ASH Clinical News December 2016 | Page 14

IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules

Table 9: Non-Hematologic Adverse Reactions in ≥ 10% of Patients
with Waldenström’s Macroglobulinemia (N=63)
Body System
Gastrointestinal disorders

Skin and subcutaneous
tissue disorders
General disorders and
administrative site
conditions
Musculoskeletal and
connective tissue disorders
Infections and infestations

Respiratory, thoracic and
mediastinal disorders
Nervous system disorders

Adverse Reaction
Diarrhea
Nausea
Stomatitis*
Gastroesophageal reflux
disease
Rash*
Bruising*
Pruritus
Fatigue
Muscle spasms
Arthropathy
Upper respiratory
tract infection
Sinusitis
Pneumonia*
Skin infection*
Epistaxis
Cough
Dizziness
Headache
Skin cancer*

37
21
16
13

Grade 3 or 4
(%)
0
0
0
0

22
16
11
21

0
0
0
0

21
13

0
0

19
19
14
14
19
13
14
13
11

0
0
6
2
0
0
0
0
0

All Grades (%)

Neoplasms benign,
malignant, and unspecified
(including cysts and polyps)
The system organ class and individual ADR preferred terms are sorted in descending frequency
order.
* Includes multiple ADR terms.
Table 10: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils
in Patients with WM (N=63)

Platelets Decreased
Neutrophils Decreased
Hemoglobin Decreased

Percent of Patients (N=63)
All Grades (%)
Grade 3 or 4 (%)
43
13
44
19
13
8

* Based on laboratory measurements.
Additional Important Adverse Reactions: Diarrhea: Diarrhea of any grade occurred at a rate of 43%
(range, 36% to 63%) of patients treated with IMBRUVICA. Grade 2 diarrhea occurred in 9% (range,
3% to 15%) and Grade 3 in 3% (range, 0 to 5%) of patients treated with IMBRUVICA. The median time
to first onset of any grade diarrhea was 12 days (range, 0 to 627), of Grade 2 was 37 days (range,
1 to 667) and of Grade 3 was 71 days (range, 3 to 627). Of the patients who reported diarrhea, 83%
had complete resolution, 1% had partial improvement and 16% had no reported improvement at time
of analysis. The median time from onset to resolution or improvement of any grade diarrhea was
5 days (range, 1 to 418), and was similar for Grades 2 and 3. Less than 1% of patients discontinued
IMBRUVICA due to diarrhea.
Visual Disturbance: Blurred vision and decreased visual acuity of any grade occurred in 10% of
patients treated with IMBRUVICA (9% Grade 1, 2% Grade 2). The median time to first onset was
88 days (range, 1 to 414 days). Of the patients with visual disturbance, 64% had complete resolution
and 36% had no reported improvement at time of analysis. The median time from onset to resolution
or improvement was 29 days (range, 1 to 281 days).
Postmarketing Experience: The following adverse reactions have been identified during postapproval 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 (includes multiple terms)
Respiratory disorders: interstitial lung disease (includes multiple terms)
Metabolic and nutrition disorders: tumor lysis syndrome [see Warnings & Precautions]
Skin and subcutaneous tissue disorders: anaphylactic shock, angioedema, urticaria
DRUG INTERACTIONS
CYP3A Inhibitors: Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A (CYP3A). In
healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and
AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical
trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values
of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the
highest indicated dose (560 mg).
Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A.
For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less,
e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin)
consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A
inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the
IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be
monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in Full
Prescribing Information].
Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate
inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in Full
Prescribing Information].
CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased
ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.
Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, and
St. John’s Wort). Consider alternative agents with less CYP3A induction [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. 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 malformations [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.
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.

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
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.
Geriatric Use: Of the 839 patients in clinical studies of IMBRUVICA, 62% were ≥ 65 years of age,
while 21% were ≥75 years of age. No overall differences in effectiveness were observed between
younger and older patients. Grade 3 or higher pneumonia occurred more frequently among older
patients treated with IMBRUVICA [see Clinical Studies (14.2) in Full Prescribing Information].
Hepatic Impairment: Ibrutinib is metabolized in the liver. In a hepatic impairment study, data
showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib
increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh
class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal
liver function.
The safety of IMBRUVICA has not been evaluated in cancer patients with mild to severe hepatic
impairment by Child-Pugh criteria.
Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as
needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe
hepatic impairment (Child-Pugh class B and C) [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].
• Atrial fibrillation: 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 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 capsules should be swallowed whole with a glass of water without being opened,
broken, or chewed at 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 capsules 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.
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 2016
© Janssen Biotech, Inc. 2016

PRC-02067