CV: hypertension, peripheral edema, atrial fibrillation/flutter, HF, SUDDEN CARDIAC DEATH, VENTRICULAR ARRHYTHMIAS.
EENT: rash.
GI: abdominal pain, constipation, ↓appetite, diarrhea, vomiting.
GU: RENAL FAILURE.
Hemat: thrombocytopenia, anemia, BLEEDING, NEUTROPENIA.
MS: musculoskeletal pain.
Neuro: fatigue, PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML), STROKE, transient ischemic attack.
Resp: dyspnea.
Misc: infection, MALIGNANCY, tumor lysis syndrome.
Drug-Drug:
- Chronic concurrent use of strong CYP3A inhibitors including clarithromycin, cobicistat, conivaptan, diltiazem, idelalisib, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, and ritonavir significantly ↑ levels and should be avoided. If short term use of strong CYP3A inhibitors is necessary, ibrutinib may be temporarily interrupted.
- Moderate CYP3A inhibitors, including aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib or verapamil↑ levels and the risk of toxicity; if concurrent therapy is necessary, ↓ ibrutinib dose in patients with mantle cell lymphoma, marginal zone lymphoma, CLL/small lymphocytic leukemia, or Waldenströms Macroglobulinemia; in patients with cGVHD, ibrutinib dose may be modified if adverse reactions develop.
- Posaconazole and voriconazole↑ levels and the risk of toxicity; if voriconazole is necessary, ↓ ibrutinib dose; if concurrent therapy with posaconazole is necessary, concurrent therapy may need to be avoided or dose of ibrutinib may need to be ↓ based on dose of posaconazole used.
- Concurrent therapy with strong CYP3A inducers, including carbamazepine, enzalutamide, phenytoin, and rifampin significantly ↓ blood levels and effectiveness and should be avoided.
- Concurrent use of antiplatelet agents or anticoagulants↑ risk of bleeding.
Natural-Natural Products:
- Concurrent use of St. John's wort↓ blood levels and effectiveness and should be avoided.
Natural-Food Products:
- Grapefruit juice or Seville oranges↑ blood levels and the risk of toxicity, avoid concurrent ingestion.
Mantle Cell Lymphoma or Marginal Zone Lymphoma
- PO (Adults): 560 mg once daily until disease progression or unacceptable toxicity; Concurrent use of moderate CYP3A inhibitors 280 mg once daily until disease progression or unacceptable toxicity; Concurrent use of posaconazole suspension (100 mg once daily, 100 mg twice daily, or 200 mg twice daily), or voriconazole 200 mg twice daily 140 mg once daily until disease progression or unacceptable toxicity; Concurrent use of posaconazole suspension (200 mg 3 times daily or 400 mg twice daily), posaconazole IV 300 mg once daily, or posaconazole delayed-release tablets 300 mg once daily 70 mg once daily until disease progression or unacceptable toxicity;Concurrent use of other strong CYP3A inhibitors Avoid concurrent use.
Hepatic Impairment
- PO (Adults): Mild hepatic impairment 140 mg once daily. Moderate hepatic impairment 70 mg once daily.
Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia or Waldenströms Macroglobulinemia
- PO (Adults): 420 mg once daily until disease progression or unacceptable toxicity; if given with rituximab or obinutuzumab, administer ibrutinib before the rituximab or obinutuzumab when given on the same day; Concurrent use of moderate CYP3A inhibitors 280 mg once daily until disease progression or unacceptable toxicity; Concurrent use of posaconazole suspension (100 mg once daily, 100 mg twice daily, or 200 mg twice daily), or voriconazole 200 mg twice daily 140 mg once daily until disease progression or unacceptable toxicity; Concurrent use of posaconazole suspension (200 mg 3 times daily or 400 mg twice daily), posaconazole IV 300 mg once daily, or posaconazole delayed-release tablets 300 mg once daily 70 mg once daily until disease progression or unacceptable toxicity;Concurrent use of other strong CYP3A inhibitors Avoid concurrent use.
Hepatic Impairment
- PO (Adults): Mild hepatic impairment 140 mg once daily. Moderate hepatic impairment 70 mg once daily.
Chronic Graft-Versus-Host Disease
- PO (Adults and Children 12 yr): 420 mg once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity; Concurrent use of moderate CYP3A inhibitors 420 mg once daily until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity; Concurrent use of posaconazole suspension (100 mg once daily, 100 mg twice daily, or 200 mg twice daily), or voriconazole 200 mg twice daily 280 mg once daily until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity; Concurrent use of posaconazole suspension (200 mg 3 times daily or 400 mg twice daily), posaconazole IV 300 mg once daily, or posaconazole delayed-release tablets 300 mg once daily 140 mg once daily until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity;Concurrent use of other strong CYP3A inhibitors Avoid concurrent use.
- PO (Children 111 yr): 240 mg/m2 (max = 420 mg) once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity (oral suspension should be used if BSA 0.7 m2; capsule, tablets, or oral suspension can be used if BSA >0.7 m2); Concurrent use of moderate CYP3A inhibitors 240 mg/m2 (max = 420 mg) once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity (oral suspension should be used if BSA 0.7 m2; capsule, tablets, or oral suspension can be used if BSA >0.7 m2); Concurrent use of voriconazole suspension 9 mg/kg twice daily 160 mg/m2 once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity (oral suspension should be used if BSA 0.7 m2; capsule, tablets, or oral suspension can be used if BSA >0.7 m2); Concurrent use of posaconazole 80 mg/m2 once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity (oral suspension should be used if BSA 0.7 m2; capsule, tablets, or oral suspension can be used if BSA >0.7 m2);Concurrent use of other strong CYP3A inhibitors Avoid concurrent use.
Hepatic Impairment
- PO (Adults and Children 12 yr): Total bilirubin level 1.513× ULN (unless due to non-hepatic cause or Gilbert's syndrome) 140 mg once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity; Total bilirubin level >3× ULN (unless due to non-hepatic cause or Gilbert's syndrome) Avoid use.
Hepatic Impairment
- (Children 111 yr): Total bilirubin level 1.513× ULN (unless due to non-hepatic cause or Gilbert's syndrome) 80 mg/m2 once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity; Total bilirubin level >3× ULN (unless due to non-hepatic cause or Gilbert's syndrome) Avoid use.
Therapeutic Classification: antineoplastics
Pharmacologic Classification: kinase inhibitors
Absorption: Well absorbed following oral administration.
Distribution: Unknown.
Protein Binding: 97.3%.
Metabolism/Excretion: Primarily metabolized by the liver via the CYP3A isoenzymes. One minor metabolite has antineoplastic activity. Metabolites are mostly eliminated in feces (80%), <10% excreted in urine.
Half-life: 46 hr.
(response)
Median time to response.