Brief Summary of Prescribing Information for IMBRUVICA ® (ibrutinib)
IMBRUVICA ® (ibrutinib) capsules, for oral use
IMBRUVICA ® (ibrutinib) tablets, for oral use
INDICATIONS AND USAGE
Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of adult patients with mantle cell
lymphoma (MCL) who have received 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 and description of clinical benefit in
a confirmatory trial [see Clinical Studies (14.1) in Full Prescribing Information].
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.
Waldenström’s Macroglobulinemia: IMBRUVICA is indicated for the treatment of adult patients
with Waldenström’s macroglobulinemia (WM).
Marginal Zone Lymphoma: IMBRUVICA is indicated for the treatment of adult patients with marginal
zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-
based therapy.
Accelerated approval was granted for this indication based on overall response rate [see Clinical
Studies (14.4) in Full Prescribing Information]. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in a confirmatory trial.
Chronic Graft versus Host Disease: IMBRUVICA is indicated for the treatment of adult patients with
chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.
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 1,011 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 1,011 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 1,011 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 has occurred in 12% of 1,011 patients treated with IMBRUVICA in
clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for
new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.
Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as
appropriate.
Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have
occurred in 1,011 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 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.
Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial
(Study 1104) 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.
IMBRUVICA ® (ibrutinib)
Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111)
Adverse
All Grades
Grade 3 or 4
Body System
Reaction
(%)
(%)
Gastrointestinal disorders
Diarrhea
51
5
Nausea
31
0
Constipation
25
0
Abdominal pain
24
5
Vomiting
23
0
Stomatitis
17
1
Dyspepsia
11
0
Infections and infestations
Upper respiratory tract
34
0
infection
Urinary tract infection
14
3
Pneumonia
14
7
Skin infections
14
5
Sinusitis
13
1
General disorders and administration
Fatigue
41
5
site conditions
Peripheral edema
35
3
Pyrexia
18
1
Asthenia
14
3
Skin and subcutaneous tissue disorders Bruising
30
0
Rash
25
3
Petechiae
11
0
Musculoskeletal and connective tissue Musculoskeletal pain
37
1
disorders
Muscle spasms
14
0
Arthralgia
11
0
Respiratory, thoracic and mediastinal
Dyspnea
27
4
disorders
Cough
19
0
Epistaxis
11
0
Metabolism and nutrition disorders
Decreased appetite
21
2
Dehydration
12
4
Nervous system disorders
Dizziness
14
0
Headache
13
0
Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities
in Patients with MCL (N=111)
Percent of Patients (N=111)
All Grades
Grade 3 or 4
(%)
(%)
Platelets Decreased
57
17
Neutrophils Decreased
47
29
Hemoglobin Decreased
41
9
* 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/Small Lymphocytic Lymphoma: The data described below reflect
exposure in one single-arm, open-label clinical trial (Study 1102) and three randomized controlled
clinical trials (RESONATE, RESONATE-2, and HELIOS) in patients with CLL/SLL (n=1278 total and
n=668 patients exposed to IMBRUVICA). Study 1102 included 51 patients with previously treated
CLL/SLL, RESONATE included 391 randomized patients with previously treated CLL or SLL who
received single agent IMBRUVICA or ofatumumab, RESONATE-2 included 269 randomized patients
65 years or older with treatment naïve-CLL or SLL who received single agent IMBRUVICA or
chlorambucil, and HELIOS included 578 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.
The most commonly occurring adverse reactions in Studies 1102, RESONATE, RESONATE-2, and
HELIOS in patients with CLL/SLL receiving IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia,
anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage.
Four to 10 percent of patients receiving IMBRUVICA in Studies 1102, RESONATE, RESONATE-2, and
HELIOS discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage,
atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction
occurred in approximately 6% 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.
Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients
with CLL/SLL (N=51) in Study 1102
Adverse
All Grades
Grade 3 or 4
Body System
Reaction
(%)
(%)
4
59
Gastrointestinal disorders
Diarrhea
2
22
Constipation
2
20
Nausea
0
20
Stomatitis
2
18
Vomiting
0
14
Abdominal pain
0
12
Dyspepsia
2
47
Infections and infestations
Upper respiratory tract
infection
6
22
Sinusitis
6
16
Skin infection
10
12
Pneumonia
2
12
Urinary tract infection
6
33
General disorders and administration
Fatigue
2
24
site conditions
Pyrexia
0
22
Peripheral edema
6
14
Asthenia
0
12
Chills
2
51
Skin and subcutaneous tissue disorders Bruising
0
25
Rash
0
16
Petechiae
0
22
Respiratory, thoracic and mediastinal
Cough
0
14
disorders
Oropharyngeal pain
0
12
Dyspnea