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  • CLASSES

    Small Molecule Antineoplastic Bruton's Tyrosine Kinase (BTK) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral Bruton tyrosine kinase (BTK) inhibitor
    Used in adult patients with mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma
    Serious bleeding events have been reported

    COMMON BRAND NAMES

    CALQUENCE

    HOW SUPPLIED

    Acalabrutinib Oral Cap: 100mg

    DOSAGE & INDICATIONS

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

    100 mg orally twice daily (approximately 12 hours apart) 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 independent review committee-assessed overall response rate was 80% (complete response rate, 40%) in patients with relapsed or refractory mantle cell lymphoma who received acalabrutinib in a multicenter, phase 2 trial (n = 124; ACE-LY-004 trial). At a median follow-up of 15.2 months, the median time to best response was 1.9 months; the median duration of response, progression-free survival (PFS) time, and overall survival (OS) time were not reached. The estimated 12-month PFS and OS rates were 67% and 87%, respectively. Patients (median age, 68 years; range, 42 to 90 years) in this trial had received a median of 2 prior treatments (range, 1 to 5); 18% of patients had a prior stem-cell transplant.

    For the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
    NOTE: Acalabrutinib has been designated by the FDA as an orphan drug for the treatment of CLL.
    For the treatment of CLL or SLL, as a single agent.
    Oral dosage
    Adults

    100 mg orally twice daily (approximately 12 hours apart) until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. At a median follow-up time of 16.1 months (range, 0.03 to 22.4 months), the median progression-free survival (PFS) time was significantly improved in patients with relapsed or refractory CLL/SLL who received acalabrutinib monotherapy (n = 155) compared with investigator choice therapy (median time not reached vs. 16.5 months; HR = 0.31; 95% CI, 0.2 to 0.49; p less than 0.0001) in a multicenter, open-label, randomized, phase 3 trial (n = 310; the ASCEND trial). The median overall survival (OS) time had not been reached in either treatment arm at the time of this analysis. Investigator choice therapy consisted of idelalisib plus rituximab (n = 119) or bendamustine plus rituximab (n = 36). Patients (median age, 67 years; range, 32 to 90 years) in this trial had previously received at least 1 prior therapy (acalabrutinib arm, median of 1 prior therapy; range, 1 to 8 therapies). The median PFS time was significantly improved in patients with previously untreated CLL/SLL who received acalabrutinib monotherapy compared with obinutuzumab plus chlorambucil (median time not reached vs. 22.6 months; HR = 0.2; 95% CI, 0.13 to 0.3; p less than 0.0001) in a multicenter, open-label, randomized, 3-arm, phase 3 trial (n = 535; the ELEVATE-TN trial). At a median follow-up time of 28.3 months, the median OS time had not been reached in any treatment arm. Eligible patients (median age, 70 years; range, 41 to 91 years) in this trial were 65 years of age or older or had coexisting conditions (i.e., a total Cumulative Illness Rating Scale (CIRS) score of greater than 6 or a creatinine clearance of 30 to 69 mL/min).

    For the treatment of previously untreated CLL or SLL, in combination with obinutuzumab.
    Oral dosage
    Adults

    100 mg orally twice daily (approximately 12 hours apart) until disease progression in combination with up to 6 cycles of obinutuzumab therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interaction. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. In a clinical trial, acalabrutinib therapy was started on day 1 of cycle 1 and obinutuzumab therapy was given starting on day 1 of cycle 2 as follows: 100 mg IV on day 1, 900 mg IV on day 2, and then 1,000 mg IV on days 8 and 15 followed by obinutuzumab 1,000 mg IV on day 1 of cycles 3, 4, 5, 6, and 7; cycles were repeated every 28 days. The median progression-free survival time was significantly improved in patients with previously untreated CLL/SLL who received acalabrutinib plus obinutuzumab compared with obinutuzumab plus chlorambucil (median time not reached vs. 22.6 months; HR = 0.1; 95% CI, 0.06 to 0.17; p less than 0.0001) in a multicenter, open-label, randomized, 3-arm, phase 3 trial (n = 535; the ELEVATE-TN trial). At a median follow-up time of 28.3 months, the median overall survival time had not been reached in any treatment arm. Eligible patients (median age, 70 years; range, 41 to 91 years) in this trial were 65 years of age or older or had coexisting conditions (i.e., a total Cumulative Illness Rating Scale (CIRS) score of greater than 6 or a creatinine clearance of 30 to 69 mL/min).

    For the treatment of Waldenstrom macroglobulinemia†.
    NOTE: Acalabrutinib has been designated as an orphan drug by the FDA for the treatment of Waldenstrom macroglobulinemia.
    Oral dosage
    Adults

    100 mg orally twice daily until disease progression was evaluated in a phase 2 trial (n = 106). 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    100 mg PO twice daily.

    Geriatric

    100 mg PO twice daily.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Dosage adjustment not necessary.
    Severe hepatic impairment (Child-Pugh class C): Avoid use.

