Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to IMBRUVICA in 6 trials. IMBRUVICA was  administered as a single agent at 420 mg orally once daily (475 patients), as a single agent at 560 mg orally once daily [1.3 times the recommended adult dosage (174 patients)], and in combination with other drugs at 420 mg orally once daily (827 patients) in patients with B-cell malignancies. In this pooled safety population of 1,476 patients, 87% were exposed for 6 months or longer and 68% were exposed for greater than one year. The most common adverse reactions (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.

Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received IMBRUVICA in unapproved monotherapy or combination regimens.

The data described below reflect exposure to IMBRUVICA in one single-arm, open-label clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE, RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total, including n=1,133 patients exposed to IMBRUVICA). In general, patients with creatinine clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN (unless of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients with previously treated CLL/SLL. RESONATE included 386 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab. RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65 years or older and received single agent IMBRUVICA or chlorambucil. HELIOS included 574 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with BR or placebo in combination with BR. iLLUMINATE included 228 randomized patients with treatment naïve CLL/SLL who were 65 years or older or with coexisting medical conditions and received IMBRUVICA in combination with obinutuzumab or chlorambucil in combination with obinutuzumab. E1912 included 510 patients with previously untreated CLL/SLL who were 70 years or younger and received IMBRUVICA in combination with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR).

The most common adverse reactions in patients with CLL/SLL receiving IMBRUVICA (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.

Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, neutropenia, arthralgia, rash, and thrombocytopenia. Adverse reactions leading to dose reduction occurred in approximately 9% of patients.

Adverse reactions and laboratory abnormalities from Study 1102 (N=51) using single agent IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Table 

* Based on laboratory measurements per IWCLL criteria and adverse reactions.

Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%) occurred in patients.

Adverse reactions and laboratory abnormalities described below in Table 

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.

Adverse reactions and laboratory abnormalities described below in Table 

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 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.

Adverse reactions described below in Table 

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

* Includes multiple ADR terms.

<1 used for frequency above 0 and below 0.5%.

† 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.

Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and 2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was 3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo + BR.

Adverse reactions described below in Table

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

* Includes multiple ADR terms.

† Includes one event with a fatal outcome.

Adverse reactions described below in Table 

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

* Includes multiple ADR terms.

Based on laboratory measurements per IWCLL criteria.

The data described below reflect exposure to IMBRUVICA in two single-arm clinical trials (Study 1118 and the INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE), including a total of 169 patients with WM exposed to IMBRUVICA. Study 1118 included 63 patients with previously treated WM who received single agent IMBRUVICA. INNOVATE included 150 patients with treatment naïve or previously treated WM who received IMBRUVICA or placebo in combination with rituximab. The INNOVATE monotherapy arm included 31 patients with previously treated WM who received IMBRUVICA after failure of prior rituximab-containing therapy.

The most common adverse reactions in Studies 1118 and INNOVATE (≥ 20%) were neutropenia, diarrhea, bruising, thrombocytopenia, hemorrhage, musculoskeletal pain, rash, and nausea.

Five percent of patients receiving IMBRUVICA across Studies 1118 and INNOVATE discontinued treatment due to adverse reactions. The most common adverse reaction leading to discontinuation was atrial fibrillation. Adverse reactions leading to dose reduction occurred in 14% of patients.

Adverse reactions and laboratory abnormalities described below in Table 

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

* Includes multiple ADR terms.

Treatment-emergent Grade 4 thrombocytopenia (4%) and neutropenia (7%) occurred in patients.

Adverse reactions described below in Table 

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

* Includes multiple ADR terms.

† Includes one event with a fatal outcome.

Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with IR.

The data described below reflect exposure to IMBRUVICA in an open-label clinical trial (Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid therapy and required additional therapy 

The most common adverse reactions in Study 1129 (≥ 20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. Atrial fibrillation occurred in one patient (2%) which was Grade 3.

Twenty-four percent of patients receiving IMBRUVICA in Study 1129 discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients.

Adverse reactions and laboratory abnormalities described below in Table 

The system organ class and individual ADR preferred terms are sorted in descending frequency order.

* Includes multiple ADR terms.

† Includes 2 events with a fatal outcome.

