6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Hemorrhage [see Warnings and Precautions (5.1)]
Infections [see Warnings and Precautions (5.2)]
Cardiac Arrhythmias, Cardiac Failure, and Sudden Death [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Cytopenias [see Warnings and Precautions (5.5)]
Second Primary Malignancies [see Warnings and Precautions (5.6)]
Hepatotoxicity, including DILI [see Warnings and Precautions (5.7)]
Tumor Lysis Syndrome [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

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.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

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.

Study 1102

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 5 and Table 6.

Table 5: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL/SLL (N=51) in Study 1102
Body System	Adverse Reaction	All Grades (%)	Grade 3 or Higher (%)
Gastrointestinal disorders	Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia	59 22 20 20 18 14 12	4 2 2 0 2 0 0
Skin and subcutaneous tissue disorders	Bruising Rash Petechiae	51 25 16	2 0 0
Infections and infestations	Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection	47 22 16 12 12	2 6 6 10 2
General disorders and administration site conditions	Fatigue Pyrexia Peripheral edema Asthenia Chills	33 24 22 14 12	6 2 0 6 0
Musculoskeletal and connective tissue disorders	Musculoskeletal pain Arthralgia Muscle spasms	25 24 18	6 0 2
Respiratory, thoracic and mediastinal disorders	Cough Oropharyngeal pain Dyspnea	22 14 12	0 0 0
Nervous system disorders	Dizziness Headache	20 18	0 2
Vascular disorders	Hypertension	16	8
Metabolism and nutrition disorders	Decreased appetite	16	2
Neoplasms benign, malignant, unspecified	Second malignancies	10	2†

†One patient death due to histiocytic sarcoma.

Table 6: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with CLL/SLL (N=51) in Study 1102
	Percent of Patients (N=51)
	All Grades (%)	Grade 3 or 4 (%)
Platelets decreased	69	12
Neutrophils decreased	53	26
Hemoglobin decreased	43	0

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

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

RESONATE

Adverse reactions and laboratory abnormalities described below in Table 7 and Table 8 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.

Table 7: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE
Body System Adverse Reaction	IMBRUVICA (N=195)		Ofatumumab (N=191)
	All Grades (%)	Grade 3 or Higher (%)	All Grades (%)	Grade 3 or Higher (%)
Gastrointestinal disorders
Diarrhea	48	4	18	2
Nausea	26	2	18	0
Stomatitis*	17	1	6	1
Constipation	15	0	9	0
Vomiting	14	0	6	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	28	2	18	1
Arthralgia	17	1	7	0
Muscle spasms	13	0	8	0
Skin and subcutaneous tissue disorders
Rash*	24	3	13	0
Petechiae	14	0	1	0
Bruising*	12	0	1	0
General disorders and administration site conditions
Pyrexia	24	2	15	2†
Respiratory, thoracic and mediastinal disorders
Cough	19	0	23	1
Dyspnea	12	2	10	1
Infections and infestations
Upper respiratory tract infection	16	1	11	2†
Pneumonia*	15	12†	13	10†
Sinusitis*	11	1	6	0
Urinary tract infection	10	4	5	1
Nervous system disorders
Headache	14	1	6	0
Dizziness	11	0	5	0
Injury, poisoning and procedural complications
Contusion	11	0	3	0
Eye disorders
Vision blurred	10	0	3	0
The body system and 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.

Table 8: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE

	IMBRUVICA (N=195)		Ofatumumab (N=191)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Neutrophils decreased	51	23	57	26
Platelets decreased	52	5	45	10
Hemoglobin decreased	36	0	21	0

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.

RESONATE-2

Adverse reactions and laboratory abnormalities described below in Table 9 and Table 10 reflect exposure to IMBRUVICA with a median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in RESONATE-2.

Table 9: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2
Body System Adverse Reaction	IMBRUVICA (N=135)		Chlorambucil (N=132)
	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.

Table 10: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE-2
	IMBRUVICA (N=135)		Chlorambucil (N=132)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
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.

HELIOS

Adverse reactions described below in Table 11 reflect exposure to IMBRUVICA + BR with a median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in HELIOS in patients with previously treated CLL/SLL.