    Renal Impairment

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

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Take acalabrutinib orally with or without food approximately 12 hours apart each day.
    Swallow capsules whole with water; do not open, break, or chew capsules.
    Take acalabrutinib 2 hours before taking a H2-blocker; separate the dose from antacids by at least 2 hours.
    If a dose is missed, take within 3 hours of missing the dose. If more than 3 hours have passed, skip the dose and take the next dose at its regularly scheduled time.

    STORAGE

    CALQUENCE:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

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

    Major bleeding events such as intracranial bleeding have been reported with acalabrutinib therapy; some cases were fatal. Monitor patients for signs or symptoms of bleeding and manage appropriately. Patients receiving concomitant antithrombotic agents (e.g., antiplatelet or anticoagulant therapy) may be at increased risk for bleeding. Evaluate the risk/benefit of using concomitant antithrombotic therapy or for continuing acalabrutinib therapy in patients scheduled to have surgery. Consider stopping acalabrutinib for 3 to 7 days pre- and post-surgery depending on the type of surgery (e.g., dental work/procedures) and the risk of bleeding.

    Anemia, neutropenia, thrombocytopenia

    Severe hematologic toxicity (e.g., neutropenia, thrombocytopenia, and anemia) has been reported with acalabrutinib therapy; monitor complete blood counts regularly. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe hematologic toxicity occurs (e.g., grade 4 neutropenia lasting longer than 7 days, grade 3 thrombocytopenia with bleeding, or grade 4 thrombocytopenia).

    Fungal infection, hepatitis B exacerbation, infection, progressive multifocal leukoencephalopathy, viral infection

    Progressive multifocal leukoencephalopathy, hepatitis B exacerbation/reactivation, Epstein-Barr virus reactivation, Pneumocystis jiroveci pneumonia, and cytomegalovirus have been reported with acalabrutinib therapy. Other serious infection (e.g., bacterial infection, viral infection, and fungal infection) has occurred; some cases were fatal. Evaluate patients for signs and symptoms of infection and treat promptly. Consider infection prophylaxis in patients at risk for opportunistic infections.

    New primary malignancy, sunlight (UV) exposure

    New primary malignancy (e.g., skin cancer and other solid tumors) has been reported in patients who received acalabrutinib. Monitor patients for evidence of skin cancer. Patients should use sun protection prior to sunlight (UV) exposure during acalabrutinib therapy.

    Hepatic disease

    Avoid the use of acalabrutinib in patients with severe hepatic disease/impairment (Child-Pugh class C). No initial dosage adjustment is necessary for patients with mild or moderate impairment.

    Cardiac arrhythmias, hypertension

    Cardiac arrhythmias have been reported in patients who received acalabrutinib. Monitor patients for signs and symptoms of arrhythmias (e.g., palpitation, dizziness, syncope, or dyspnea) and manage appropriately. Patients with cardiac risk factors, hypertension, a history of arrhythmias, and acute infections may be at increased risk for developing an arrhythmia.

    Geriatric

    Grade 3 or higher adverse reactions occurred more often (68% vs. 45%) in geriatric patients 65 years and older who received acalabrutinib compared with younger patients in a clinical trials.

    Pregnancy

    Acalabrutinib may cause fetal harm and dystocia if administered during pregnancy based on data from animal studies. Females of reproductive potential should avoid pregnancy during acalabrutinib therapy. Pregnant women should be apprised of the potential hazard to the fetus. In animal studies in pregnant rats and rabbits, dystocia occurred in rats and decreased fetal body weights and delayed skeletal ossification were observed in rabbits following acalabrutinib doses that resulted in drug exposure 2-times of that reported at clinical human doses (100 mg twice daily).

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during acalabrutinib treatment. Pregnancy testing should be performed prior to starting acalabrutinib in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for at least 1 week after acalabrutinib therapy. Women who become pregnant while receiving acalabrutinib should be apprised of the potential hazard to the fetus.

    Breast-feeding

    It is not known if acalabrutinib or its active metabolite is 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 infants, women should discontinue breast-feeding during acalabrutinib therapy and for at least 2 weeks after the last dose.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 13.0-37.0
    hyperuricemia / Delayed / 0-29.0
    lymphocytosis / Delayed / 0-19.0
    infection / Delayed / 19.0-19.0
    anemia / Delayed / 8.0-15.0
    thrombocytopenia / Delayed / 3.4-12.0
    new primary malignancy / Delayed / 12.0-12.0
    elevated hepatic enzymes / Delayed / 0-7.0
    skin cancer / Delayed / 6.0-6.0
    nephrotoxicity / Delayed / 1.3-4.8
    diarrhea / Early / 0.6-4.5
    atrial fibrillation / Early / 4.1-4.1
    atrial flutter / Early / 4.1-4.1
    bleeding / Early / 0-3.1
    intracranial bleeding / Delayed / 0-3.0
    fatigue / Early / 0.8-2.2
    asthenia / Delayed / 0-2.2
    lethargy / Early / 0-2.2
    musculoskeletal pain / Early / 0-2.2
    rash / Early / 0.8-2.2
    headache / Early / 0.6-1.6
    abdominal pain / Early / 0-1.6
    vomiting / Early / 0-1.6
    hyperbilirubinemia / Delayed / 0-1.3
    arthralgia / Delayed / 0-1.1
    nausea / Early / 0-0.8
    myalgia / Early / 0-0.8
    hepatitis B exacerbation / Delayed / Incidence not known
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 0-15.0
    hypertension / Early / 0-5.0
    hematuria / Delayed / Incidence not known
    hemoptysis / Delayed / Incidence not known
    tracheitis / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known

