b'IMBRUVICA (ibrutinib)IMBRUVICA (ibrutinib) AdditionalImportantAdverseReactions:CardiovascularEvents:DataDRUG INTERACTIONSon cardiovascular events are based on randomized controlled trials withEffect of CYP3A Inhibitors on Ibrutinib: The coadministration of IMBRUVICA IMBRUVICA (n=2,115; median treatment duration of 19.1 months for 1,157with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma patients treated with IMBRUVICA and 5.3 months for 958 patients in theconcentrations[seeClinicalPharmacology(12.3)inFullPrescribing controlarm).Theincidenceofventriculartachyarrhythmias(ventricularInformation]. Increased ibrutinib concentrations may increase the risk of extrasystoles,ventriculararrhythmias,ventricularfibrillation,ventriculardrug-related toxicity.flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and ofDosemodificationsofIMBRUVICAarerecommendedwhenused Grade 3 or greater was 0.3% versus 0% in patients treated with IMBRUVICAconcomitantly with posaconazole, voriconazole and moderate CYP3A compared to patients in the control arm. In addition, the incidence of atrialinhibitors [see Dosage and Administration (2.3) in Full Prescribing Information]. fibrillation and atrial flutter of any grade was 8.4% versus 1.6% and for GradeAvoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA 3 or greater was 4.0% versus 0.5% in patients treated with IMBRUVICAif these inhibitors will be used short-term (such as anti-infectives for seven days compared to patients in the control arm. or less) [see Dosage and Administration (2.3) in Full Prescribing Information].Theincidenceofischemiccerebrovascularevents(cerebrovascularAvoid grapefruit and Seville oranges during IMBRUVICA treatment, as these accidents,ischemicstroke,cerebralischemia,andtransientischemiccontain strong or moderate inhibitors of CYP3A.attack) of any grade was 1% versus 0.4% and Grade 3 or greater was 0.5%Effect of CYP3A Inducers on Ibrutinib: The coadministration of IMBRUVICA versus 0.2% in patients treated with IMBRUVICA compared to patients in thewith strong CYP3A inducers may decrease ibrutinib concentrations. Avoid control arm, respectively. coadministration with strong CYP3A inducers [see Clinical Pharmacology Diarrhea: In randomized controlled trials (n=2,115; median treatment duration(12.3) in Full Prescribing Information]. of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months forUSE IN SPECIFIC POPULATIONS958 patients in the control arm), diarrhea of any grade occurred at a rate ofPregnancy: Risk Summary: IMBRUVICA can cause fetal harm based on 43% of patients treated with IMBRUVICA compared to 19% of patients in thefindings from animal studies. There are no available data on IMBRUVICA control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA- use in pregnant women to inform a drug-associated risk of major birth treated patients compared to the control arm, respectively. Less than 1%defects and miscarriage. Inanimal reproduction studies, administration of (0.3%) of subjects discontinued IMBRUVICA due to diarrhea compared withibrutinib to pregnant rats and rabbits during the period of organogenesis at 0% in the control arm.exposures up to 2-20times the clinical doses of 420-560mg daily produced Based on data from 1,605 of these patients, the median time to first onsetembryofetal toxicity including structural abnormalities (see Data). Advise was 21 days (range, 0 to 708) versus 46 days (range, 0 to 492) for any gradepregnant women of the potential risk to a fetus.diarrhea and 117 days (range, 3 to 414) versus 194 days (range, 11 to 325) forAll pregnancies have a background risk of birth defect, loss, or other adverse Grade 3 diarrhea in IMBRUVICA-treated patients compared to the controloutcomes. Theestimated background risk of major birth defects and miscarriage arm, respectively. Of the patients who reported diarrhea, 85% versus 89%for the indicated population is unknown. In the U.S. general population, the had complete resolution, and 15% versus 11% had not reported resolutionestimated background risk of major birth defects and miscarriage in clinically at time of analysis in IMBRUVICA-treated patients compared to the controlrecognized pregnancies is 2-4% and 15-20%, respectively.arm, respectively. The median time from onset to resolution in IMBRUVICA- Data: Animal Data: Ibrutinib was administered orally to pregnant rats during treated subjects was 7 days (range, 1 to 655) versus 4 days (range, 1 to 367)the period of organogenesis at doses of 10, 40 and 80mg/kg/day. Ibrutinib at for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days (range,a dose of 80mg/kg/day was associated with visceral malformations (heart 1 to 56) for Grade 3 diarrhea in IMBRUVICA-treated subjects compared to theand major vessels) and increased resorptions and post-implantation loss. control arm, respectively. The dose of 80mg/kg/day in rats is approximately 14 times the exposure VisualDisturbance:Inrandomizedcontrolledtrials(n=2,115;median(AUC) in