ASH Clinical News ACN_4.14_Full Issue_web | Page 71

IMBRUVICA ® (ibrutinib) IMBRUVICA ® (ibrutinib)
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]. 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.
Hepatic Impairment: Avoid use of IMBRUVICA in patients with severe hepatic impairment (Child-
Pugh class C). The safety of IMBRUVICA has not been evaluated in patients with mild to severe
hepatic impairment by Child-Pugh criteria.
Dose modifications of IMBRUVICA are recommended in patients with mild or moderate hepatic
impairment (Child-Pugh class A and B). Monitor patients for adverse reactions of IMBRUVICA
closely [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in Full Prescribing
Information].
Plasmapheresis: Management of hyperviscosity in WM patients may include plasmapheresis before
and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
• Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms
(severe headache, blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient
that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and
Precautions].
• Infections: Inform patients of the possibility of serious infection, and to report any signs or
symptoms (fever, chills, weakness, confusion) suggestive of infection [see Warnings and
Precautions].
• Cardiac Arrhythmias: Counsel patients to report any signs of palpitations, lightheadedness,
dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions].
• Hypertension: Inform patients that high blood pressure has occurred in patients taking
IMBRUVICA, which may require treatment with anti-hypertensive therapy [see Warnings and
Precautions].
• Second primary malignancies: Inform patients that other malignancies have occurred in patients
who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see
Warnings and Precautions].
• Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and to report
any signs and symptoms associated with this event to their healthcare provider for evaluation
[see Warnings and Precautions].
• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming
pregnant during treatment and for 1 month after the last dose of IMBRUVICA [see Warnings and
Precautions].
• Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions
and that the oral dosage (capsules or tablets) should be swallowed whole with a glass of water
without opening, breaking or chewing the capsules or cutting, crushing or chewing the tablets
approximately the same time each day [see Dosage and Administration].
• Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon
as possible on the same day with a return to the normal schedule the following day. Patients
should not take extra doses to make up the missed dose [see Dosage and Administration].
• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions].
Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
• Advise patients to inform their health care providers of all concomitant medications, including
prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug
Interactions].
• Advise patients that they may experience loose stools or diarrhea, and should contact their
doctor if their diarrhea persists. Advise patients to maintain adequate hydration [see Adverse
Reactions].
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.
Active ingredient made in China.
Distributed and Marketed by:
Pharmacyclics LLC
Sunnyvale, CA USA 94085
and
Marketed by:
Janssen Biotech, Inc.
Horsham, PA USA 19044
Patent http://www.imbruvica.com
IMBRUVICA ® is a registered trademark owned by Pharmacyclics LLC
© Pharmacyclics LLC 2018
© Janssen Biotech, Inc. 2018
PRC-04483