    Mild

    dizziness / Early / 0-20.0
    ecchymosis / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known
    menorrhagia / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    back pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Coadministration of acalabrutinib and dolutegravir may increase dolutegravir exposure and increase the risk of dolutegravir toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Dolutegravir is a BCRP transporter substrate in vitro.
    Alpelisib: (Major) Avoid coadministration of alpelisib with acalabrutinib 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 acalabrutinib is a BCRP inhibitor.
    Aluminum Hydroxide: (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Amiodarone: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with amiodarone. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of acalabrutinib and clarithromycin; significantly increased acalabrutinib exposure may occur. If short-term clarithromycin use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Major) Avoid the concomitant use of acalabrutinib and omeprazole; decreased acalabrutinib exposure occurred in a drug interaction study. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with omeprazole 40 mg/day for 5 days.
    Antacids: (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Apalutamide: (Major) Avoid the concomitant use of acalabrutinib and apalutamide due to decreased plasma concentrations of acalabrutinib. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Acalabrutinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Aprepitant, Fosaprepitant: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with a multi-day regimen of aprepitant and for several days after administration of aprepitant. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate. Aprepitant is a moderate CYP3A4 inhibitor when administered as a 3-day regimen and a weak inhibitor when given as a single dose. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions; it is also a weak CYP3A4 inhibitor when administered as a single dose. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Aspirin, ASA; Omeprazole: (Major) Avoid the concomitant use of acalabrutinib and omeprazole; decreased acalabrutinib exposure occurred in a drug interaction study. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with omeprazole 40 mg/day for 5 days.
    Atazanavir: (Major) Avoid the concomitant use of acalabrutinib and atazanavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Atazanavir; Cobicistat: (Major) Avoid the concomitant use of acalabrutinib and atazanavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Major) Avoid the concomitant use of acalabrutinib and cobicistat; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the concomitant use of acalabrutinib and phenobarbital. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking acalabrutinib. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, decrease the acalabrutinib dose to 100 mg PO once daily as coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Berotralstat is a BCRP substrate and moderate CYP3A4 inhibitor; acalabrutinib is a CYP3A4 substrate and BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%; the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of acalabrutinib and tenofovir alafenamide may increase the absorption and plasma concentration of tenofovir alafenamide. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir alafenamide is a BCRP substrate.
    Calcium Carbonate: (Moderate) Separate the administration of acalabrutinib and calcium carbonate by at least 2 hours if these agents are used together; decreased acalabrutinib exposure occurred when acalabrutinib and calcium carbonate were coadministered in a drug interaction study. Acalabrutinib solubility decreases with increasing pH values. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with calcium carbonate 1 gram.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Separate the administration of acalabrutinib and calcium carbonate by at least 2 hours if these agents are used together; decreased acalabrutinib exposure occurred when acalabrutinib and calcium carbonate were coadministered in a drug interaction study. Acalabrutinib solubility decreases with increasing pH values. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with calcium carbonate 1 gram. (Moderate) Separate the administration of acalabrutinib and H2-blockers if these agents are used together; administer acalabrutinib 2 hours before the H2-blocker. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Separate the administration of acalabrutinib and calcium carbonate by at least 2 hours if these agents are used together; decreased acalabrutinib exposure occurred when acalabrutinib and calcium carbonate were coadministered in a drug interaction study. Acalabrutinib solubility decreases with increasing pH values. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with calcium carbonate 1 gram.
    Calcium Carbonate; Risedronate: (Moderate) Separate the administration of acalabrutinib and calcium carbonate by at least 2 hours if these agents are used together; decreased acalabrutinib exposure occurred when acalabrutinib and calcium carbonate were coadministered in a drug interaction study. Acalabrutinib solubility decreases with increasing pH values. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with calcium carbonate 1 gram.
    Calcium Carbonate; Simethicone: (Moderate) Separate the administration of acalabrutinib and calcium carbonate by at least 2 hours if these agents are used together; decreased acalabrutinib exposure occurred when acalabrutinib and calcium carbonate were coadministered in a drug interaction study. Acalabrutinib solubility decreases with increasing pH values. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with calcium carbonate 1 gram.
    Carbamazepine: (Major) Avoid the concomitant use of acalabrutinib and carbamazepine. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Ceritinib: (Major) Avoid the concomitant use of acalabrutinib and ceritinib; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Chloramphenicol: (Major) Avoid the concomitant use of acalabrutinib and chloramphenicol; significantly increased acalabrutinib exposure may occur. If short-term chloramphenicol use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    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.
    Cimetidine: (Moderate) Separate the administration of acalabrutinib and H2-blockers if these agents are used together; administer acalabrutinib 2 hours before the H2-blocker. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness.
