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ADRs in CLL/SLL Trials

IMBRUVICA® has an established safety profile in CLL/SLL1

  • The most commonly occurring adverse reactions in patients with CLL/SLL receiving IMBRUVICA (≥20%) were neutropenia, thrombocytopenia, anemia, diarrhea, rash, musculoskeletal pain, bruising, nausea, fatigue, pyrexia, hemorrhage, and cough

IMBRUVICA® safety and tolerability data in the RESONATE™-2 trial1

  • Results from the primary analysis based on a median of 18.4 months of follow-up2

 
adverse_reactions_resonate2 
 

 Subjects with multiple events for a given ADR term are counted once only for each ADR term.

 Individual ADR terms are sorted in descending frequency order in the IMBRUVICA® arm.

*Includes multiple ADR terms.

  • ARs ≥15% were primarily grade 1/2 in frontline CLL/SLL patients ≥65 years1

Long-term safety3

The long-term safety data over 4 years from 330 patients with CLL/SLL (from RESONATE™ and RESONATE™-2) treated with IMBRUVICA® were analyzed. The median treatment duration was 46 months, with 74% and 40% of patients receiving treatment for more than 2 and 4 years, respectively.

Prevalence trends for adverse events were assessed based on IMBRUVICA® treatment duration by yearly intervals and generally decreased or remained stable over time except for hypertension.

The prevalence of hypertension (all grades) increased and was reported as 11% (year 0-1), 14% (year 1-2), 20% (year 2-3), and 21% (year 3-4), with overall incidence being 22% (years 0-4). The prevalence of hypertension grade ≥3 remained stable and was reported as 4% (year 0-1), 6% (year 1-2), 4% (year 2-3), and 4% (year 3-4), with overall incidence being 8% (years 0-4).

The long-term safety follow-up results are not included in the Prescribing Information for IMBRUVICA®.

‡RESONATE™ is a randomized, multicenter, open-label, phase 3 study with previously treated CLL/SLL patients.1

Established safety profile in the iLLUMINATE™ trial1

 
Adverse reactions from the RESONATE™ trial 

*Includes multiple ADR terms.

Includes one event with a fatal outcome.

 Individual ADR terms are sorted in descending frequency order in the IMBRUVICA® arm.

 Data are not an adequate basis for comparison of ADR rates between treatment arms.

Non-hematologic ARs in previously treated CLL/SLL patients in the RESONATE™ trial1

Adverse reactions from the RESONATE™ trial 

 Subjects with multiple events for a given adverse reaction (ADR) term are counted once only for each ADR term.

 Individual ADR terms are sorted in descending frequency order in the IMBRUVICA® arm.

*Includes multiple ADR terms.

†Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper respiratory tract infection with a fatal outcome in the ofatumumab arm.

Treatment-emergent decrease in hematologic measures in the RESONATE™ trial1

Adverse reactions from the Phase 1b/2 trial 

Treatment-emergent Grade 4 thrombocytopenia (2% in the IMBRUVICA® arm vs 3% in the ofatumumab arm) and neutropenia (8% in the IMBRUVICA® arm vs 8% in the ofatumumab arm) occurred in patients.1

Long-term safety3

The long-term safety data over 4 years from 330 patients with CLL/SLL (from RESONATE™ and RESONATE™-2) treated with IMBRUVICA® were analyzed. The median treatment duration was 46 months, with 74% and 40% of patients receiving treatment for more than 2 and 4 years, respectively.

Prevalence trends for adverse events were assessed based on IMBRUVICA® treatment duration by yearly intervals and generally decreased or remained stable over time except for hypertension.

The prevalence of hypertension (all grades) increased and was reported as 11% (year 0-1), 14% (year 1-2), 20% (year 2-3), and 21% (year 3-4), with overall incidence being 22% (years 0-4). The prevalence of hypertension grade ≥3 remained stable and was reported as 4% (year 0-1), 6% (year 1-2), 4% (year 2-3), and 4% (year 3-4), with overall incidence being 8% (years 0-4).

The long-term safety follow-up results are not included in the Prescribing Information for IMBRUVICA®.

‡RESONATE™-2 is a randomized, multicenter, open-label, phase 3 study with treatment-naïve CLL/SLL patients.

ARs in relapsed/refractory CLL/SLL patients in the HELIOS trial1

Non-hematologic adverse reactions from the Phase 1b/2 trial

*Includes multiple ADR terms.

Includes 2 events of hemorrhage with fatal outcome in the IMBRUVICA® arm and 1 event of neutropenia with a fatal outcome in the placebo + BR arm.

 The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA® arm.

 <1 used for frequency above 0 and below 0.5%

Discontinuation and dose reduction rates in the CLL/SLL registration studies1

The data below are pooled from 4 randomized controlled clinical trials (RESONATE™, RESONATE™-2, HELIOS, and iLLUMINATE™) and 1 single-arm, open-label clinical trial (Study 1102) in patients with CLL/SLL (N=1506 total and n=781 patients exposed to IMBRUVICA®)

  • 4% to 10% of patients discontinued due to ARs

    • ARs leading to discontinuation included pneumonia, hemorrhage, atrial fibrillation, rash, and neutropenia

  • Approximately 7% of patients had a dose reduction due to ARs

ADR=adverse drug reaction, AR=adverse reaction, BR=bendamustine and rituximab, CI=confidence interval, CLL=chronic lymphocytic leukemia, ECOG=Eastern Cooperative Oncology Group, HR=hazard ratio, IGHV=immunoglobulin heavy-chain variable, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, ORR=overall response rate, PFS=progression-free survival, SLL=small lymphocytic lymphoma, ULN=upper limit of normal.

 
 
 

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IMBRUVICA® (ibrutinib) is now approved in a new
formulation as one pill, once daily.

As of May 15, 2018, the original 140 mg capsules will no longer be available.
Every IMBRUVICA® patient will need a new prescription for the new pill.

Learn More
05/18 PRC-04135
References: 1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC. 2019. 2. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. 3. 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 1,124 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 1,124 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: Modify IMBRUVICA® dose as described 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).

  • CLL/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.


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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).

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