Table 11: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the IMBRUVICA Arm in Patients with CLL/SLL in HELIOS
Body System Adverse Reaction	IMBRUVICA + BR (N=287)		Placebo + BR (N=287)
	All Grades (%)	Grade 3 or Higher (%)	All Grades (%)	Grade 3 or Higher (%)
Blood and lymphatic system disorders
Neutropenia*	66	61	60	56†
Thrombocytopenia*	34	16	26	16
Gastrointestinal disorders
Diarrhea	36	2	23	1
Abdominal pain	12	1	8	<1
Skin and subcutaneous tissue disorders
Rash*	32	4	25	1
Bruising *	20	<1	8	<1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	29	2	20	0
Muscle spasms	12	<1	5	0
General disorders and administration site conditions
Pyrexia	25	4	22	2
Vascular disorders
Hemorrhage*	19	2†	9	1
Hypertension*	11	5	5	2
Infections and infestations
Bronchitis	13	2	10	3
Skin infection*	10	3	6	2
Metabolism and nutrition disorders
Hyperuricemia	10	2	6	0

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.

iLLUMINATE

Adverse reactions described below in Table 12 reflect exposure to IMBRUVICA + obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil + obinutuzumab with a median of 5.1 months in iLLUMINATE in patients with previously untreated CLL/SLL.

Table 12: Adverse Reactions Reported in ≥ 10% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in iLLUMINATE
Body System Adverse Reaction	IMBRUVICA + Obinutuzumab (N=113)		Chlorambucil + Obinutuzumab (N=115)
	All Grades (%)	Grade 3 or Higher (%)	All Grades (%)	Grade 3 or Higher (%)
Blood and lymphatic system disorders
Neutropenia*	48	39	64	48
Thrombocytopenia*	36	19	28	11
Anemia	17	4	25	8
Skin and subcutaneous tissue disorders
Rash*	36	3	11	0
Bruising*	32	3	3	0
Gastrointestinal disorders
Diarrhea	34	3	10	0
Constipation	16	0	12	1
Nausea	12	0	30	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	33	1	23	3
Arthralgia	22	1	10	0
Muscle spasms	13	0	6	0
Respiratory, thoracic and mediastinal disorders
Cough	27	1	12	0
Injury, poisoning and procedural complications
Infusion related reaction	25	2	58	8
Vascular disorders
Hemorrhage*	25	1	9	0
Hypertension*	17	4	4	3
General disorders and administration site conditions
Pyrexia	19	2	26	1
Fatigue	18	0	17	2
Peripheral edema	12	0	7	0
Infections and infestations
Pneumonia*	16	9	9	4†
Upper respiratory tract infection	14	1	6	0
Skin infection*	13	1	3	0
Urinary tract infection	12	3	7	1
Nasopharyngitis	12	0	3	0
Conjunctivitis	11	0	2	0
Metabolism and nutrition disorders
Hyperuricemia	13	1	0	0
Cardiac disorders
Atrial fibrillation	12	5	0	0
Psychiatric disorders
Insomnia	12	0	4	0

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.

E1912

Adverse reactions described below in Table 13 reflect exposure to IMBRUVICA + rituximab with a median duration of 34.3 months and exposure to FCR with a median of 4.7 months in E1912 in patients with previously untreated CLL/SLL who were 70 years or younger.

Table 13: Adverse Reactions Reported in ≥ 15% of Patients in the IMBRUVICA Arm in Patients with CLL/SLL in E1912
Body System Adverse Reaction	IMBRUVICA + Rituximab (N=352)		Fludarabine + Cyclophosphamide + Rituximab (N=158)
	All Grades (%)	Grade 3 or Higher (%)	All Grades (%)	Grade 3 or Higher (%)
General disorders and administration site conditions
Fatigue	80	2	78	3
Peripheral edema	28	1	17	0
Pyrexia	27	1	27	1
Pain	23	2	8	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	61	5	35	2
Arthralgia	41	5	10	1
Gastrointestinal disorders
Diarrhea	53	4	27	1
Nausea	40	1	64	1
Stomatitis*	22	1	8	1
Abdominal pain*	19	2	10	1
Vomiting	18	2	28	0
Constipation	17	0	32	0
Skin and subcutaneous tissue disorders
Rash*	49	4	29	5
Bruising*	36	1	4	1
Vascular disorders
Hypertension*	42	19	22	6
Hemorrhage*	31	2	8	1
Nervous system disorders
Headache	40	1	27	1
Dizziness	21	1	13	1
Peripheral neuropathy*	19	1	13	1
Respiratory, thoracic and mediastinal disorders
Cough	32	0	25	0
Dyspnea	22	2	21	1
Infections and infestations
Upper respiratory tract	29	1	19	2
infection
Skin infection*	16	1	3	1
Metabolism and nutrition disorders
Hyperuricemia	19	1	4	0
Decreased appetite	15	0	20	1
Psychiatric disorders
Insomnia	16	1	19	1

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

* Includes multiple ADR terms.

