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 Waldenström’s 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 Waldenström’s 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 1–11 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 1.51–3× 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 1–11 yr): Total bilirubin level 1.51–3× 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: 4–6 hr.
(response)
†Median time to response.