patients with MCL or marginal zone lymphoma (MZL) and 20 times treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICAthe exposure in patients with CLL/SLL or Waldenstrms Macroglobulinemia and 5.3 months for 958 patients in the control arm), blurred vision and(WM) administered the dose of 560mg daily and 420mg daily, respectively. decreased visual acuity of any grade occurred in 11% of patients treated withIbrutinib at doses of 40mg/kg/day or greater was associated with decreased IMBRUVICA (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6%fetal weights. The dose of 40mg/kg/day in rats is approximately 6 times the in the control arm (5% Grade 1 and 1% Grade 2 and 3).exposure (AUC) in patients with MCL administered the dose of 560mg daily.Based on data from 1,605 of these patients, the median time to first onset wasIbrutinib was also administered orally to pregnant rabbits during the period 91 days (range, 0 to 617) versus 100 days (range, 2 to 477) in IMBRUVICA- of organogenesis at doses of 5, 15, and 45mg/kg/day. Ibrutinib at a dose treated patients compared to the control arm, respectively. Of the patientsof 15mg/kg/day or greater was associated with skeletal variations (fused who reported visual disturbances, 60% versus 71% had complete resolutionsternebrae) and ibrutinib at a dose of 45mg/kg/day was associated with and 40% versus 29% had not reported resolution at the time of analysis inincreased resorptions and post-implantation loss. The dose of 15mg/kg/day IMBRUVICA-treated patients compared to the control arm, respectively. Thein rabbits is approximately 2.0 times the exposure (AUC) in patients with MCL median time from onset to resolution was 37 days (range, 1 to 457) versusand 2.8 times the exposure in patients with CLL/SLL or WM administered the 26 days (range, 1 to 721) in IMBRUVICA-treated subjects compared to thedose of 560 and 420mg daily, respectively. control arm, respectively.Lactation: Risk Summary: There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed Long-Term Safety The safety data from long-term follow-up over 5 years ofchild, or the effects on milk production. Because of the potential for serious 1,178 patients (treatment-nave CLL/SLL n=162, relapsed/refractory CLL/SLLadverse reactions in the breastfed child, advise women not to breastfeed n=646, and relapsed/refractory mantle cell lymphoma (MCL) n=370) treatedduring treatment with IMBRUVICA and for 1 week after the last dose.with IMBRUVICA were analyzed. The median treatment duration for CLL/SLL Females and Males of Reproductive Potential: Pregnancy Testing: Verify was 51 months (range, 0.2 to 98 months). The median treatment durationpregnancy status in females of reproductive potential prior to initiating for MCL was 11 months (range, 0 to 87 months). The cumulative rate ofIMBRUVICA.hypertension increased over time with prolonged IMBRUVICA treatment. TheContraception: Females: IMBRUVICA can cause fetal harm when administered prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 6% (yearto pregnant women [see Use in Specific Populations]. Advise females of 1-2), 8% (year 2-3), 9% (year 3-4), and 9% (year 4-5). The incidence for thereproductive potential to use effective contraception during treatment with 5-year period was 11%.IMBRUVICA and for 1 month after the last dose.Postmarketing Experience: The following adverse reactions have beenMales: Advise males with female partners of reproductive potential to use identified during postapproval use of IMBRUVICA. Because these reactionseffective contraception during treatment with IMBRUVICA and for 1 month arereportedvoluntarilyfromapopulationofuncertainsize,itisnotfollowing the last dose.always possible to reliably estimate their frequency or establish a causalPediatric Use: The safety and effectiveness of IMBRUVICA in pediatric relationship to drug exposure. patients has not been established. Hepatobiliary disorders: hepatic failure including acute and/or fatalGeriatric Use: Of the 1,124 patients in clinical studies of IMBRUVICA, 64% were events, hepatic cirrhosis65 years of age, while 23% were 75 years of age. No overall differences in Respiratory disorders: interstitial lung disease effectiveness were observed between younger and older patients. Anemia Metabolic and nutrition disorders: tumor lysis syndrome (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension, Immune system disorders: anaphylactic shock, angioedema, urticaria and atrial fibrillation occurred more frequently among older patients treated Skin and subcutaneous tissue disorders: Stevens-Johnson Syndromewith IMBRUVICA.(SJS), onychoclasis, panniculitis, neutrophilic dermatoses HepaticImpairment:AvoiduseofIMBRUVICAinpatientswithsevere Infections: hepatitis B reactivation hepatic impairment (Child-Pugh class C). The safety of IMBRUVICA has not Nervous system disorders: peripheral neuropathy been evaluated in patients with mild to severe hepatic impairment by Child-Pugh criteria.'