Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib)
IMBRUVICA® (ibrutinib) capsules, for oral use
See package insert for Full Prescribing Information
INDICATIONS AND USAGE
Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of 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 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) [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].
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 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 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 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. Evaluate patients for fever
and infections and treat appropriately.
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, hypertension, 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. Atrial fibrillation should be managed appropriately and if it persists, consider the risks
and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in Full
Prescribing Information].
Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with
a median time to onset of 4.5 months (range, 0.03 to 18.40 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 (range, 5 to 16%) including non-skin carcinomas
(range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary
malignancy was non-melanoma skin cancer (range, 4 to 13%).
Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy.
Assess the baseline risk (eg, 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 embryofetal toxicity including malformations at exposures that were 2-20 times
higher than those reported in patients with MCL, CLL or WM. 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]
• Atrial Fibrillation [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 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)
Grade 3 or 4
All Grades (%)
Body System
Adverse 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 infection
34
0
Urinary tract infection
14
3
Pneumonia
14
7
Skin infections
14
5
Sinusitis
13
1
General disorders and
Fatigue
41
5
administration site conditions
Peripheral edema
35
3
Pyrexia
18
1
Asthenia
14
3
IMBRUVICA® (ibrutinib) capsules
Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111)
(continued)
Body System
Skin and subcutaneous tissue
disorders
Musculoskeletal and connective
tissue disorders
Respiratory, thoracic and
mediastinal disorders
Metabolism and nutrition
disorders
Nervous system disorders
Adverse Reaction
Bruising
Rash
Petechiae
Musculoskeletal pain
Muscle spasms
Arthralgia
Dyspnea
Cough
Epistaxis
Decreased appetite
Dehydration
Dizziness
Headache
All Grades (%)
30
25
11
37
14
11
27
19
11
21
12
14
13
Grade 3 or 4
(%)
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 one single
arm, open-label clinical trial and two randomized controlled clinical trials in patients with CLL/SLL.
Study 1 included 48 patients with previously treated CLL, Study 2 included 391 randomized patients with
previously treated CLL or SLL who received single agent ibrutinib or ofatumumab, and Study 3 included
269 randomized patients 65 years or older with treatment naïve CLL or SLL who received single agent
ibrutinib or chlorambucil.
The most commonly occurring adverse reactions in Studies 1, 2, and 3 in patients with CLL/SLL receiving
IMBRUVICA (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, musculoskeletal pain, fatigue,
bruising, nausea, rash, pyrexia and cough. Four to ten percent of patients receiving IMBRUVICA in Studies 1,
2, and 3 discontinued treatment due to adverse reactions. These included pneumonia, subdural hematomas
and atrial fibrillation (1% each). Adverse reactions leading to dose reduction occurred in approximately
4% 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% 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 (N=48) in Study 1
Body System
Adverse Reaction
All Grades (%)
Grade 3 or 4
(%)
Gastrointestinal disorders
Diarrhea
Constipation
Nausea
Stomatitis
Vomiting
Abdominal pain
Dyspepsia
63
23
21
21
19
15
13
4
2
2
0
2
0
0
Infections and infestations
Upper respiratory tract infection
Sinusitis
Skin infection
Pneumonia
Urinary tract infection
48
21
17
10
10
2
6
6
8
0
General disorders and
administration site conditions
Fatigue
Pyrexia
Peripheral edema
Asthenia
Chills
31
25
23
13
13
4
2
0
4
0
Skin and subcutaneous tissue
disorders
Bruising
Rash
Petechiae
54
27
17
2
0
0
Respiratory, thoracic and
mediastinal disorders
Cough
Oropharyngeal pain
Dyspnea
19
15
10
0
0
0
Musculoskeletal and connective
tissue disorders
Musculoskeletal pain
Arthralgia
Muscle spasms
27
23
19
6
0
2
Nervous system disorders
Dizziness
Headache
Peripheral neuropathy
21
19
10
0
2
0
Metabolism and nutrition
disorders
Decreased appetite
17
2
Neoplasms benign, malignant,
unspecified
Second malignancies*
10*
0
Injury, poisoning and procedural
complications
Laceration
10
2
Psychiatric disorders
Anxiety
Insomnia
10
10
0
0
Vascular disorders
Hypertension
17
8
* One patient death due to histiocytic sarcoma.