    Ciprofloxacin: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with ciprofloxacin. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Clarithromycin: (Major) Avoid the concomitant use of acalabrutinib and clarithromycin; significantly increased acalabrutinib exposure may occur. If short-term clarithromycin use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Cobicistat: (Major) Avoid the concomitant use of acalabrutinib and cobicistat; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Conivaptan: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with conivaptan. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Crizotinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with crizotinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Cyclosporine: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with cyclosporine. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Danazol: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with danazol. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Darunavir: (Major) Avoid the concomitant use of acalabrutinib and darunavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Darunavir; Cobicistat: (Major) Avoid the concomitant use of acalabrutinib and cobicistat; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Major) Avoid the concomitant use of acalabrutinib and darunavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid the concomitant use of acalabrutinib and cobicistat; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Major) Avoid the concomitant use of acalabrutinib and darunavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Moderate) Coadministration of acalabrutinib and tenofovir alafenamide may increase the absorption and plasma concentration of tenofovir alafenamide. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir alafenamide is a BCRP substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of acalabrutinib and ritonavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Moderate) Coadministration of acalabrutinib and dasabuvir may increase dasabuvir exposure and increase the risk of dasabuvir toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Dasabuvir is a substrate and inhibitor of BCRP. (Moderate) Coadministration of acalabrutinib and ombitasvir, paritaprevir, ritonavir may increase the exposure and the risk of toxicity of ombitasvir, paritaprevir, ritonavir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Ombitasvir is a BCRP transporter substrate and paritaprevir is a substrate and inhibitor of BCRP.
    Delavirdine: (Major) Avoid the concomitant use of acalabrutinib and delavirdine; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Dexlansoprazole: (Major) Avoid the concomitant use of acalabrutinib and proton pump inhibitors (PPI), such as dexlansoprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with another PPI for 5 days.
    Diltiazem: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with diltiazem. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Dolutegravir: (Moderate) Coadministration of acalabrutinib and dolutegravir may increase dolutegravir exposure and increase the risk of dolutegravir toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Dolutegravir is a BCRP transporter substrate in vitro.
    Dolutegravir; Lamivudine: (Moderate) Coadministration of acalabrutinib and dolutegravir may increase dolutegravir exposure and increase the risk of dolutegravir toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Dolutegravir is a BCRP transporter substrate in vitro.
    Dolutegravir; Rilpivirine: (Moderate) Coadministration of acalabrutinib and dolutegravir may increase dolutegravir exposure and increase the risk of dolutegravir toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Dolutegravir is a BCRP transporter substrate in vitro.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of acalabrutinib and tenofovir disoproxil fumerate may increase may increase the absorption and plasma concentration of tenofovir disoproxil fumerate. Monitor patients for tenofovir-related adverse reactions and discontinue use in patients who experience an adverse reaction. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir disoproxil fumerate is a BCRP substrate.
    Dronedarone: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with dronedarone. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Duvelisib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with duvelisib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Coadministration of acalabrutinib and tenofovir disoproxil fumerate may increase may increase the absorption and plasma concentration of tenofovir disoproxil fumerate. Monitor patients for tenofovir-related adverse reactions and discontinue use in patients who experience an adverse reaction. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir disoproxil fumerate is a BCRP substrate.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of acalabrutinib and tenofovir disoproxil fumerate may increase may increase the absorption and plasma concentration of tenofovir disoproxil fumerate. Monitor patients for tenofovir-related adverse reactions and discontinue use in patients who experience an adverse reaction. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir disoproxil fumerate is a BCRP substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the concomitant use of acalabrutinib and cobicistat; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Moderate) Coadministration of acalabrutinib and tenofovir alafenamide may increase the absorption and plasma concentration of tenofovir alafenamide. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir alafenamide is a BCRP substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of acalabrutinib and cobicistat; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Moderate) Coadministration of acalabrutinib and tenofovir disoproxil fumerate may increase may increase the absorption and plasma concentration of tenofovir disoproxil fumerate. Monitor patients for tenofovir-related adverse reactions and discontinue use in patients who experience an adverse reaction. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir disoproxil fumerate is a BCRP substrate.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of acalabrutinib and tenofovir alafenamide may increase the absorption and plasma concentration of tenofovir alafenamide. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir alafenamide is a BCRP substrate.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of acalabrutinib and tenofovir disoproxil fumerate may increase may increase the absorption and plasma concentration of tenofovir disoproxil fumerate. Monitor patients for tenofovir-related adverse reactions and discontinue use in patients who experience an adverse reaction. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir disoproxil fumerate is a BCRP substrate.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of acalabrutinib and tenofovir alafenamide may increase the absorption and plasma concentration of tenofovir alafenamide. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir alafenamide is a BCRP substrate.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of acalabrutinib and tenofovir disoproxil fumerate may increase may increase the absorption and plasma concentration of tenofovir disoproxil fumerate. Monitor patients for tenofovir-related adverse reactions and discontinue use in patients who experience an adverse reaction. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir disoproxil fumerate is a BCRP substrate.
