IMBRUVICA ® (ibrutinib) IMBRUVICA ® (ibrutinib)
Table 14: Treatment-Emergent Hematologic Laboratory Abnormalities
in Patients with MZL in Study 1121 (N=63)
Percent of Patients (N=63)
All Grades (%)
Grade 3 or 4 (%)
Platelets Decreased
49
6
Hemoglobin Decreased
43
13
Neutrophils Decreased
22
13
Treatment-emergent Grade 4 thrombocytopenia (3%) and neutropenia (6%)
occurred in patients.
Chronic Graft versus Host Disease: The data described below reflect
exposure to IMBRUVICA in an open-label clinical trial (Study 1129) that
included 42 patients with cGVHD after failure of first line corticosteroid
therapy and required additional therapy.
The most commonly occurring adverse reactions in the cGVHD trial (≥ 20%)
were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle
spasms, nausea, hemorrhage, anemia, and pneumonia. Atrial fibrillation
occurred in one patient (2%) which was Grade 3.
Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial
discontinued treatment due to adverse reactions. The most common adverse
reactions leading to discontinuation were fatigue and pneumonia. Adverse
reactions leading to dose reduction occurred in 26% of patients.
Adverse reactions and laboratory abnormalities described below in Tables 15
and 16 reflect exposure to IMBRUVICA with a median duration of 4.4 months
in the cGVHD trial. Additional Important Adverse Reactions: Cardiac Arrhythmias: In randomized
controlled trials (n=1605; median treatment duration of 14.8 months for 805
patients treated with IMBRUVICA and 5.6 months for 800 patients in the
control arm), the incidence of ventricular tachyarrhythmias (ventricular
extrasystoles, ventricular arrhythmias, ventricular fibrillation, ventricular
flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.5% and of
Grade 3 or greater was 0.2% versus 0% in patients treated with IMBRUVICA
compared to patients in the control arm. In addition, the incidence of atrial
fibrillation and atrial flutter of any grade was 9% versus 1.4% and for Grade
3 or greater was 4.1% versus 0.4% in patients treated with IMBRUVICA
compared to patients in the control arm.
Diarrhea: In randomized controlled trials (n=1605; median treatment duration
of 14.8 months for 805 patients treated with IMBRUVICA and 5.6 months for
800 patients in the control arm), diarrhea of any grade occurred at a rate
of 39% of patients treated with IMBRUVICA compared to 18% of patients in
the control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA-
treated patients compared to the control arm, respectively. The median time
to first onset was 21 days (range, 0 to 708) versus 46 days (range, 0 to 492) for
any grade diarrhea and 117 days (range, 3 to 414) versus 194 days (range, 11
to 325) for Grade 3 diarrhea in IMBRUVICA-treated patients compared to the
control arm, respectively. Of the patients who reported diarrhea, 85% versus
89% had complete resolution, and 15% versus 11% had not reported resolution
at time of analysis in IMBRUVICA-treated patients compared to the control
arm, respectively. The median time from onset to resolution in IMBRUVICA-
treated subjects was 7 days (range, 1 to 655) versus 4 days (range, 1 to 367)
for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days (range,
1 to 56) for Grade 3 diarrhea in IMBRUVICA-treated subjects compared to the
control arm, respectively. Less than 1% of subjects discontinued IMBRUVICA
due to diarrhea compared with 0% in the control arm.
Visual Disturbance: In randomized controlled trials (n=1605; median
treatment duration of 14.8 months for 805 patients treated with IMBRUVICA
and 5.6 months for 800 patients in the control arm), blurred vision and
decreased visual acuity of any grade occurred in 11% of patients treated
with IMBRUVICA (10% Grade 1, 2% Grade 2, no Grade 3 or higher) compared
to 6% in the control arm (6% Grade 1 and <1% Grade 2 and 3). The median
time to first onset was 91 days (range, 0 to 617) versus 100 days (range,
2 to 477) in IMBRUVICA-treated patients compared to the control arm,
respectively. Of the patients who reported visual disturbances, 60%
versus 71% had complete resolution and 40% versus 29% had not reported
resolution at the time of analysis in IMBRUVICA-treated patients compared
to the control arm, respectively. The median time from onset to resolution
was 37 days (range, 1 to 457) versus 26 days (range, 1 to 721) in IMBRUVICA-
treated subjects compared to the control arm, respectively.
Postmarketing Experience: The following adverse reactions have been
identified during post-approval use of IMBRUVICA. Because these
reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
• Hepatobiliary disorders: hepatic failure including acute and/or fatal
events, hepatic cirrhosis
• Respiratory disorders: interstitial lung disease
• Metabolic and nutrition disorders: tumor lysis syndrome [see Warnings
& Precautions]
• Immune system disorders: anaphylactic shock, angioedema, urticaria
• Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome
(SJS), onychoclasis, panniculitis
• Infections: hepatitis B reactivation
• Nervous system disorders: peripheral neuropathy
DRUG INTERACTIONS
Effect of CYP3A Inhibitors on Ibrutinib: The coadministration of IMBRUVICA
with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma
concentrations [see Clinical Pharmacology (12.3) in Full Prescribing
Information]. Increased ibrutinib concentrations may increase the risk of
drug-related toxicity.
Dose modifications of IMBRUVICA are recommended when used
concomitantly with posaconazole, voriconazole and moderate CYP3A
inhibitors [see Dosage and Administration (2.4) in Full Prescribing Information].
Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA
if these inhibitors will be used short-term (such as anti-infectives for seven
days or less) [see Dosage and Administration (2.4) in Full Prescribing
Information].
Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these
contain strong or moderate inhibitors of CYP3A.
Effect of CYP3A Inducers on Ibrutinib: The coadministration of IMBRUVICA
with strong CYP3A inducers may decrease ibrutinib concentrations. Avoid
coadministration with strong CYP3A inducers [see Clinical Pharmacology
(12.3) in Full Prescribing Information].
Table 15: Non-Hematologic Adverse Reactions in ≥ 10% of Patients
with cGVHD (N=42)
Body System
Adverse Reaction
All
Grades
(%) Grade 3
or Higher
(%)
General disorders and
administration site
conditions Fatigue
Pyrexia
Edema peripheral 57
17
12 12
5
0
Skin and subcutaneous
tissue disorders Bruising*
Rash* 40
12 0
0
Gastrointestinal
disorders Diarrhea
Stomatitis*
Nausea
Constipation 36
29
26
12 10
2
0
0
Musculoskeletal and
connective tissue
disorders Muscle spasms
Musculoskeletal pain* 29
14 2
5
Vascular disorders Hemorrhage* 26 0
Infections and
infestations Pneumonia*
Upper respiratory tract
infection
Sepsis* 21 14 †
19
10 0
10
Nervous system
disorders Headache 17 5
Injury, poisoning
and procedural
complications Fall 17 0
Respiratory, thoracic
and mediastinal
disorders Cough
Dyspnea 14
12 0
2
Metabolism and
nutrition disorders Hypokalemia 12 7
The system organ class and individual ADR preferred terms are sorted in
descending frequency order.
* Includes multiple ADR terms.
† Includes 2 events with a fatal outcome.
Table 16: Treatment-Emergent Hematologic Laboratory Abnormalities
in Patients with cGVHD (N=42)
Percent of Patients (N=42)
All Grades (%)
Grade 3 or 4 (%)
Platelets Decreased
33
0
Neutrophils Decreased
10
10
Hemoglobin Decreased
24
2
Treatment-emergent Grade 4 neutropenia occurred in 2% of patients.