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Chronic Lymphocytic Leukimia Previously Treated Mantle Cell Lymphoma Waldenstrom's Macroglobulinemia Previously Treated Marginal Zone Lymphoma Previously Treated Chronic Graft Versus Host Disease
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Hemorrhage

Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA® in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA® increases the risk of major hemorrhage. In IMBRUVICA® clinical trials, 3.1% of patients taking IMBRUVICA® without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA®. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA® in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias

Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA®.

Monitor complete blood counts monthly.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA® therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA® in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA® treatment and follow dose modification guidelines.

Hypertension

Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA® in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA® and initiate or adjust antihypertensive medication throughout treatment with IMBRUVICA® as appropriate.

Second Primary Malignancies

Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA® in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome

Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA® 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.

Efficacy: Duration of Response Safety: Adverse Reactions

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA® in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA® increases the risk of major hemorrhage. In IMBRUVICA® clinical trials, 3.1% of patients taking IMBRUVICA® without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA®. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA® in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA®.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA® therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA® in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA® treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA® in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA® and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA® as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA® in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA® 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.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%),
stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA® in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA® with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA® may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA® if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA® dose.

Please see full Prescribing Information.

INDICATIONS

IMBRUVICA® (ibrutinib) is a kinase inhibitor indicated for the treatment of adult 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 rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
  • 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.
  • Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

IMPORTANT SAFETY INFORMATION

INDICATIONS

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