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IMBRUVICA ® ( ibrutinib ) capsules
Table 4 : 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 .
RESONATE : Adverse reactions and laboratory abnormalities described below in Tables 5 and 6
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 5 : Adverse Reactions Reported in ≥ 10 % of Patients and at Least 2 % Greater in the
IMBRUVICA Treated Arm in Patients with CLL / SLL in RESONATE
IMBRUVICA ( N = 195 )
Ofatumumab ( N = 191 )
Body System Adverse Reaction
All Grades (%)
Grade 3 or 4 (%)
All Grades (%)
Grade 3 or 4 (%)
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
General disorders and administration site conditions
Pyrexia
24
2
15
1
Infections and infestations Upper respiratory tract infection
16
1
11
2
Pneumonia *
15
10
13
9
Sinusitis *
11
1
6
0
Urinary tract infection
10
4
5
1
Skin and subcutaneous tissue disorders
Rash *
24
3
13
0
Petechiae
14
0
1
0
Bruising *
12
0
1
0
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain *
28
2
18
1
Arthralgia
17
1
7
0
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
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 6 : 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
RESONATE-2 : Adverse reactions described below in Table 7 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 7 : Adverse Reactions Reported in ≥ 10 % of Patients and at Least 2 % Greater
in the IMBRUVICA Treated Arm in Patients with CLL / SLL in RESONATE-2
IMBRUVICA ( N = 135 )
Chlorambucil ( N = 132 )
Body System Adverse Reaction
All Grades (%)
Grade 3 or 4 (%)
All Grades (%)
Grade 3 or 4 (%)
Gastrointestinal disorders Diarrhea
42
4
17
0
Stomatitis *
14
1
4
1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain *
36
4
20
0
Arthralgia
16
1
7
1
Muscle spasms
11
0
5
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
Skin and subcutaneous tissue disorders
Rash *
21
4
12
2
Bruising *
19
0
7
0
Infections and infestations Skin infection *
15
2
3
1
Pneumonia *
14
8
7
4
Urinary tract infections
10
1
8
1
IMBRUVICA ® ( ibrutinib ) capsules
Table 7 : Adverse Reactions Reported in ≥ 10 % of Patients and at Least 2 % Greater
in the IMBRUVICA Treated Arm in Patients with CLL / SLL in RESONATE-2 ( continued )
IMBRUVICA ( N = 135 )
Chlorambucil ( N = 132 )
Body System Adverse Reaction
All Grades (%)
Grade 3 or 4 (%)
All Grades (%)
Grade 3 or 4 (%)
Respiratory , thoracic and mediastinal disorders
Cough
22
0
15
0
General disorders and administration site conditions
Peripheral edema
19
1
9
0
Pyrexia
17
0
14
2
Vascular Disorders Hypertension *
14
4
1
0
Nervous System Disorders Headache
12
1
10
2
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
HELIOS : Adverse reactions described below in Table 8 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 8 : Adverse Reactions Reported in at Least 10 % of Patients and at Least 2 % Greater in the IMBRUVICA Arm in Patients with CLL / SLL in HELIOS
Ibrutinib + BR Placebo + BR
( N = 287 ) ( N = 287 )
Body System Adverse Reaction
All Grades (%)
Grade 3 or 4 (%)
All Grades (%)
Grade 3 or 4 (%)
Blood and lymphatic system disorders
Neutropenia *
66
61
60
55
Thrombocytopenia *
34
16
26
16
Skin and subcutaneous tissue disorders
Rash *
32
4
25
1
Bruising *
20
< 1
8
< 1
Gastrointestinal disorders Diarrhea
36
2
23
1
Abdominal Pain
12
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 %
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 .
Waldenström ’ s Macroglobulinemia and Marginal Zone Lymphoma : The data described below reflect
exposure to IMBRUVICA in open-label clinical trials that included 63 patients with previously
treated WM ( Study 1118 ) and 63 patients with previously treated MZL ( Study 1121 ).
The most commonly occurring adverse reactions in Studies 1118 and 1121 ( ≥ 20 %) were
thrombocytopenia , diarrhea , neutropenia , fatigue , bruising , hemorrhage , anemia , rash , musculoskeletal
pain , and nausea .
Nine percent of patients receiving IMBRUVICA across Studies 1118 and 1121 discontinued treatment
due to adverse reactions . The most common adverse reactions leading to discontinuation were
interstitial lung disease , diarrhea and rash . Adverse reactions leading to dose reduction occurred
in 10 % of patients .
Study 1118 : Adverse reactions and laboratory abnormalities described below in Tables 9 and 10
reflect exposure to IMBRUVICA with a median duration of 11.7 months in Study 1118 .
Table 9 : Non-Hematologic Adverse Reactions in ≥ 10 %
in Patients with WM in Study 1118 ( N = 63 )
Body System
Adverse Reaction
All Grades (%)
Grade 3 or 4 (%)
Gastrointestinal disorders
Skin and subcutaneous tissue disorders
General disorders and administrative site conditions
Musculoskeletal and connective tissue disorders
Diarrhea Nausea Stomatitis * Gastroesophageal reflux disease
Rash * Bruising * Pruritus
37 21 16 13
22 16 11
Fatigue 21 0
Muscle spasms Arthropathy
21 13
0 0 0 0
0 0 0
0 0