    Encorafenib: (Moderate) Coadministration of encorafenib with acalabrutinib may result in increased toxicity or decreased efficacy of acalabrutinib. Acalabrutinib 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.
    Enzalutamide: (Major) Avoid the concomitant use of acalabrutinib and enzalutamide. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure occurred in a drug interaction study. Acalabrutinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong inducer.
    Erythromycin: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with erythromycin. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Erythromycin; Sulfisoxazole: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with erythromycin. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Esomeprazole: (Major) Avoid the concomitant use of acalabrutinib and proton pump inhibitors (PPI), such as esomeprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with another PPI for 5 days.
    Famotidine: (Moderate) Separate the administration of acalabrutinib and H2-blockers if these agents are used together; administer acalabrutinib 2 hours before the H2-blocker. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness.
    Famotidine; Ibuprofen: (Moderate) Separate the administration of acalabrutinib and H2-blockers if these agents are used together; administer acalabrutinib 2 hours before the H2-blocker. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness.
    Fedratinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with fedratinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Fluconazole: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with fluconazole. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Fluvoxamine: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with fluvoxamine. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Fosamprenavir: (Major) Avoid the concomitant use of acalabrutinib and fosamprenavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Fosphenytoin: (Major) Avoid the concomitant use of acalabrutinib and fosphenytoin. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Glecaprevir; Pibrentasvir: (Moderate) Coadministration of acalabrutinib and glecaprevir may increase glecaprevir exposure and increase the risk of glecaprevir toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Glecaprevir is a substrate and inhibitor of BCRP. (Moderate) Coadministration of acalabrutinib and pibrentasvir may increase pibrentasvir exposure and increase the risk of pibrentasvir toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Pibrentasvir is a substrate and inhibitor of BCRP.
    Grapefruit juice: (Major) Avoid the concomitant use of acalabrutinib and grapefruit juice; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    H2-blockers: (Moderate) Separate the administration of acalabrutinib and H2-blockers if these agents are used together; administer acalabrutinib 2 hours before the H2-blocker. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness.
    Idelalisib: (Major) Avoid the concomitant use of acalabrutinib and idelalisib; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Imatinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with imatinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors. Additionally, acalabrutinib may increase imatinib exposure and increase the risk of imatinib toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Imatinib is a BCRP substrate.
    Indinavir: (Major) Avoid the concomitant use of acalabrutinib and indinavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Irinotecan Liposomal: (Moderate) Coadministration of acalabrutinib and irinotecan may increase irinotecan exposure and increase the risk of irinotecan toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Irinotecan is a BCRP subtrate.
    Irinotecan: (Moderate) Coadministration of acalabrutinib and irinotecan may increase irinotecan exposure and increase the risk of irinotecan toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Irinotecan is a BCRP subtrate.
    Isavuconazonium: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with isavuconazonium. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; isavuconazonium is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of acalabrutinib and rifampin. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure occurred in a drug interaction study. Acalabrutinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with rifampin 600 mg/day for 9 days.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of acalabrutinib and rifampin. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure occurred in a drug interaction study. Acalabrutinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with rifampin 600 mg/day for 9 days.
    Itraconazole: (Major) Avoid the concomitant use of acalabrutinib and itraconazole; significantly increased acalabrutinib exposure occurred in a drug interaction study. If short-term itraconazole use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with itraconazole 200 mg/day for 5 days.
    Ivosidenib: (Moderate) Monitor for loss of acalabrutinib efficacy if coadministration with ivosidenib is necessary; a dosage increase of acalabrutinib may be needed. Acalabrutinib is a sensitive CYP3A4 substrate. Ivosidenib is a CYP3A4 inducer and may reduce acalabrutinib exposure.
    Ketoconazole: (Major) Avoid the concomitant use of acalabrutinib and ketoconazole; significantly increased acalabrutinib exposure may occur. If short-term ketoconazole use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of acalabrutinib and tenofovir disoproxil fumerate may increase may increase the absorption and plasma concentration of tenofovir disoproxil fumerate. Monitor patients for tenofovir-related adverse reactions and discontinue use in patients who experience an adverse reaction. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir disoproxil fumerate is a BCRP substrate.
    Lansoprazole: (Major) Avoid the concomitant use of acalabrutinib and proton pump inhibitors (PPI), such as lansoprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with another PPI for 5 days.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid the concomitant use of acalabrutinib and clarithromycin; significantly increased acalabrutinib exposure may occur. If short-term clarithromycin use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Major) Avoid the concomitant use of acalabrutinib and proton pump inhibitors (PPI), such as lansoprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with another PPI for 5 days.
    Lansoprazole; Naproxen: (Major) Avoid the concomitant use of acalabrutinib and proton pump inhibitors (PPI), such as lansoprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with another PPI for 5 days.
