ASH Clinical News ACN_6.4s_SUPP_full_issue | Page 22

IMBRUVICA ® (ibrutinib) IMBRUVICA ® (ibrutinib)
• 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].
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 child,
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: Conduct
pregnancy testing in 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.
Geriatric Use: Of the 1,124 patients in clinical studies of IMBRUVICA, 64% were
≥ 65 years of age, while 23% were ≥75 years of age. No overall differences in
effectiveness were observed between younger and older patients. Anemia
(all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension,
and atrial fibrillation 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
(2.1) in Full Prescribing Information].
• 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 (2.6) in Full
Prescribing Information].
• 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].
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 2019
© Janssen Biotech, Inc. 2019
PRC-06112