IMBRUVICA ® (ibrutinib) IMBRUVICA ® (ibrutinib)
Table 14: Non-Hematologic Adverse Reactions in ≥ 10% in Patients
with MZL in Study 1121 (N=63) (continued)
Grade 3
All
Grades or Higher
(%)
(%)
Body System
Adverse Reaction
2
16
Metabolism and
Decreased appetite
0
16
nutrition disorders
Hyperuricemia
0
14
Hypoalbuminemia
0
13
Hypokalemia
Vascular disorders
Hemorrhage*
30
2 †
Hypertension*
14
5
Cough
22
2
Respiratory, thoracic
Dyspnea
21
2
and mediastinal
disorders
Nervous system
Dizziness
19
0
disorders
Headache
13
0
Psychiatric disorders
Anxiety
16
2
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.
Table 15: Treatment-Emergent Hematologic Laboratory Abnormalities
in Patients with MZL in Study 1121 (N=63)
Percent of Patients (N=63)
All Grades (%)
Grade 3 or 4 (%)
Platelets Decreased
49
6
Hemoglobin Decreased
43
13
Neutrophils Decreased
22
13
Treatment-emergent Grade 4 thrombocytopenia (3%) and neutropenia (6%)
occurred in patients.
Chronic Graft versus Host Disease: 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 commonly occurring adverse reactions in the cGVHD trial (≥ 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 the cGVHD trial
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 16
and Table 17 reflect exposure to IMBRUVICA with a median duration of 4.4
months in the cGVHD trial. Table 16: Non-Hematologic Adverse Reactions in ≥ 10% of Patients
with cGVHD (N=42) (continued)
Grade 3
All
Grades or Higher
(%)
(%)
Body System
Adverse Reaction
Respiratory, thoracic and Cough
14
0
mediastinal disorders
Dyspnea
12
2
Metabolism and
Hypokalemia
12
7
nutrition disorders
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 17: Treatment-Emergent Hematologic Laboratory Abnormalities
in Patients with cGVHD (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.
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 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.
Long-Term Safety: The safety data from long-term follow-up over 5 years of
1,178 patients (treatment-naïve CLL/SLL n=162, relapsed/refractory CLL/SLL
n=646, and relapsed/refractory MCL n=370) treated with IMBRUVICA were
analyzed. The median treatment duration for CLL/SLL was 51 months (range,
0.2 to 98 months). The median treatment duration for MCL was 11 months
(range, 0 to 87 months). The cumulative rate of hypertension increased over
time with prolonged IMBRUVICA treatment. The prevalence for Grade 3 or
greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2-3), 9%
(year 3-4), and 9% (year 4-5). The incidence for the 5-year period was 11%.
Postmarketing Experience: The following adverse reactions have been
identified during post-approval 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.
Table 16: Non-Hematologic Adverse Reactions in ≥ 10% of Patients
with cGVHD (N=42)
Grade 3
All
Grades or Higher
(%)
(%)
Body System
Adverse Reaction
12
57
Fatigue
General disorders and
5
17
Pyrexia
administration site
0
12
Edema peripheral
conditions
Skin and subcutaneous Bruising*
40
0
tissue disorders
Rash*
12
0
10
36
Gastrointestinal
Diarrhea
2
29
disorders
Stomatitis*
0
26
Nausea
0
12
Constipation
Muscle spasms
29
2
Musculoskeletal and
Musculoskeletal pain*
14
5
connective tissue
disorders
Vascular disorders
Hemorrhage*
26
0
Infections and
infestations
Nervous system
disorders
Injury, poisoning
and procedural
complications
Pneumonia*
Upper respiratory tract
infection
Sepsis*
Headache 21 14 †
19
10
17 0
10
5
Fall 17 0