    Ledipasvir; Sofosbuvir: (Moderate) Coadministration of acalabrutinib and sofosbuvir may increase the exposure and the risk of toxicity of sofosbuvir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Sofosbuvir is a BCRP transporter substrate.
    Lefamulin: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with oral lefamulin. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Letermovir: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with letermovir. Avoid concomitant use in patients also receiving cyclosporine because the magnitude of the interaction may be increased. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be like a strong CYP3A4 inhibitor.
    Lonafarnib: (Major) Avoid the concomitant use of acalabrutinib and lonafarnib; significantly increased acalabrutinib exposure may occur. If short-term lonafarnib use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Lopinavir; Ritonavir: (Major) Avoid the concomitant use of acalabrutinib and ritonavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of acalabrutinib and lumacaftor; ivacaftor. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of acalabrutinib and lumacaftor; ivacaftor. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Magnesium Hydroxide: (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Mephobarbital: (Major) Avoid the concomitant use of acalabrutinib and mephobarbital. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; mephobarbital is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Methotrexate: (Moderate) Coadministration of acalabrutinib and methotrexate may increase methotrexate exposure and increase the risk for methotrexate toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Methotrexate is a BCRP transporter substrate.
    Mifepristone: (Major) Avoid use of these drugs together if possible. Significantly increased acalabrutinib exposure may occur when mifepristone is used chronically in the treatment of hormonal conditions, such as Cushing's syndrome. If mifepristone use is unavoidable, limit the dose of acalabrutinib to 100 mg once daily and monitor closely for drug-related toxicity and need for further adjustment or interruption of acalbrutinib therapy. Acalabrutinib is a CYP3A4 substrate; mifepristone is a CYP3A4 inhibitor. Mifepristone is expected to increase the exposure of CYP3A4 substrates. Due to the slow elimination of mifepristone from the body, any drug interactions that occur may be prolonged.
    Mitotane: (Major) Avoid the concomitant use of acalabrutinib and mitotane. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Mitoxantrone: (Moderate) Coadministration of acalabrutinib and mitoxantrone may increase mitoxantrone exposure and increase the risk of mitoxantrone toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Mitoxantrone is a BCRP subtrate.
    Naproxen; Esomeprazole: (Major) Avoid the concomitant use of acalabrutinib and proton pump inhibitors (PPI), such as esomeprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with another PPI for 5 days.
    Nefazodone: (Major) Avoid the concomitant use of acalabrutinib and nefazodone; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Nelfinavir: (Major) Avoid the concomitant use of acalabrutinib and nelfinavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with netupitant. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Nicardipine: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with nicardipine. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; nicardipine is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Nilotinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with nilotinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Nizatidine: (Moderate) Separate the administration of acalabrutinib and H2-blockers if these agents are used together; administer acalabrutinib 2 hours before the H2-blocker. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of acalabrutinib and ritonavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Moderate) Coadministration of acalabrutinib and ombitasvir, paritaprevir, ritonavir may increase the exposure and the risk of toxicity of ombitasvir, paritaprevir, ritonavir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Ombitasvir is a BCRP transporter substrate and paritaprevir is a substrate and inhibitor of BCRP.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Coadministration of acalabrutinib and ombitasvir, paritaprevir, ritonavir may increase the exposure and the risk of toxicity of ombitasvir, paritaprevir, ritonavir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Ombitasvir is a BCRP transporter substrate and paritaprevir is a substrate and inhibitor of BCRP.
    Omeprazole: (Major) Avoid the concomitant use of acalabrutinib and omeprazole; decreased acalabrutinib exposure occurred in a drug interaction study. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with omeprazole 40 mg/day for 5 days.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid the concomitant use of acalabrutinib and omeprazole; decreased acalabrutinib exposure occurred in a drug interaction study. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with omeprazole 40 mg/day for 5 days.
    Omeprazole; Sodium Bicarbonate: (Major) Avoid the concomitant use of acalabrutinib and omeprazole; decreased acalabrutinib exposure occurred in a drug interaction study. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with omeprazole 40 mg/day for 5 days. (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Pantoprazole: (Major) Avoid the concomitant use of acalabrutinib and proton pump inhibitors (PPI), such as pantoprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with another PPI for 5 days.
    Pazopanib: (Moderate) Coadministration of acalabrutinib and pazopanib may increase pazopanib exposure and increase the risk of pazopanib toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Pazopanib is a BCRP substrate.
    Phenobarbital: (Major) Avoid the concomitant use of acalabrutinib and phenobarbital. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of acalabrutinib and phenobarbital. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Phenytoin: (Major) Avoid the concomitant use of acalabrutinib and phenytoin. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Posaconazole: (Major) Avoid the concomitant use of acalabrutinib and posaconazole; significantly increased acalabrutinib exposure may occur. If short-term posaconazole use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Primidone: (Major) Avoid the concomitant use of acalabrutinib and primidone. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Quinine: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with quinine. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; quinine is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Rabeprazole: (Major) Avoid the concomitant use of acalabrutinib and proton pump inhibitors (PPI), such as rabeprazole; decreased acalabrutinib exposure may occur resulting in decreased acalabrutinib effectiveness. Consider using an antacid or H2-blocker if acid suppression therapy is needed. Separate the administration of acalabrutinib and antacids by at least 2 hours; give acalabrutinib 2 hours before a H2-blocker. Acalabrutinib solubility decreases with increasing pH values. The AUC of acalabrutinib was decreased by 43% when acalabrutinib was coadministered with another PPI for 5 days.
