrutinib and ketoconazole; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of ketoconazole is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when ketoconazole is discontinued. Ibrutinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of ketoconazole, the Cmax and AUC values of ibrutinib increased by 29-fold and 24-fold, respectively.
    Lonafarnib: (Major) Avoid concomitant use of ibrutinib and lonafarnib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ibrutinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and ibrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
    Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ibrutinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and ibrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
    Lopinavir; Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of ibrutinib and lumacaftor; ivacaftor; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Methotrexate: (Moderate) Use ibrutinib and methotrexate together with caution; plasma concentrations of methotrexate may increase resulting in increased toxicity. Ibrutinib is a BCRP inhibitor in vitro; methotrexate is a BCRP substrate with a narrow therapeutic index.
    Mifepristone: (Major) Avoid concomitant use of ibrutinib and chronic mifepristone therapy; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and mifepristone is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid the concomitant use of ibrutinib and mitotane; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Modafinil: (Moderate) Use ibrutinib and modafinil together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; modafinil is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Nafcillin: (Moderate) Use ibrutinib and nafcillin together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; nafcillin is a moderate CYP3A inducer. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that moderate CYP3A4 inducers may decrease ibrutinib exposure up to 3-fold.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with ibrutinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and ibrutinib is a P-gp inhibitor.
    Nefazodone: (Major) Avoid concomitant use of ibrutinib and nefazodone; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Nelfinavir: (Major) Avoid concomitant use of ibrutinib and nelfinavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Netupitant, Fosnetupitant; Palonosetron: (Major) If ibrutinib is coadministered with netupitant, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if netupitant is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    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.
    Nilotinib: (Major) If ibrutinib is coadministered with nilotinib, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if nilotinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Use ibrutinib and rifabutin together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Pazopanib: (Moderate) Use ibrutinib and pazopanib together with caution; plasma concentrations of ibrutinib or pazopanib may be increased. Monitor patients for symptoms of ibrutinib or pazopanib toxicity if these agents are used together. Ibrutinib is a 3A4 substrate and a P-glycoprotein (P-gp) inhibitor and breast cancer resistance protein (BCRP) inhibitor in vitro; pazopanib is a weak 3A4 inhibitor and a P-gp and BCRP substrate.
    Phenobarbital: (Major) Avoid the concomitant use of ibrutinib and phenobarbital; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of ibrutinib and phenobarbital; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Phenytoin: (Major) Avoid the concomitant use of ibrutinib and phenytoin; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Posaconazole: (Major) Reduce the initial ibrutinib dosage to 140 mg/day PO in patients receiving ibrutinib for a B-cell malignancy or 280 mg/day PO in patients aged 12 years or older receiving ibrutinib for chronic graft-versus-host disease (cGVHD) if coadministered with posaconazole oral suspension 100 mg/day to 400 mg/day. Reduce the initial ibrutinib dosage to 70 mg/day PO in patients with a B-cell malignancy or 140 mg/day PO in patients aged 12 years and older with cGVHD if coadministered with posaconazole oral suspension 600 mg/day to 800 mg/day or posaconazole 300 mg (delayed-release tablets or IV) once daily. In patients aged 1 to 11 years receiving ibrutinib for cGVHD, reduce the initial ibrutinib dose to 80 mg/m2 per day PO if coadministered with any dosage of posaconazole. Resume ibrutinib at the previous dose if posaconazole is discontinued. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interrupt or modify ibrutinib therapy as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate and posaconazole is a strong CYP3A4 inhibitor. Simulations under fed conditions suggest that coadministration with posaconazole may increase ibrutinib exposure by 3- to 10-fold.
    Prasugrel: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as prasugrel may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Primidone: (Major) Avoid the concomitant use of ibrutinib and primidone; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Probenecid; Colchicine: (Major) Avoid the concurrent use of ibrutinib and colchicine; plasma concentrations of colchicine may increase resulting in serious and life-threatening toxicity. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ibrutinib is a P-glycoprotein (P-gp) inhibitor in vitro; colchicine is a narrow therapeutic index drug and a P-gp substrate.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral ibrutinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ibrutinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate and ibrutinib is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral ibrutinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ibrutinib at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-gp substrate and ibrutinib is a P-gp inhibitor.
