IMBRUVICA® (Ibrutinib) 560, 420, 280, 140 mg tablets | 140, 70 mg capsule Logo
IMBRUVICA® (Ibrutinib) 560, 420, 280, 140 mg tablets | 140, 70 mg capsule || 70mg/mL oral suspension Logo
Chronic Lymphocytic Leukemia (Adult Patients) Previously Treated Mantle Cell Lymphoma* (Adult Patients) Waldenström's Macroglobulinemia (Adult Patients) Previously Treated Marginal Zone Lymphoma* (Adult Patients) Previously Treated Chronic Graft Versus Host Disease (Adult and Pediatric Patients Age 1 Year and Older)
*

The MCL and MZL indications are approved under accelerated approval based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

RESONATE™: IMBRUVICA® for relapsed/refractory CLL/SLL

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RESONATE™ Study Design1,2

Phase 3, multicenter, open-label trial of previously treated CLL/SLL (N=391). Patients with del 17p were included (n=127). Patients were randomized 1:1 to IMBRUVICA® 420 mg once daily until disease progression or unacceptable toxicity (n=195) or IV ofatumumab for up to 12 doses (n=196). Patients on ofatumumab were able to cross over to IMBRUVICA® upon disease progression. Progression-free survival was the primary endpoint. Overall response rate and overall survival were secondary endpoints. 

RESONATE™: Prolonged progression-free survival in monotherapy for previously treated patients1

Primary endpoint: PFS with IMBRUVICA® vs ofatumumab1,2

  • Primary analysis with a median IRC-assessed follow-up of 9.4 months1,2

78% statistically significant reduction in risk of progression or death1,2

88% of patients estimated to be progression-free and alive at 6 months with IMBRUVICA® vs 65% of patients estimated to be progression-free and alive at 6 months with ofatumumab
  • Median PFS not reached for IMBRUVICA® vs 8.1 months (95% CI: 7.2, 8.3) with ofatumumab1,2

Long-term follow-up analysis: Investigator-assessed median PFS with an overall follow-up of 63 months1,3

Investigator-assessed long-term follow-up of risk of disease progression or death3

Investigator-assessed long-term follow-up of risk of disease progression or death
  • Median time on study was 56 months (range, 0.1 to 63 months)3
  • 44.1 months in the IMBRUVICA® arm (95% CI: 38.5, 56.9)1
  • 8.1 months in the ofatumumab arm (95% CI: 7.8, 8.3)1

 

The timing for long-term follow-up was not prespecified and the analysis was descriptive in nature.

Ibrutinib was superior to ofatumumab in difficult-to-treat patients with relapsed or refractory CLL or SLL, as measured by progression-free survival, overall survival, and response.2

Byrd, et al. N Engl J Med. 2014;371(3):213-223.

Addressing the treatment gap in high-risk del 17p CLL/SLL

Frequency of del 17p increases with line of therapy4-11

 

Up to 10% Frontline CLL/SLL patients. Up to 50% Previously treated CLL/SLL patients

Del 17p is a strong genetic predictor of poor outcomes4

Rapid disease progression Reduced survival
Patients with del 17p have a median PFS <1 year from diagnosis vs >4 years for all other CLL/SLL patients with normal cytogenetics9 Patients with del 17p have a median OS <3 years from diagnosis vs >9 years for all other CLL/SLL patients with normal cytogenetics9

Results from an independent, prospective, single-center, observational analysis of patients with CLL (N=325). The primary endpoint was survival from the time of diagnosis based on mutation status (high-risk cytogenetics included del 17p, del 11q, or 12q trisomy). Median follow-up was 70 months.9 (Note: This was not an IMBRUVICA® study.)

Prolonged progression-free survival in previously treated patients with del 17p1

Primary analysis for del 17p subgroup: IRC-assessed PFS with IMBRUVICA® vs ofatumumab with a median follow-up of 9.7 months1,3

75% reduction in risk of disease progression or death1-3

83% of patients estimated to be progression-free and alive at 6 months with IMBRUVICA® vs of patients estimated to be progression-free and alive at 6 months with ofatumumab

PFS results for IMBRUVICA® (n=63) vs ofatumumab (n=64) in the del 17p subset of RESONATE™ patients1

  • Median PFS not reached for IMBRUVICA® vs 5.8 months (95% Cl: 5.3, 7.9) with ofatumumab1

Long-term follow-up analysis for del 17p subgroup: Investigator-assessed PFS with an overall follow-up of 63 months per iwCLL criteria1-3

Investigator-assessed long-term follow-up of risk of disease progression or death3

Investigator-assessed long-term follow-up of risk of disease progression or death

Investigator-assessed median PFS in patients with del 17p per iwCLL criteria1,3,5,12

  • Median time on study was 56 months (range, 0.1 to 63 months)3
  • 40.6 months in the IMBRUVICA® arm (95% CI: 25.4, 44.6)1
  • 6.2 months in the ofatumumab arm (95% CI: 4.6, 8.1)1

The timing for long-term follow-up was not prespecified and the analysis was descriptive in nature.

