Brief Summary of Prescribing Information for IMBRUVICA ® (ibrutinib)
IMBRUVICA ® (ibrutinib) capsules, for oral use
IMBRUVICA ® (ibrutinib) tablets, for oral use
INDICATIONS AND USAGE
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: IMBRUVICA is indicated for the
treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion: IMBRUVICA
is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small
lymphocytic lymphoma (SLL) with 17p deletion.
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or
higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal
bleeding, hematuria, and post procedural hemorrhage) have occurred in 3% of patients, with
fatalities occurring in 0.3% of 1,124 patients exposed to IMBRUVICA in clinical trials. Bleeding
events of any grade, including bruising and petechiae, occurred in 44% 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 and patients should be monitored for signs of bleeding.
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 (including bacterial, viral, or fungal) have occurred with
IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed
to IMBRUVICA in clinical trials [see Adverse Reactions]. Cases of progressive multifocal
leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients
treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are
at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections
and treat appropriately.
Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%),
thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients
with B-cell malignancies treated with single agent IMBRUVICA.
Monitor complete blood counts monthly.
Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA
therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3
or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA
in clinical trials. These events have occurred particularly in patients with cardiac risk factors,
hypertension, acute infections, and a previous history of cardiac arrhythmias. See Additional
Important Adverse Reactions.
Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who
develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new
onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks
and benefits of IMBRUVICA treatment and follow dose modification guidelines [see Dosage and
Administration (2.3) in Full Prescribing Information].
Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with
IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a
median time to onset of 5.9 months (range, 0.03 to 24 months).
Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive
medication throughout treatment with IMBRUVICA as appropriate.
Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have
occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second
primary malignancy was non-melanoma skin cancer (6%).
Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA
therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.
Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when
administered to a pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during
the period of organogenesis caused embryo-fetal toxicity including malformations at exposures
that were 2-20 times higher than those reported in patients with hematologic malignancies. Advise
women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of
therapy. 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 clinically significant 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]
• Cardiac Arrhythmias [see Warnings and Precautions]
• Hypertension [see Warnings and Precautions]
• Second Primary Malignancies [see Warnings and Precautions]
• Tumor Lysis Syndrome [see Warnings and Precautions]
Clinical Trials Experience: 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.
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 1 and 2.
IMBRUVICA ® (ibrutinib)
Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with
CLL/SLL (N=51) in Study 1102
Body System
Gastrointestinal disorders
Infections and infestations
General disorders and administration 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
Vascular disorders
† One patient death due to histiocytic sarcoma.
Adverse Reaction
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
Decreased appetite
Second malignancies
Hypertension
All Grades
(%)
59
22
20
20
18
14
12 Grade 3
or Higher
(%)
4
2
2
0
2
0
0
47
22
16
12
12
33
24
22
14
12
51
25
16
22
14
12
25
24
18
20
18
16
10
16 2
6
6
10
2
6
2
0
6
0
2
0
0
0
0
0
6
0
2
0
2
2
2 †
8
Table 2: 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 3 and 4
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 3: 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)
Grade 3
All
Grade 3
All
or Higher
Grades
or Higher
Grades
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 †
Infections and infestations
Upper respiratory tract infection
16
1
11
2 †
Pneumonia*
Sinusitis*
Urinary tract infection
Skin and subcutaneous tissue disorders
Rash*
Petechiae
Bruising*
Musculoskeletal and connective tissue
disorders
Musculoskeletal pain*
Arthralgia
Nervous system disorders
Headache
Dizziness
Injury, poisoning and procedural
complications
Contusion
Eye disorders
Vision blurred
15
11
10 12 †
1
4 13
6
5 10 †
0
1
24
14
12 3
0
0 13
1
1 0
0
0
28
17 2
1 18
7 1
0
14
11 1
0 6
5 0
0
11 0 3 0
10 0 3 0
Subjects with multiple events for a given adverse reaction (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
† Includes 3 events of pneumonia with fatal outcome in each arm, and 1 event of pyrexia and upper
respiratory tract infection with a fatal outcome in the ofatumumab arm.