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RESONATE™-2: Supporting an established safety and tolerability profile1

ARs in ≥10% of patients in the IMBRUVICA® treated arm in patients with CLL/SLL1

RESONATE™-2 Trial

Median duration of exposure was 17.4 months for IMBRUVICA® vs 7.1 months for chlorambucil1

  IMBRUVICA® (n=135) Chlorambucil (n=132)
Adverse Reaction All Grades (%) Grade 3 or Higher (%) All Grades (%) Grade 3 or Higher (%)
Gastrointestinal disorders  
Diarrhea 42 4 17 0
Nausea 22 1 39 1
Constipation 16 1 16 0
Stomatitis* 14 1 4 1
Vomiting 13 0 20 1
Abdominal pain 13 3 11 1
Dyspepsia 11 0 2 0
Musculoskeletal and connective tissue disorders  
Musculoskeletal pain* 36 4 20 0
Arthralgia 16 1 7 1
Muscle spasms 11 0 5 0
General disorders and administration site conditions  
Fatigue 30 1 38 5
Peripheral edema 19 1 9 0
Pyrexia 17 0 14 2
Respiratory, thoracic, and mediastinal disorders  
Cough 22 0 15 0
Dyspnea 10 1 10 0
Skin and subcutaneous tissue disorders  
Rash* 21 4 12 2
Bruising* 19 0 7 0
Eye disorders  
Dry eye 17 0 5 0
Lacrimation increased 13 0 6 0
Vision blurred 13 0 8 0
Visual acuity reduced 11 0 2 0
Infections and infestations  
Upper respiratory tract infection 17 2 17 2
Skin infection* 15 2 3 1
Pneumonia* 14 8 7 4
Urinary tract infections 10 1 8 1
Vascular disorders  
Hypertension* 14 4 1 0
Nervous system disorders  
Headache 12 1 10 2
Dizziness 11 0 12 1
Investigations  
Weight decreased 10 0 12 0

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

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

*

 Includes multiple ADR terms

Treatment emergent decrease in hematologic measures1

RESONATE™-2 Trial

Median duration of exposure was 17.4 months for IMBRUVICA® vs 7.1 months for chlorambucil1

  IMBRUVICA® (n=135) Chlorambucil (n=132)
Adverse Reaction All Grades (%) Grade 3 or Higher (%) All Grades (%) Grade 3 or Higher (%)
Neutrophils Decreased 55 28 67 31
Platelets Decreased 47 7 58 14
Hemoglobin Decreased 36 0 39 2

Treatment-emergent Grade 4 thrombocytopenia (1% in the IMBRUVICA® arm vs 3% in the chlorambucil arm) and neutropenia (11% in the IMBRUVICA® arm vs 12% in the chlorambucil arm) occurred in patients. 

MOST COMMON ARs ACROSS 5 YEARS (median duration of treatment: 57.1 months [range, 0.7-66 months]; n=135)2‡§

  • The most common ARs (all grades) occurring in ≥20% of patients receiving IMBRUVICA® were diarrhea (50%), fatigue (36%), cough (36%), peripheral edema (27%), pyrexia (27%), anemia (26%), nausea (26%), arthralgia (26%), upper respiratory tract infection (26%), hypertension (23%), constipation (21%), and vomiting (20%)
  • The most common ARs (grades ≥3) occurring in ≥4% of patients receiving IMBRUVICA® were neutropenia (13%), pneumonia(12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), cataract (5%), and diarrhea (4%)
5+ years follow-up data included in CLL/SLL patients from PCYC-1115 and the open-label extension study (PCYC-1116), collectively referred to as RESONATE™-2. Patients in PCYC-1115 were transferred to PCYC-1116 after IRC confirmed disease progression or a study closure, whichever occurred first.
§

One patient did not receive any doses of IMBRUVICA®

ADR=adverse drug reaction, AR=adverse reaction, CLL=chronic lymphocytic leukemia, SLL=small lymphocytic lymphoma.

References:

  1. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC. 2020.
  2. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. DOI: 10.1038/s41375-019-0602-x.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Hemorrhage: Fatal bleeding events have occurred in patients who received 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) occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA® in 27 clinical trials. Bleeding events, including bruising and petechiae, occurred in 39% of patients who received 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. Across clinical trials, 3.1% of 2,838 patients who received 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 21% of 1,476 patients who received 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: In 645 patients with B-cell malignancies who received IMBRUVICA® as a single agent, Grade 3 or 4 neutropenia occurred in 23% of patients, Grade 3 or 4 thrombocytopenia in 8% and Grade 3 or 4 anemia in 3%, based on laboratory measurements.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA®. 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 1,476 patients who received 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 occurred in 19% of 1,476 patients who received IMBRUVICA® in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 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%), occurred among the 1,476 patients who received 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®. 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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA® and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥30%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (54.5%)*, diarrhea (43.8%), fatigue (39.1%), musculoskeletal pain (38.8%), neutropenia (38.6%)*, rash (35.8%), anemia (35.0%)*, and bruising (32.0%).

The most common Grade ≥ 3 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (20.7%)*, thrombocytopenia (13.6%)*, pneumonia (8.2%), and hypertension (8.0%).

Approximately 9% (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 2.3 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 recommended IMBRUVICA® dose and monitor more frequently for adverse reactions of IMBRUVICA®.

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