IMBRUVICA ® (ibrutinib)
IMBRUVICA ® (ibrutinib)
Table 1: Non-Hematologic Adverse Reactions in ≥ 10%
of Patients with MCL (N=111) (continued)
Body System
Adverse Reaction
Bruising
Skin and
Rash
subcutaneous
Petechiae
tissue disorders
Musculoskeletal pain
Musculoskeletal
Muscle spasms
and connective
Arthralgia
tissue disorders
Dyspnea
Respiratory,
Cough
thoracic and
Epistaxis
mediastinal
disorders
Metabolism and
Decreased appetite
nutrition disorders Dehydration
Nervous system
Dizziness
disorders
Headache
† Includes one event with a fatal outcome.
Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients
with CLL/SLL (N=51) in Study 1102
All Grades
(%)
30
25
11
37
14
11
27
19
11 Grade 3 or
Higher (%)
0
3
0
1
0
0
5 †
0
0
21
12
14
13 2
4
0
0
Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities
in Patients with MCL (N=111)
Platelets Decreased
Neutrophils Decreased
Hemoglobin Decreased
Percent of Patients (N=111)
All Grades (%)
Grade 3 or 4 (%)
57
17
47
29
41
9
* Based on laboratory measurements and adverse reactions
Treatment-emergent Grade 4 thrombocytopenia (6%) and neutropenia (13%)
occurred in patients.
Ten patients (9%) discontinued treatment due to adverse reactions in the
trial (N=111). The most frequent adverse reaction leading to treatment
discontinuation was subdural hematoma (1.8%). Adverse reactions leading
to dose reduction occurred in 14% of patients.
Patients with MCL who develop lymphocytosis greater than 400,000/mcL have
developed intracranial hemorrhage, lethargy, gait instability, and headache.
However, some of these cases were in the setting of disease progression.
Forty percent of patients had elevated uric acid levels on study including
13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was
reported for 15% of patients.
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: The data
described below reflect exposure in one single-arm, open-label clinical
trial (Study 1102) and four randomized controlled clinical trials (RESONATE,
RESONATE-2, and HELIOS, and iLLUMINATE) in patients with CLL/SLL
(n=1,506 total and n=781 patients exposed to IMBRUVICA). Patients with
creatinine clearance (CrCl) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN (upper
limit of normal), or total bilirubin ≥ 1.5x ULN (unless of non-hepatic origin)
were excluded from these trials. 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
bendamustine and rituximab or placebo in combination with bendamustine
and rituximab, and iLLUMINATE included 228 randomized patients with
treatment naïve CLL who were 65 years or older or with coexisting medical
conditions and received IMBRUVICA in combination with obinutuzumab or
chlorambucil in combination with obinutuzumab.
The most commonly occurring adverse reactions in patients with CLL/SLL
receiving IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia, anemia,
diarrhea, rash, musculoskeletal pain, bruising, nausea, fatigue, pyrexia,
hemorrhage, and cough.
Four to 10 percent of patients with CLL/SLL receiving IMBRUVICA discontinued
treatment due to adverse reactions. These included pneumonia, hemorrhage,
atrial fibrillation, rash and neutropenia. Adverse reactions leading to dose
reduction occurred in approximately 7% of patients.
Study 1102: Adverse reactions and laboratory abnormalities from the
CLL/SLL trial (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 Tables 3 and 4.
Body System
Gastrointestinal
disorders
Adverse Reaction
Diarrhea
Constipation
Nausea
Stomatitis
Vomiting
Abdominal pain
Dyspepsia
Infections and
Upper respiratory
infestations
tract infection
Sinusitis
Skin infection
Pneumonia
Urinary tract infection
General disorders and Fatigue
Pyrexia
administration site
Peripheral edema
conditions
Asthenia
Chills
Skin and subcutaneous Bruising
tissue disorders
Rash
Petechiae
Cough
Respiratory, thoracic
Oropharyngeal pain
and mediastinal
Dyspnea
disorders
Musculoskeletal pain
Musculoskeletal and
Arthralgia
connective tissue
Muscle spasms
disorders
Nervous system
Dizziness
disorders
Headache
Metabolism and
Decreased appetite
nutrition disorders
Neoplasms benign,
Second malignancies
malignant, unspecified
Vascular disorders
Hypertension
† One patient death due to histiocytic sarcoma.
All Grades Grade 3 or
(%)
Higher (%)
4
59
2
22
2
20
0
20
2
18
0
14
0
12
47
22
16
12
12
33
24
22
14
12
51
25
16
22
14
12
25
24
18
20
18
16 2
6
6
10
2
6
2
0
6
0
2
0
0
0
0
0
6
0
2
0
2
2
10 2 †
16 8
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.
Treatment-emergent Grade 4 thrombocytopenia (8%) and neutropenia (12%)
occurred in patients.
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 in the IMBRUVICA
Treated Arm in Patients with CLL/SLL in RESONATE
IMBRUVICA
Ofatumumab
(N=195)
(N=191)
Grade 3
All
Grade 3
All
Grades or Higher Grades or Higher
Body System
(%)
(%)
(%)
(%)
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
2 †