Treatment-emergent Grade 4 neutropenia occurred in 2% of patients.

The safety of IMBRUVICA was evaluated in the iMAGINE study, which included 47 pediatric and young adult patients 1 year to less than 22 years of age with cGVHD after failure of one or more lines of systemic therapy. Patients age 12 years and older were treated with IMBRUVICA 420 mg orally once daily, and patients age 1 year to less than 12 years were treated with IMBRUVICA 240 mg/m

Serious adverse reactions occurred in 64% of patients who received IMBRUVICA. Serious adverse reactions in more than two patients included pneumonia, pyrexia, sepsis, and stomatitis. Fatal adverse reactions occurred in two patients who received IMBRUVICA, including sepsis and acute respiratory distress syndrome (ARDS).

Permanent discontinuation of IMBRUVICA due to an adverse reaction occurred in 23% of patients. Adverse reactions which resulted in permanent discontinuation in at least two patients included hemorrhage. Dose reductions of IMBRUVICA due to an adverse reaction occurred in 19% of patients. Adverse reactions which required dose reduction in at least two patients included stomatitis.

The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.

The system organ class and individual ADR preferred terms are sorted in descending frequency order.

* Includes multiple ADR terms.

† Includes 1 fatal outcome.

Treatment-emergent Grade 4 neutropenia occurred in 3% of patients.

Data on cardiovascular events are based on randomized controlled trials with IMBRUVICA (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm). The incidence of ventricular tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias, ventricular fibrillation, ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade 3 or greater was 0.3% versus 0% in patients treated with IMBRUVICA compared to patients in the control arm. The incidence of atrial fibrillation and atrial flutter of any grade was 8.4% versus 1.6% and for Grade 3 or greater was 4.0% versus 0.5% in patients treated with IMBRUVICA compared to patients in the control arm. In addition, the incidence of cardiac failure of any grade was 1.7% versus 0.5% and for Grade 3 or greater was 1.2% versus 0.3% in patients treated with IMBRUVICA compared to patients in the control arm.

The incidence of ischemic cerebrovascular events (cerebrovascular accidents, ischemic stroke, cerebral ischemia, and transient ischemic attack) of any grade was 1% versus 0.4% and Grade 3 or greater was 0.5% versus 0.2% in patients treated with IMBRUVICA compared to patients in the control arm, respectively.

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm), diarrhea of any grade occurred at a rate of 43% of patients treated with IMBRUVICA compared to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA-treated patients compared to the control arm, respectively. Less than 1% (0.3%) of subjects discontinued IMBRUVICA due to diarrhea compared with 0% in the control arm.

Based on data from 1,605 of these patients, the median time to first onset was 21 days (range, 0 to 708) versus 46 days (range, 0 to 492) for any grade diarrhea and 117 days (range, 3 to 414) versus 194 days (range, 11 to 325) for Grade 3 diarrhea in IMBRUVICA-treated patients compared to the control arm, respectively. Of the patients who reported diarrhea, 85% versus 89% had complete resolution, and 15% versus 11% had not reported resolution at time of analysis in IMBRUVICA-treated patients compared to the control arm, respectively. The median time from onset to resolution in IMBRUVICA-treated subjects was 7 days (range, 1 to 655) versus 4 days (range, 1 to 367) for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days (range, 1 to 56) for Grade 3 diarrhea in IMBRUVICA-treated subjects compared to the control arm, respectively.

In randomized controlled trials (n=2,115; median treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months for 958 patients in the control arm), blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with IMBRUVICA (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control arm (5% Grade 1 and < 1% Grade 2 and 3).

Based on data from 1,605 of these patients, the median time to first onset was 91 days (range, 0 to 617) versus 100 days (range, 2 to 477) in IMBRUVICA-treated patients compared to the control arm, respectively. Of the patients who reported visual disturbances, 60% versus 71% had complete resolution and 40% versus 29% had not reported resolution at the time of analysis in IMBRUVICA-treated patients compared to the control arm, respectively. The median time from onset to resolution was 37 days (range, 1 to 457) versus 26 days (range, 1 to 721) in IMBRUVICA-treated subjects compared to the control arm, respectively. 

The following adverse reactions have been identified during postapproval use of IMBRUVICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.