The US Food and Drug Administration has approved the Bruton's tyrosine kinase inhibitor (BTK) ibrutinib for the treatment of patients with mantle cell lymphoma who have received at least one prior treatment, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), CLL and SLL with 17p deletion, Waldenström's macroglobulinemia (WM) and marginal zone lymphoma (MZL).
This medication is developed by Pharmacyclics LLC, a wholly owned subsidiary of AbbVie, focused on developing and commercializing innovative small molecule drugs for the treatment of cancer and immune-mediated diseases.
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Ibrutinib is a kinase inhibitor indicated for the treatment of patients with:
- Mantle cell lymphoma (MCL) who have received at least one prior therapy.
- Accelerated approval was granted for this indication based on overall response rates. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).
- Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion
- Waldenström's macroglobulinemia (WM).
- Marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.
- Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
DOSAGE AND ADMINISTRATION
- MCL and MZL: 560 mg taken orally once daily (four 140 mg capsules once daily).
- CLL/SLL and WM: 420 mg taken orally once daily (three 140 mg capsules once daily).
Capsules should be taken orally with a glass of water. Do not open, break, or chew the capsules.
DOSAGE FORMS AND STRENGTHS
Capsule: 140 mg
WARNINGS AND PRECAUTIONS
Hemorrhage - Fatal bleeding events have occurred in patients treated with ibrutinib Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with ibrutinib.
The mechanism for the bleeding events is not well understood. ibrutinib may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.
Infections - Fatal and nonfatal infections have occurred with ibrutinib therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with ibrutinib. Evaluate patients for fever and infections and treat appropriately.
Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 13%) based on laboratory measurements occurred in patients treated with single agent ibrutinib. Monitor complete blood counts monthly.
Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with ibrutinib particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of ibrutinib treatment and follow dose modification guidelines.
Hypertension - Hypertension (range, 6% to 17%) has occurred in patients treated with ibrutinib with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting ibrutinib. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.
Second Primary Malignancies - Other malignancies (range, 3% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with ibrutinib. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2% to 13%).
Tumor Lysis Syndrome - Tumor lysis syndrome has been infrequently reported with ibrutinib therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity - Based on findings in animals, ibrutinib can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking ibrutinib and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.
The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia* (61%), thrombocytopenia* (62%), diarrhea (43%), anemia* (41%), musculoskeletal pain (30%), rash (30%), nausea (29%), bruising (30%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).
*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).
The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).
The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MZL patients were pneumonia (10%), fatigue (6%), diarrhea (5%), rash (5%), and hypertension (5%).
Approximately 6%(CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), 6% (WM) and 13% (MZL) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash, and neutropenia (1% each) in CLL/SLL patients and subdural hematoma (1.8%) in MCL patients. The most common adverse reactions leading to discontinuation were interstitial lung disease, diarrhea, and rash (1.6% each) in WM and MZL patients.
CYP3A Inhibitors - Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the ibrutinib dose.
CYP3A Inducers - Avoid coadministration with strong CYP3A inducers.
Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce ibrutinib dose.
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