ASH Clinical News February 2017 New | Page 12

IMBRUVICA ® ( ibrutinib ) capsules

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

Neoplasms benign , malignant , and unspecified ( including cysts and polyps )

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

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 )

Percent of Patients ( N = 63 )

All Grades (%) Grade 3 or 4 (%) Platelets Decreased 43 13 Neutrophils Decreased 44 19 Hemoglobin Decreased 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 C max 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 C max 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 .

IMBRUVICA ® ( ibrutinib ) capsules

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