Table 14: Select Laboratory Abnormalities (≥ 15% Any Grade), New or Worsening from Baseline in Patients Receiving IMBRUVICA (E1912)
	IMBRUVICA + Rituximab (N=352)		Fludarabine + Cyclophosphamide + Rituximab (N=158)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology abnormalities Neutrophils decreased Platelets decreased Hemoglobin decreased	53 43 26	30 7 0	70 69 51	44 25 2
Chemistry abnormalities Creatinine increased Bilirubin increased AST increased	38 30 25	1 2 3	17 15 23	1 0 <1

Based on laboratory measurements per IWCLL criteria.

Waldenström’s Macroglobulinemia

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.

Study 1118 and INNOVATE Monotherapy Arm

Adverse reactions and laboratory abnormalities described below in Table 15 and Table 16 reflect exposure to IMBRUVICA with a median duration of 11.7 months in Study 1118 and 33 months in the INNOVATE Monotherapy Arm.

Table 15: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
Body System	Adverse Reaction	All Grades (%)	Grade 3 or Higher (%)
Gastrointestinal disorders	Diarrhea Nausea Stomatitis* Constipation Gastroesophageal reflux disease	38 21 15 12 12	2 0 0 1 0
Skin and subcutaneous tissue disorders	Bruising* Rash*	28 21	1 1
Vascular disorders	Hemorrhage* Hypertension*	28 14	0 4
General disorders and administrative site conditions	Fatigue Pyrexia	18 12	2 2
Musculoskeletal and connective tissue disorders	Musculoskeletal pain* Muscle spasms	21 19	0 0
Infections and infestations	Upper respiratory tract infection Skin infection* Sinusitis* Pneumonia*	19 18 16 13	0 3 0 5
Nervous system disorders	Headache Dizziness	14 13	0 0
Respiratory, thoracic and mediastinal disorders	Cough	13	0

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

* Includes multiple ADR terms.

Table 16: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
	Percent of Patients (N=94)
	All Grades (%)	Grade 3 or 4 (%)
Platelets Decreased	38	11
Neutrophils Decreased	43	16
Hemoglobin Decreased	21	6

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

INNOVATE

Adverse reactions described below in Table 17 reflect exposure to IMBRUVICA + R with a median duration of 25.8 months and exposure to placebo + R with a median duration of 15.5 months in patients with treatment naïve or previously treated WM in INNOVATE.

Table 17: Adverse Reactions Reported in ≥ 10% of Patients and ≥ 2% Greater in the IMBRUVICA Arm in Patients with WM in INNOVATE
Body System Adverse Reaction	IMBRUVICA + R (N=75)		Placebo + R (N=75)
	All Grades (%)	Grade 3 or Higher (%)	All Grades (%)	Grade 3 or Higher (%)
Skin and subcutaneous tissue disorders
Bruising*	37	1	5	0
Rash*	24	1	11	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	35	4	21	3
Arthralgia	24	3	11	1
Muscle spasms	17	0	12	1
Vascular disorders
Hemorrhage*	32	3	17	4†
Hypertension*	20	13	5	4
Gastrointestinal disorders
Diarrhea	28	0	15	1
Nausea	21	0	12	0
Dyspepsia	16	0	1	0
Constipation	13	1	11	1
Infections and infestations
Pneumonia*	19	13	5	3
Skin infection*	17	3	3	0
Urinary tract infection	13	0	0	0
Bronchitis	12	3	7	0
Influenza	12	0	7	1
Viral upper respiratory tract infection	11	0	7	0
General disorders and administration site conditions
Peripheral edema	17	0	12	1
Respiratory, thoracic, and mediastinal disorders
Cough	17	0	11	0
Blood and lymphatic system disorders
Neutropenia*	16	12	11	4
Cardiac disorders
Atrial fibrillation	15	12	3	1
Nervous system disorders
Dizziness	11	0	7	0
Psychiatric disorders
Insomnia	11	0	4	0
Metabolism and nutrition disorders
Hypokalemia	11	0	1	1

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.

