IMBRUVICA ® (ibrutinib)
Table 4: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients
with CLL/SLL in RESONATE
IMBRUVICA
Ofatumumab
(N=195)
(N=191)
All
Grade
All
Grade
Grades
3 or 4
Grades
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 described below in Table 5 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 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-2
IMBRUVICA
Chlorambucil
(N=135)
(N=132)
All
Grade 3
All
Grade 3
Body System
Grades
or Higher
Grades
or Higher
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
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
HELIOS: Adverse reactions described below in Table 6 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 6: 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)
Grade 3
All
Grade 3
All
or Higher
Grades
or Higher
Grades
Body System
(%)
(%)
(%)
(%)
Adverse Reaction
Blood and lymphatic system
disorders
Neutropenia*
66
61
60
56 †
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.
IMBRUVICA ® (ibrutinib)
* 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 7 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 7: Adverse Reactions Reported in at Least 10% of Patients in the IMBRUVICA Arm
in Patients with CLL/SLL in iLLUMINATE
Chlorambucil +
IMBRUVICA +
Obinutuzumab
Obinutuzumab
(N=115)
(N=113)
Grade 3
All
Grade 3
All
or Higher
Grades
or Higher
Grades
Body System
(%)
(%)
(%)
(%)
Adverse Reaction §
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
Infections and Infestations
Pneumonia*
16
9
9
4 †
Upper Respiratory Tract
14
1
6
0
Infection
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
General Disorders and Administration
Site Conditions
Pyrexia
19
2
26
1
Fatigue
18
0
17
2
Peripheral edema
12
0
7
0
Psychiatric disorders
Insomnia
12
0
4
0
§ The data are not an adequate basis for comparison of ADR rates between treatment arms.
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.
Additional Important Adverse Reactions: Cardiac Arrhythmias: In randomized controlled trials
(n=1605; median treatment duration of 14.8 months for 805 patients treated with IMBRUVICA and 5.6
months for 800 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 0.5% and of Grade 3 or greater was 0.2% versus 0% in
patients treated with IMBRUVICA compared to patients in the control arm. In addition, the incidence
of atrial fibrillation and atrial flutter of any grade was 9% versus 1.4% and for Grade 3 or greater was
4.1% versus 0.4% in patients treated with IMBRUVICA compared to patients in the control arm.
Diarrhea: In randomized controlled trials (n=1605; median treatment duration of 14.8 months
for 805 patients treated with IMBRUVICA and 5.6 months for 800 patients in the control arm),
diarrhea of any grade occurred at a rate of 39% of patients treated with IMBRUVICA compared
to 18% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA-
treated patients compared to the control arm, respectively. 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. Less than 1% of subjects discontinued IMBRUVICA due to diarrhea compared with 0%
in the control arm.
Visual Disturbance: In randomized controlled trials (n=1605; median treatment duration of 14.8
months for 805 patients treated with IMBRUVICA and 5.6 months for 800 patients in the control arm),
blurred vision and decreased visual acuity of any grade occurred in 11% of patients treated with
IMBRUVICA (10% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control arm (6%
Grade 1 and <1% Grade 2 and 3). 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