IMBRUVICA ® (ibrutinib) IMBRUVICA ® (ibrutinib)
Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients
with CLL/SLL (N=51) in Study 1102 (continued)
All Grades
Grade 3 or 4
Body System
Adverse Reaction
(%)
(%)
Musculoskeletal and connective tissue Musculoskeletal pain
25
6
disorders
Arthralgia
24
0
Muscle spasms
18
2
Nervous system disorders
Dizziness
20
0
Headache
18
2
Metabolism and nutrition disorders
Decreased appetite
16
2
Neoplasms benign, malignant,
Second malignancies*
12*
0
unspecified
Vascular disorders
Hypertension
16
8
* One patient death due to histiocytic sarcoma. 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
Chlorambucil
(N=135)
(N=132)
Body System
All Grades Grade 3 or 4 All Grades Grade 3 or 4
Adverse Reaction
(%)
(%)
(%)
(%)
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
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
Table 4: Treatment-Emergent* Hematologic Laboratory Abnormalities
in Patients with CLL/SLL (N=51) in Study 1102
Platelets Decreased
Neutrophils Decreased
Hemoglobin Decreased
Percent of Patients (N=51)
All Grades (%)
Grade 3 or 4 (%)
69
12
53
26
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
Ofatumumab
(N=195)
(N=191)
Body System
All Grades Grade 3 or 4 All Grades Grade 3 or 4
Adverse Reaction
(%)
(%)
(%)
(%)
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
Ofatumumab
(N=195)
(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
Chlorambucil
(N=135)
(N=132)
Body System
All Grades Grade 3 or 4 All Grades Grade 3 or 4
Adverse Reaction
(%)
(%)
(%)
(%)
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
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
All Grades Grade 3 or 4 All Grades Grade 3 or 4
Adverse Reaction
(%)
(%)
(%)
(%)
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 three single-arm open-label clinical trials (Study 1118, Study 1121, and
INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE) in patients with WM
or MZL, including a total n=307 patients overall and n=232 patients exposed to IMBRUVICA. Study
1118 included 63 patients with previously treated WM who received single agent IMBRUVICA. Study
1121 included 63 patients with previously treated MZL 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 failed prior rituximab-containing therapy and received
IMBRUVICA.
The most commonly occurring adverse reactions in Studies 1118, 1121, and INNOVATE (≥ 20%) were
thrombocytopenia, diarrhea, bruising, neutropenia, musculoskeletal pain, hemorrhage, anemia,
rash, fatigue, and nausea.
Seven percent of patients receiving IMBRUVICA across Studies 1118, 1121, and INNOVATE
discontinued treatment due to adverse reactions. The most common adverse reactions leading
to discontinuation were atrial fibrillation, interstitial lung disease, diarrhea and rash. Adverse
reactions leading to dose reduction occurred in 13% of patients.
Study 1118 and INNOVATE Monotherapy Arm: 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 and 33 months in the INNOVATE Monotherapy Arm.