    Ranitidine: (Moderate) Separate the administration of acalabrutinib and H2-blockers if these agents are used together; administer acalabrutinib 2 hours before the H2-blocker. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness.
    Ribociclib: (Major) Avoid the concomitant use of acalabrutinib and ribociclib; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong CYP3A inhibitor for 5 days.
    Ribociclib; Letrozole: (Major) Avoid the concomitant use of acalabrutinib and ribociclib; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong CYP3A inhibitor for 5 days.
    Rifampin: (Major) Avoid the concomitant use of acalabrutinib and rifampin. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure occurred in a drug interaction study. Acalabrutinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with rifampin 600 mg/day for 9 days.
    Rifapentine: (Major) Avoid the concomitant use of acalabrutinib and rifapentine. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure occurred in a drug interaction study. Acalabrutinib is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong inducer.
    Rimegepant: (Major) Avoid coadministration of rimegepant with acalabrutinib; concurrent use may increase rimegepant exposure. Rimegepant is a substrate of BCRP and acalabrutinib is a BCRP inhibitor.
    Ritonavir: (Major) Avoid the concomitant use of acalabrutinib and ritonavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Rosuvastatin: (Moderate) Coadministration of acalabrutinib and rosuvastatin may increase rosuvastatin exposure and increase the risk of rosuvastatin toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Rosuvastatin is a BCRP substrate.
    Rosuvastatin; Ezetimibe: (Moderate) Coadministration of acalabrutinib and rosuvastatin may increase rosuvastatin exposure and increase the risk of rosuvastatin toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Rosuvastatin is a BCRP substrate.
    Saquinavir: (Major) Avoid the concomitant use of acalabrutinib and saquinavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    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.
    Sodium Bicarbonate: (Moderate) Separate the administration of acalabrutinib and antacids by at least 2 hours if these agents are used together. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness. In healthy subjects, the AUC of acalabrutinib was decreased by 53% when acalabrutinib was coadministered with another antacid.
    Sofosbuvir: (Moderate) Coadministration of acalabrutinib and sofosbuvir may increase the exposure and the risk of toxicity of sofosbuvir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Sofosbuvir is a BCRP transporter substrate.
    Sofosbuvir; Velpatasvir: (Moderate) Coadministration of acalabrutinib and sofosbuvir may increase the exposure and the risk of toxicity of sofosbuvir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Sofosbuvir is a BCRP transporter substrate. (Moderate) Coadministration of acalabrutinib and velpatasvir may increase the exposure and the risk of toxicity of either drug. Both acalabrutinib and velpatasvir are a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter; acalabrutinib may inhibit intestinal BCRP.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Coadministration of acalabrutinib and sofosbuvir may increase the exposure and the risk of toxicity of sofosbuvir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Sofosbuvir is a BCRP transporter substrate. (Moderate) Coadministration of acalabrutinib and velpatasvir may increase the exposure and the risk of toxicity of either drug. Both acalabrutinib and velpatasvir are a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter; acalabrutinib may inhibit intestinal BCRP.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of acalabrutinib and St. Johns Wort. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; St. Johns Wort is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
    Sulfasalazine: (Moderate) Coadministration of acalabrutinib and sulfasalazine may increase sulfasalazine exposure and increase the risk of sulfasalazine toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Sulfasalazine is a BCRP subtrate.
    Talazoparib: (Major) Avoid coadministration of acalabrutinib 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 substrate and acalabrutinib is a BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure.
    Telithromycin: (Major) Avoid the concomitant use of acalabrutinib and telithromycin; significantly increased acalabrutinib exposure may occur. If short-term telithromycin use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Tenofovir Alafenamide: (Moderate) Coadministration of acalabrutinib and tenofovir alafenamide may increase the absorption and plasma concentration of tenofovir alafenamide. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir alafenamide is a BCRP substrate.
    Tenofovir Alafenamide: (Moderate) Coadministration of acalabrutinib and tenofovir alafenamide may increase the absorption and plasma concentration of tenofovir alafenamide. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir alafenamide is a BCRP substrate.
    Tenofovir, PMPA: (Moderate) Coadministration of acalabrutinib and tenofovir disoproxil fumerate may increase may increase the absorption and plasma concentration of tenofovir disoproxil fumerate. Monitor patients for tenofovir-related adverse reactions and discontinue use in patients who experience an adverse reaction. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir disoproxil fumerate is a BCRP substrate.
    Tipranavir: (Major) Avoid the concomitant use of acalabrutinib and tipranavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Topotecan: (Major) Avoid coadministration of acalabrutinib with oral topotecan due to increased topotecan exposure; acalabrutinib may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and acalabrutinib is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Trandolapril; Verapamil: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with verapamil. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Tucatinib: (Major) Avoid the concomitant use of acalabrutinib and tucatinib; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with acalabrutinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP drug transporter; acalabrutinib is a BCRP inhibitor.
    Verapamil: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with verapamil. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Voriconazole: (Major) Avoid the concomitant use of acalabrutinib and voriconazole; significantly increased acalabrutinib exposure may occur. If short-term voriconazole use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.

