Approved for treatment-naïve and previously treated patients

iNNOVATE™: STUDIED THE EFFICACY AND SAFETY OF IMBRUVICA® + RITUXIMAB VS RITUXIMAB MONOTHERAPY IN WM1

phase-three-innovate-trial-chart 
THE iNNOVATE™ TRIAL IS THE FIRST AND LARGEST PHASE 3 STUDY LEADING TO FDA APPROVAL IN COMBINATION FOR WM1 
IgM=immunoglobulin M, IRC=independent review committee, PFS=progression-free survival, WM=Waldenström’s macroglobulinemia.

IMBRUVICA® + RITUXIMAB SIGNIFICANTLY PROLONGED PROGRESSION-FREE SURVIVAL VS RITUXIMAB MONOTHERAPY1

  • Median follow-up was 26.5 months1
80%
statistically significant reduction in risk of progression or death with IMBRUVICA® + rituximab vs rituximab monotherapy1
HR=0.20 (95% CI: 0.11, 0.38); P<0.0001*
82%
of patients estimated to be progression-free at 30 months with IMBRUVICA® + rituximab vs 28% with rituximab monotherapy2
*P-value is from log-rank test stratified by WM IPSS (low, medium, high) and number of prior systemic treatment regimens (0, ≥1).1
CI=confidence interval, HR=hazard ratio, NE=not evaluable, PFS=progression-free survival, WM IPSS=International Prognostic Scoring System for Waldenström’s macroglobulinemia.

ADDING IMBRUVICA® TO RITUXIMAB SIGNIFICANTLY IMPROVED RESPONSE VS RITUXIMAB MONOTHERAPY1

  • Response rate was defined as partial response (PR) + very good partial response (VGPR) + complete response (CR)1
  • Observed minor response (MR) rates of 20% in the IMBRUVICA® + rituximab arm and 15% in the rituximab monotherapy arm were not included in the response rate calculation2
    • MR was defined as at least 25% but less than 50% reduction of serum IgM from baseline3
CR=complete response, IgM=immunoglobulin M, MR=minor response, PR=partial response, RR=response rate, VGPR=very good partial response.
  • Median follow-up was 26.5 months1
  • Only patients who demonstrated at least a partial response ongoing at 24 weeks were included in the duration of response analysis2
NE=not evaluable

ESTABLISHED SAFETY PROFILE IN WM1

The body system and individual ADR preferred terms are sorted in descending frequency order.
*Includes multiple ADR terms.

ADR=adverse drug reaction.

  • The rate of discontinuation due to adverse reactions was 5% with IMBRUVICA® + rituximab vs 4% with placebo + rituximab2
    • ARs leading to IMBRUVICA® discontinuation were reported in 4 patients: atrial fibrillation (3 patients), rash macular, and interstitial lung disease (1 patient each) (1 patient was reported with both atrial fibrillation and rash macular)4
  • 16% of patients had a dose reduction of IMBRUVICA® due to adverse drug reactions4

References: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC. 2018. 2. Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia. N Engl J Med. 2018;378(25):2399-2410.  3. Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia. N Engl J Med. 2018;378(25)(suppl):2399-2410. 4. Data on file. Pharmacyclics LLC.

 

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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA® in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood.

IMBRUVICA® 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 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 1,011 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 1,011 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 has occurred in 12% of 1,011 patients treated with IMBRUVICA® in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA®. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 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%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), 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 (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (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%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (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 and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustments may be recommended.

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.

Indication

IMBRUVICA® (ibrutinib) is a kinase inhibitor indicated for the treatment of adult patients with:

  • Waldenström's macroglobulinemia (WM).


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IMBRUVICA® (ibrutinib) is covered by U.S. Patents, which are listed in FDA's Orange Book (available at https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm).

© Pharmacyclics LLC 2018

© Janssen Biotech, Inc. 2018

08/18 PRC-04368