    Ribociclib: (Major) Avoid concomitant use of ibrutinib and ribociclib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Ribociclib; Letrozole: (Major) Avoid concomitant use of ibrutinib and ribociclib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Rifabutin: (Moderate) Use ibrutinib and rifabutin together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Rifampin: (Major) Avoid the concomitant use of ibrutinib and rifampin; significantly reduced ibrutinib plasma concentrations have occurred. Ibrutinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. When ibrutinib was administered with rifampin, the Cmax and AUC values of ibrutinib decreased by more than 13-fold and 10-fold, respectively.
    Rifapentine: (Major) Avoid concurrent use of ibrutinib with rifapentine due to decreased plasma concentrations of ibrutinib. Ibrutinib is a sensitive CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ibrutinib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ibrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with ibrutinib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and ibrutinib is a P-gp inhibitor.
    Ritonavir: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Rivaroxaban: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as rivaroxaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Saquinavir: (Major) Avoid concomitant use of ibrutinib and saquinavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and saquinavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Sirolimus: (Major) Avoid coadministration of sirolimus with ibrutinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and ibrutinib is a P-gp inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of ibrutinib and St. John's Wort; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
    Talazoparib: (Major) Avoid coadministration of ibrutinib with talazoparib due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a BCRP and P-glycoprotein (P-gp) substrate; ibrutinib is a BCRP and P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    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.
    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: (Major) Avoid concomitant use of ibrutinib and tipranavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and tipranavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Tirofiban: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as tirofiban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
    Topotecan: (Major) Avoid coadministration of ibrutinib with oral topotecan due to increased topotecan exposure; ibrutinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); ibrutinib is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Trandolapril; Verapamil: (Major) If ibrutinib is coadministered with verapamil, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if verapamil is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Tucatinib: (Major) Avoid concomitant use of ibrutinib and tucatinib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with ibrutinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP and P-gp drug transporters; ibrutinib is a BCRP and P-gp inhibitor.
    Verapamil: (Major) If ibrutinib is coadministered with verapamil, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if verapamil is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
    Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of ibrutinib and clarithromycin; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of clarithromycin is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when clarithromycin is discontinued. Ibrutinib is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
    Voriconazole: (Major) If ibrutinib is coadministered with voriconazole 200 mg twice daily, reduce the initial ibrutinib dosage to 140 mg/day PO in patients receiving ibrutinib for a B-cell malignancy or 280 mg/day PO in patients aged 12 years and older receiving ibrutinib for chronic graft-versus-host disease (cGVHD). If ibrutinib is coadministered with voriconazole suspension 9 mg/kg (max dose of 350 mg) twice daily, reduce the initial ibrutinib dosage to 160 mg/m2 per day PO in patients aged 1 to 11 years receiving ibrutinib for cGVHD. Resume ibrutinib at the previous dose if voriconazole is discontinued. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with multiple doses of voriconazole increased steady-state ibrutinib exposure by 5.7-fold.
    Voxelotor: (Major) If ibrutinib is coadministered with voxelotor, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for a B-cell malignancy. Resume ibrutinib at the previous dose if voxelotor is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration with multiple doses of another moderate CYP3A4 inhibitor increased steady-state ibrutinib exposure by 3-fold.
    Warfarin: (Moderate) The concomitant use of ibrutinib and 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.

    It is not known if ibrutinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing children, women should discontinue breast-feeding during ibrutinib therapy and for 1 week after the last dose.[56410]

    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 its 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). At the recommended ibrutinib dosage, the BTK active site was 93% occupied in peripheral blood mononuclear cells in adult patients with chronic graft-versus-host disease.
    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. The dose may need to be reduced if ibrutinib is administered with a moderate CYP3A inhibitor; monitor these 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.[56410]

    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%), 707 (CV, 72%), 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.[56410]