 

CI=confidence interval, CLL=chronic lymphocytic leukemia, del=deletion, HR=hazard ratio, IRC=independent review committee, iwCLL=International Workshop on Chronic Lymphocytic Leukemia, OS=overall survival, PFS=progression-free survival, SLL=small lymphocytic lymphoma.

RESONATE™: Study Design RESONATE™: Overall Response Rate

References:

  1. IMBRUVICA® (ibrutinib) Prescribing Information.
  2. Byrd JC, Brown JR, O’Brien S, et al. lbrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
  3. Data on file. Pharmacyclics LLC.
  4. Schnaiter A, Stilgenbauer S. 17p deletion in chronic lymphocytic leukemia: risk stratification and therapeutic approach. Hematol Oncol Clin North Am. 2013;27(2):289-301.
  5. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute—Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
  6. Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup phase III trial E2997. J Clin Oncol. 2007;25(7):799-804.
  7. Stilgenbauer S, Zenz T, Winkler D, et al. Genomic aberrations, VH mutation status and outcome after fludarabine and cyclophosphamide (FC) of FC plus rituximab (FCR) in the CLL8 trial. Presented at: 50th Annual ASH Meeting; December 6-9, 2008; San Francisco, CA. Abstract 781.
  8. Stilgenbauer S, Kröber A, Busch R, et al. 17p deletion predicts for inferior overall survival after fludarabine-based first line therapy in chronic lymphocytic leukemia: first analysis of genetics in the CLL4 trial of the GCLLSG. In: Blood (ASH Annual Meeting Abstracts). 2005;106(11):Abstract 715.
  9. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910-1916.
  10. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103(9):3278-3281.
  11. Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2009;27(24):3994-4001.
  12. Hallek M, Cheson BD, Catovsky D, et al. Response assessment in chronic lymphocytic leukemia treated with novel agents causing an increase of peripheral blood lymphocytes (e-Letter). Blood. 2012;119(23):5348.

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 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA® in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA®, respectively.

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.

Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA®. Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received IMBRUVICA® in clinical trials, including in patients who received IMBRUVICA® in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events.

Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was reported in 1.3% of 4,896 patients who received IMBRUVICA® in clinical trials, including in patients who received IMBRUVICA® in unapproved monotherapy or combination regimens. These events have occurred particularly in patients with cardiac risk factors including hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients with acute infections.

Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines, and consider the risks and benefits of continued IMBRUVICA® treatment.

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®, initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA® as appropriate, and follow dosage modification guidelines for Grade 3 or higher hypertension.

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 2.8%, based on laboratory measurements. Monitor complete blood counts monthly.

Second Primary Malignancies: Other malignancies (10%), including non-skin carcinomas (3.9%), 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 adult 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 adult 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 adult 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 adult or pediatric patients with cGVHD were fatigue (57%), anemia (49%)*, bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, musculoskeletal pain (30%), pyrexia (30%), muscle spasms (29%), stomatitis (29%), hemorrhage (26%), nausea (26%), abdominal pain (23%), pneumonia (23%), and headache (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in adult or pediatric patients with cGVHD were pneumonia (14%), anemia (13%)*, fatigue (12%), pyrexia (11%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), osteonecrosis (9%), stomatitis (9%), hypokalemia (7%), headache (5%), and musculoskeletal pain (5%).

Discontinuation of IMBRUVICA® treatment due to an adverse reaction occurred in 24% of adult patients and 23% of pediatric patients. Adverse reactions leading to dose reduction occurred in 26% of adult patients and 19% of pediatric 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. Increased ibrutinib concentrations may increase the risk of drug-related toxicity. Dose modifications of IMBRUVICA® are 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). Avoid grapefruit and Seville oranges during IMBRUVICA® treatment, as these contain strong or moderate inhibitors of CYP3A. See dose modification guidelines in USPI sections 2.3 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Pediatric Use: The safety and effectiveness of IMBRUVICA® have not been established for the treatment of cGVHD after failure of one or more lines of therapy in pediatric patients less than 1 year of age. The safety and effectiveness of IMBRUVICA® in pediatric patients have not been established in MCL, CLL/SLL, CLL/SLL with 17p deletion, WM, MZL or in patients with mature B-cell non-Hodgkin lymphoma.

In the randomized population from a study that included 35 patients (26 pediatric patients age 5 to less than 17 years) with previously treated mature B-cell non-Hodgkin lymphoma, major hemorrhage and discontinuation of chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm.

Hepatic Impairment:

Adult Patients with B-cell Malignancies: Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with severe hepatic impairment. In patients with mild or moderate impairment, reduce recommended IMBRUVICA® dose and monitor more frequently for adverse reactions of IMBRUVICA®.

Patients with cGVHD: Avoid use of IMBRUVICA® in patients with total bilirubin level > 3x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering IMBRUVICA® to patients with total bilirubin level > 1.5 to 3x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).

Please see full Prescribing Information.

 

INDICATIONS

IMBRUVICA® is a kinase inhibitor indicated for the treatment of:

  • Adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.
    • This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  • Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).
  • Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion.
  • Adult patients with Waldenström's macroglobulinemia (WM).
  • Adult patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.
    • This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
  • Adult and pediatric patients age 1 year and older with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

IMPORTANT SAFETY INFORMATION

INDICATIONS

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