Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib)
IMBRUVICA® (ibrutinib) capsules, for oral use
See package insert for Full Prescribing Information
IMBRUVICA® (ibrutinib) capsules
INDICATIONS AND USAGE
Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell
lymphoma (MCL) who have rece ived at least one prior therapy.
Accelerated approval was granted for this indication based on overall response rate. Continued
approval for this indication may be contingent upon verification of clinical benefit in confirmatory
trials [see Clinical Studies (14.1) in Full Prescribing Information].
Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic
lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2)
in Full Prescribing Information].
Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of
patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in
Full Prescribing Information].
Waldenström’s Macroglobulinemia: IMBRUVICA is indicated for the treatment of patients with
Waldenström’s macroglobulinemia (WM) [see Clinical Studies (14.3) in Full Prescribing Information].
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade
3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and
post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any
grade, including bruising and petechiae, occurred in approximately half of patients treated with
IMBRUVICA.
The mechanism for the bleeding events is not well understood.
IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant
therapies.
Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery
depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in Full
Prescribing Information].
Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or
greater infections occurred in 14% to 26% of patients. [See Adverse Reactions]. Cases of progressive
multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor
patients for fever and infections and evaluate promptly.
Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%),
thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with
IMBRUVICA.
Monitor complete blood counts monthly.
Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients
treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and
a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation.
Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset
dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and
benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in
Full Prescribing Information].
Second Primary Malignancies: Other malignancies (range, 5 to 14%) including non-skin carcinomas
(range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second
primary malignancy was non-melanoma skin cancer (range, 4 to 11 %).
Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor
patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g.
high tumor burden).
Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when
administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times
those reported in patients with MCL and 20 times those reported in patients with CLL or WM,
receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal
weights were observed at lower exposures. Advise women to avoid becoming pregnant while
taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific
Populations].
ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling:
• Hemorrhage [see Warnings and Precautions]
• Infections [see Warnings and Precautions]
• Cytopenias [see Warnings and Precautions]
• Atrial Fibrillation [see Warnings and Precautions]
• Second Primary Malignancies [see Warnings and Precautions]
• Tumor Lysis Syndrome [see Warnings and Precautions]
Because clinical trials are conducted under widely variable conditions, adverse event rates
observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
another drug and may not reflect the rates observed in practice.
Clinical Trials Experience: Mantle Cell Lymphoma: The data described below reflect exposure to
IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560
mg daily with a median treatment duration of 8.3 months.
The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea,
neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract
infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased
appetite (see Tables 1 and 2).
The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia,
abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.
Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in
creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.
Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring
at a rate of ≥ 10% are presented in Table 1.
Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients
with MCL (N=111)
System Organ Class
Gastrointestinal
disorders
Infections and
infestations
General disorders
and administrative
site conditions
Preferred Term
Diarrhea
Nausea
Constipation
Abdominal pain
Vomiting
Stomatitis
Dys pepsia
Upper respiratory tract infection
Urinary tract infection
Pneumonia
Skin infections
Sinusitis
Fatigue
Peripheral edema
Pyrexia
Asthenia
All Grades
(%)
51
31
25
24
23
17
11
34
14
14
14
13
41
35
18
14
Grade 3 or 4
(%)
5
0
0
5
0
1
0
0
3
7
5
1
5
3
1
3
Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
Mantle Cell Lymphoma (N=111) (continued)
System Organ Class
Preferred Term
Skin and
subcutaneous
tissue disorders
Musculoskeletal and
connective tissue
disorders
Respiratory, thoracic
and mediastinal
disorders
Metabolism and
nutrition disorders
Nervous system
disorders
Bruising
Rash
Petechiae
Musculoskeletal pain
Muscle spasms
Arthralgia
Dyspnea
Cough
Epistaxis
Decreased appetite
Dehydration
Dizziness
Headache
All Grades
(%)
Grade 3 or 4
(%)
30
25
11
37
14
11
27
19
11
21
12
14
13
0
3
0
1
0
0
4
0
0
2
4
0
0
Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or
Neutrophils in Patients with MCL (N=111)
Percent of Patients (N=111)
All Grades
Grade 3 or 4
(%)
(%)
57
17
47
29
41
9
Platelets Decreased
Neutrophils Decreased
Hemoglobin Decreased
* Based on laboratory measurements and adverse reactions
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: The data described below reflect exposure to IMBRUVICA in
an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a
randomized clinical trial (Study 2) that included 391 randomized patients with previously treated
CLL or SLL.
The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were
thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory
tract infection, rash, nausea, and pyrexia.
Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2 discontinued
treatment due to adverse events. These included infections, subdural hematomas and diarrhea.
Adverse events leading to dose reduction occurred in approximately 6% of patients.
Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent
IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4.
Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients
with CLL (N=48) in Study 1
All Grades
(%)
Grade 3 or 4
(%)
Diarrhea
Constipation
Nausea
Stomatitis
Vomiting
Abdominal pain
Dyspepsia
Upper respiratory tract infection
Sinusitis
Skin infection
Pneumonia
Urinary tract infection
Fatigue
Pyrexia
Peripheral edema
Asthenia
Chills
Bruising
Rash
Petechiae
Cough
Oropharyngeal pain
Dyspnea
Musculoskeletal pain
Arthralgia
Muscle spasms
Dizziness
Headache
Peripheral neuropathy
Decreased appetite
63
23
21
21
19
15
13
48
21
17
10
10
31
25
23
13
13
54
27
17
19
15
10
27
23
19
21
19
10
17
4
2
2
0
2
0
0
2
6
6
8
0
4
2
0
4
0
2
0
0
0
0
0
6
0
2
0
2
0
2
Second malignancies*
10*
0
Laceration
10
2
Anxiety
Insomnia
Hypertension
10
10
17
0
0
8
System Organ Class
Gastrointestinal
disorders
Infections and
infestations
General disorders
and administrative
site conditions
Skin and
subcutaneous
tissue disorders
Respiratory, thoracic
and mediastinal
disorders
Musculoskeletal and
connective tissue
disorders
Nervous system
disorders
Metabolism and
nutrition disorders
Neoplasms
benign, malignant,
unspecified
Injury, poisoning
and procedural
complications
Psychiatric disorders
Vascular disorders
Preferred Term
*One patient death due to histiocytic sarcoma.