Chronic Graft versus Host Disease

Study 1129

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 [see Clinical Studies (14.3)].

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 18 and Table 19 reflect exposure to IMBRUVICA with a median duration of 4.4 months in Study 1129.

Table 18: Non-Hematologic Adverse Reactions in ≥ 10% of Adult Patients with cGVHD in Study 1129 (N=42)
Body System	Adverse Reaction	All Grades (%)	Grade 3 or Higher (%)
General disorders and administration site conditions	Fatigue Pyrexia Edema peripheral	57 17 12	12 5 0
Skin and subcutaneous tissue disorders	Bruising* Rash*	40 12	0 0
Gastrointestinal disorders	Diarrhea Stomatitis* Nausea Constipation	36 29 26 12	10 2 0 0
Musculoskeletal and connective tissue disorders	Muscle spasms Musculoskeletal pain*	29 14	2 5
Vascular disorders	Hemorrhage*	26	0
Infections and infestations	Pneumonia* Upper respiratory tract infection Sepsis*	21 19 10	14† 0 10
Nervous system disorders	Headache	17	5
Injury, poisoning and procedural complications	Fall	17	0
Respiratory, thoracic and mediastinal disorders	Cough Dyspnea	14 12	0 2
Metabolism and nutrition disorders	Hypokalemia	12	7

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.

Table 19: Treatment-Emergent Hematologic Laboratory Abnormalities in Adult Patients with cGVHD in Study 1129 (N=42)
	Percent of Patients (N=42)
	All Grades (%)	Grade 3 or 4 (%)
Platelets decreased	33	0
Neutrophils decreased	10	10
Hemoglobin decreased	24	2

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

iMAGINE

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/m2 orally once daily [see Clinical Studies (14.3)]. The median duration of exposure to IMBRUVICA was 7.1 months (range, 0.2 to 25.9 months).

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.

Table 20 summarizes the adverse reactions in iMAGINE.

Table 20: Adverse Reactions (≥ 10%) in Patients with Previously Treated cGVHD Who Received IMBRUVICA in iMAGINE
	IMBRUVICA (N=47)
Body System Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
General disorders and administration site conditions
Pyrexia	30	11
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	30	2
Osteonecrosis	11	9
Gastrointestinal disorders
Diarrhea	28	2
Abdominal pain*	23	4
Stomatitis*	23	9
Vomiting	19	2
Nausea	19	4
Infections and infestations
Pneumonia*	23	13
Skin infection*	17	4
Sepsis*	11	9†
Nervous system disorders
Headache	21	2
Skin and subcutaneous tissue disorders
Rash*	19	2
Pruritus	13	0
Petechiae	13	0
Respiratory, thoracic and mediastinal disorders
Cough	19	2
Vascular disorders
Hemorrhage*	17	0
Hypertension*	11	4
Blood and lymphatic system disorders
Hypokalemia	15	6
Hypogammaglobulinemia*	11	0
Cardiac Disorders
Sinus tachycardia	11	0
Investigations
Alanine aminotransferase increased	11	2

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

* Includes multiple ADR terms.

† Includes 1 fatal outcome.

Table 21 summarizes the laboratory abnormalities in iMAGINE.

Table 21: Select Hematologic Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients with Previously Treated cGVHD Who Received IMBRUVICA in iMAGINE
	IMBRUVICA (N=47)
	All Grades (%)	Grade 3 or 4 (%)
Hemoglobin decreased	49	13
Platelets decreased	21	4
Neutrophils decreased	13	6

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

Additional Important Adverse Reactions

Cardiovascular Events

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.

Diarrhea

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.

Visual Disturbance

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.

6.2 Postmarketing Experience

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.

Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic cirrhosis, drug-induced liver injury
Respiratory disorders: interstitial lung disease
Metabolic and nutrition disorders: tumor lysis syndrome
Immune system disorders: anaphylactic shock, angioedema, urticaria
Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis, neutrophilic dermatoses, cutaneous vasculitis
Infections: hepatitis B reactivation
Nervous system disorders: peripheral neuropathy