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 1,124 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).
IMBRUVICA ® (ibrutinib)
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.
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.
Table 1: Non-Hematologic Adverse Reactions in ≥ 10%
of Patients with MCL (N=111)
All Grades Grade 3 or
Body System
Adverse Reaction
(%)
Higher (%)
5
51
Gastrointestinal
Diarrhea
0
31
disorders
Nausea
0
25
Constipation
5
24
Abdominal pain
0
23
Vomiting
1
17
Stomatitis
0
11
Dyspepsia
Infections and
Upper respiratory tract
0
34
infestations
infection
3
14
Urinary tract infection
8 †
14
Pneumonia
14
Skin infections
5
13
Sinusitis
1
5
41
General disorders Fatigue
3
35
and administration Peripheral edema
1
18
Pyrexia
site conditions
3
14
Asthenia