IMBRUVICA ® (ibrutinib)
IMBRUVICA ® (ibrutinib)
Table 15: 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
Additional Important Adverse Reactions: Cardiac Arrhythmias: In
randomized controlled trials (n=1377; median treatment duration of
14.0 months for patients treated with IMBRUVICA and 7.5 months for
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 0.4% 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 8% versus
2% and for Grade 3 or greater was 4% versus 0.4% in patients treated with
IMBRUVICA compared to patients in the control arm.
Diarrhea: Diarrhea of any grade occurred at a rate of 40% of patients
treated with IMBRUVICA compared to 19% 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 475) versus 47 days (range: 0 to 492) for any grade
diarrhea and 77 days (range: 3 to 310) 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, 84% versus 88%
had complete resolution, and 16% versus 12% 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 6 days (range: 1 to 655) versus 5 days (range: 1 to 367)
for any grade diarrhea and 6 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: Blurred vision and decreased visual acuity of
any grade occurred in 12% of patients treated with IMBRUVICA (10%
Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control
arm (5% Grade 1 and <1% Grade 2 and 3). The median time to first onset was
96 days (range, 0 to 617) versus 109 days (range, 2 to 477) in IMBRUVICA-
treated patients compared to the control arm, respectively. Of the patients
who reported visual disturbances, 61% versus 71% had complete resolution
and 39% 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 31 days (range, 1 to 457) versus
29 days (range, 1 to 253) 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
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].
USE IN SPECIFIC POPULATIONS
Pregnancy: Risk Summary: IMBRUVICA, a kinase inhibitor, can cause fetal
harm based on findings from animal studies. There are no available data
on IMBRUVICA use in pregnant women to inform a drug-associated risk
of major birth defects and miscarriage. In animal reproduction studies,
administration of ibrutinib to pregnant rats and rabbits during the period of
organogenesis at exposures up to 2-20 times the clinical doses of 420-560 mg
daily produced embryofetal toxicity including structural abnormalities (see
Data). If IMBRUVICA is used during pregnancy or if the patient becomes
pregnant while taking IMBRUVICA, the patient should be apprised of the
potential hazard to the fetus.
All pregnancies have a background risk of birth defect, loss, or other
adverse outcomes. The estimated background risk of major birth defects
and miscarriage for the indicated population is unknown. In the U.S.
general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.
Data: Animal Data: Ibrutinib was administered orally to pregnant rats during
the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. Ibrutinib at
a dose of 80 mg/kg/day was associated with visceral malformations (heart
and major vessels) and increased resorptions and post-implantation loss.
The dose of 80 mg/kg/day in rats is approximately 14 times the exposure
(AUC) in patients with MCL or MZL and 20 times the exposure in patients
with CLL/SLL or WM administered the dose of 560 mg daily and 420 mg
daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was
associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is
approximately 6 times the exposure (AUC) in patients with MCL administered
the dose of 560 mg daily.
Ibrutinib was also administered orally to pregnant rabbits during the period
of organogenesis at doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose
of 15 mg/kg/day or greater was associated with skeletal variations (fused
sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with
increased resorptions and post-implantation loss. The dose of 15 mg/kg/day
in rabbits is approximately 2.0 times the exposure (AUC) in patients with MCL
and 2.8 times the exposure in patients with CLL/SLL or WM administered the
dose of 560 and 420 mg daily, respectively.
Lactation: Risk Summary: There is no information regarding the presence of
ibrutinib or its metabolites in human milk, the effects on the breastfed infant,
or the effects on milk production.
The development and health benefits of breastfeeding should be considered
along with the mother’s clinical need for IMBRUVICA and any potential
adverse effects on the breastfed child from IMBRUVICA or from the underlying
maternal condition.
Females and Males of Reproductive Potential: Pregnancy Testing: Verify
the pregnancy status of females of reproductive potential prior to initiating
IMBRUVICA therapy.
Contraception: Females: Advise females of reproductive potential to avoid
pregnancy while taking IMBRUVICA and for up to 1 month after ending
treatment. If this drug is used during pregnancy or if the patient becomes
pregnant while taking this drug, the patient should be informed of the
potential hazard to a fetus.
Males: Advise men to avoid fathering a child while receiving IMBRUVICA,
and for 1 month following the last dose of IMBRUVICA.
Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric
patients has not been established. Pediatric studies have not been completed.
Geriatric Use: Of the 1011 patients in clinical studies of IMBRUVICA,
62% were ≥ 65 years of age, while 22% were ≥75 years of age. No overall
differences in effectiveness were observed between younger and older
patients. Anemia (all grades) and Grade 3 or higher pneumonia occurred
more frequently among older patients treated with IMBRUVICA.