    PREGNANCY AND LACTATION

    Pregnancy

    Acalabrutinib may cause fetal harm and dystocia if administered during pregnancy based on data from animal studies. Females of reproductive potential should avoid pregnancy during acalabrutinib therapy. Pregnant women should be apprised of the potential hazard to the fetus. In animal studies in pregnant rats and rabbits, dystocia occurred in rats and decreased fetal body weights and delayed skeletal ossification were observed in rabbits following acalabrutinib doses that resulted in drug exposure 2-times of that reported at clinical human doses (100 mg twice daily).

    It is not known if acalabrutinib or its active metabolite is 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 infants, women should discontinue breast-feeding during acalabrutinib therapy and for at least 2 weeks after the last dose.

    MECHANISM OF ACTION

    Acalabrutinib is an irreversible Bruton tyrosine kinase (BTK) inhibitor. 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, trafficking, chemotaxis, and adhesion. Acalabrutinib and its active metabolite, ACP-5862, form 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. It has also demonstrated an inhibition of BTK-mediated activation of downstream signaling proteins CD86 and CD69. Acalabrutinib is a second generation BTK inhibitor that was designed to be more potent and selective than ibrutinib. It has a higher selectivity for BTK (IC50 greater than 1000 nM) compared with ibrutinib. Additionally, acalabrutinib does not inhibit EGFR, ITK, or TEC kinases or platelet aggregation and may have a more favorable safety profile.

    PHARMACOKINETICS

    Acalabrutinib is administered orally. It is highly (97.5%) and reversibly bound to plasma proteins with a mean blood-to-plasma ratio of 0.8 in vitro. For acalabrutinib, the geometric mean steady state volume of distribution is 101 L (coefficient of variation (CV), 52%), the geometric mean apparent oral clearance is 71 L/hour (CV, 35%), and the geometric mean terminal elimination half-life is 1 hour (CV, 59%). Acalabrutinib is metabolized via CYP3A enzymes (major pathway) and by glutathione conjugation and amide hydrolysis to a lesser extent. The major active metabolite is ACP-5862; its potency for inhibiting Bruton tyrosine kinase (BTK) is approximately 50% less than acalabrutinib. For ACP-5862, the geometric mean steady state volume of distribution is 67 L (CV, 32%), the geometric mean apparent oral clearance is 13 L/hour (CV, 42%), and the geometric mean terminal elimination half-life is 3.5 hours (CV, 24%). Acalabrutinib is eliminated primarily via feces. In healthy subjects, about 84% and 12% of the radioactivity was excreted in the feces and urine, respectively, following a single 100 mg-dose of radiolabeled acalabrutinib. Unchanged acalabrutinib accounted for less than 2% of the radiolabeled excretion product. In patients with B-cell malignancies, the BTK active site was over 95% occupied in the peripheral blood throughout the recommended dosing interval (12 hours) following the administration of acalabrutinib 100 mg twice daily.
    Affected cytochrome P450 isoenzymes or transporters: CYP3A4, BCRP, MATE1
    Acalabrutinib is metabolized primarily by CYP3A; it is a sensitive CYP3A substrate. Avoid the concomitant use of acalabrutinib with strong CYP3A inhibitors and inducers. If acalabrutinib is administered with a moderate CYP3A inhibitor, reduce the acalabrutinib dose. If coadministration with a strong CYP3A inducer is unavoidable, increase the acalabrutinib dose. In vitro, acalabrutinib is a weak inhibitor of CYP3A4/5, CYP2C8, and CYP2C9 and a weak inducer of CYP1A2, CYP2B6 and CYP3A4. The active metabolite, ACP-5862, is a weak inhibitor of CYP2C8, CYP2C9 and CYP2C19 and a weak CYP3A4 inducer. No interactions are expected with CYP450 substrates at clinically relevant concentrations based on in vitro data. Acalabrutinib and ACP-5862 are substrates of P-glycoprotein and breast cancer resistance protein (BCRP) transporters in vitro; ACP-5862 is an inhibitor of MATE1 . Coadministration with BCRP substrates (e.g., methotrexate) may increase the exposure of the BCRP substrate due to intestinal BCRP inhibition. Coadministration with MATE1 substrates (e.g., metformin) may increase the exposure of the MATE1 substrate.

    Oral Route

    The geometric mean absolute bioavailability of oral acalabrutinib is 25%. Maximum concentrations are reached at a median Tmax of 0.9 hour for acalabrutinib and 1.6 hours for the major active metabolite, ACP-5862. Acalabrutinib exhibits dose-proportionality and almost linear kinetics over a dose range of 75 mg to 250 mg in patients with B-cell malignancies. The acalabrutinib geometric mean Cmax and AUC(0-24h) values were 563 ng/mL (coefficient of variation (CV), 29%) and 1,843 ng x hour/mL (CV, 38%), respectively, following the recommended dose of acalabrutinib 100 mg twice daily. The geometric mean AUC of ACP-5862 is approximately 2- to 3-fold higher than the acalabrutinib AUC value.
    Effects of Food: In healthy volunteers, the mean AUC of acalabrutinib was not significantly different following the administration of a single 75-mg dose of acalabrutinib with a high-fat and high-calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat, and 39 grams protein) compared with the same dose administered under fasted conditions. The acalabrutinib Cmax value was decreased by 73% and the Tmax was delayed 1 to 2 hours when acalabrutinib was given with a high-fat and high-calorie meal.