b'B:8.125"T:7.875"S:6.875"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%DosemodificationsofIMBRUVICAarerecommendedwhenused and of Grade 3 or greater was 0.3% versus 0% in patients treated withconcomitantly with posaconazole, voriconazole and moderate CYP3A IMBRUVICA compared to patients in the control arm. 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. In addition, the incidence of cardiacor less) [see Dosage and Administration (2.3) in Full Prescribing Information].failure of any grade was 1.7% versus 0.5% and for Grade 3 or greater wasAvoid grapefruit and Seville oranges during IMBRUVICA treatment, as these 1.2% versus 0.3% in patients treated with IMBRUVICA compared to patientscontain strong or moderate inhibitors of CYP3A.in the control arm. Effect of CYP3A Inducers on Ibrutinib: The coadministration of IMBRUVICA Theincidenceofischemiccerebrovascularevents(cerebrovascularwith strong CYP3A inducers may decrease ibrutinib concentrations. Avoid accidents,ischemicstroke,cerebralischemia,andtransientischemiccoadministration with strong CYP3A inducers [see Clinical Pharmacology attack) of any grade was 1% versus 0.4% and Grade 3 or greater was 0.5%(12.3) in Full Prescribing Information]. versus 0.2% in patients treated with IMBRUVICA compared to patients in theUSE IN SPECIFIC POPULATIONScontrol arm, respectively. Pregnancy: Risk Summary: IMBRUVICA can cause fetal harm based on Diarrhea: In randomized controlled trials (n=2,115; median treatment durationfindings from animal studies. There are no available data on IMBRUVICA of 19.1 months for 1,157 patients treated with IMBRUVICA and 5.3 months foruse in pregnant women to inform a drug-associated risk of major birth 958 patients in the control arm), diarrhea of any grade occurred at a rate ofdefects and miscarriage. Inanimal reproduction studies, administration of 43% of patients treated with IMBRUVICA compared to 19% of patients in theibrutinib to pregnant rats and rabbits during the period of organogenesis at control arm. Grade 3 diarrhea occurred in 3% versus 1% of IMBRUVICA- exposures up to 2-20times the clinical doses of 420-560mg daily produced treated patients compared to the control arm, respectively. Less than 1%embryofetal toxicity including structural abnormalities (see Data). Advise (0.3%) of subjects discontinued IMBRUVICA due to diarrhea compared withpregnant women of the potential risk to a fetus.0% in the control arm.All pregnancies have a background risk of birth defect, loss, or other adverse Based on data from 1,605 of these patients, the median time to first onsetoutcomes. Theestimated background risk of major birth defects and miscarriage was 21 days (range, 0 to 708) versus 46 days (range, 0 to 492) for any gradefor the indicated population is unknown. In the U.S. general population, the diarrhea and 117 days (range, 3 to 414) versus 194 days (range, 11 to 325) forestimated background risk of major birth defects and miscarriage in clinically Grade 3 diarrhea in IMBRUVICA-treated patients compared to the controlrecognized pregnancies is 2-4% and 15-20%, respectively.arm, respectively. Of the patients who reported diarrhea, 85% versus 89%Data: Animal Data: Ibrutinib was administered orally to pregnant rats during had complete resolution, and 15% versus 11% had not reported resolutionthe period of organogenesis at doses of 10, 40 and 80mg/kg/day. Ibrutinib at at time of analysis in IMBRUVICA-treated patients compared to the controla dose of 80mg/kg/day was associated with visceral malformations (heart arm, respectively. The median time from onset to resolution in IMBRUVICA- and major vessels) and increased resorptions and post-implantation loss. treated subjects was 7 days (range, 1 to 655) versus 4 days (range, 1 to 367)The dose of 80mg/kg/day in rats is approximately 14 times the exposure for any grade diarrhea and 7 days (range, 1 to 78) versus 19 days (range,(AUC) in patients with MCL or marginal zone lymphoma (MZL) and 20 timesS:9.75" T:10.75" B:11"1 to 56) for Grade 3 diarrhea in IMBRUVICA-treated subjects compared to thethe exposure in patients with CLL/SLL or Waldenstrms Macroglobulinemia control arm, respectively. (WM) administered the dose of 560mg daily and 420mg daily, respectively. VisualDisturbance:Inrandomizedcontrolledtrials(n=2,115;medianIbrutinib at doses of 40mg/kg/day or greater was associated with decreased treatment duration of 19.1 months for 1,157 patients treated with IMBRUVICAfetal weights. The dose of 40mg/kg/day in rats is approximately 6 times the and 5.3 months for 958 patients in the control arm), blurred vision andexposure (AUC) in patients with MCL administered the dose of 560mg daily.decreased visual acuity of any grade occurred in 11% of patients treated withIbrutinib was also administered orally to pregnant rabbits during the period IMBRUVICA (9% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6%of organogenesis at doses of 5, 15, and 45mg/kg/day. Ibrutinib at a dose in the control arm (5% Grade 1 and 1% Grade 2 and 3).of 15mg/kg/day or greater was associated with skeletal variations (fused Based on data from 1,605 of these patients, the median time to first onset wassternebrae) and ibrutinib at a dose of 45mg/kg/day was associated with 91 days (range, 0 to 617) versus 100 days (range, 2 to 477) in IMBRUVICA- increased resorptions and post-implantation loss. The dose of 15mg/kg/day treated patients compared to the control arm, respectively. Of the patientsin rabbits is approximately 2.0 times the exposure (AUC) in patients with MCL who reported visual disturbances, 60% versus 71% had complete resolutionand 2.8 times the exposure in patients with CLL/SLL or WM administered the and 40% versus 29% had not reported resolution at the time of analysis indose of 560 and 420mg daily, respectively. IMBRUVICA-treated patients compared to the control arm, respectively. TheLactation: Risk Summary: There is no information regarding the presence median time from onset to resolution was 37 days (range, 1 to 457) versusof ibrutinib or its metabolites in human milk, the effects on the breastfed 26 days (range, 1 to 721) in IMBRUVICA-treated subjects compared to thechild, or the effects on milk production. Because of the potential for serious control arm, respectively.adverse reactions in the breastfed child, advise women not to breastfeed Long-Term Safety The safety data from long-term treatment with IMBRUVICAduring treatment with IMBRUVICA and for 1 week after the last dose.over5yearsof1,284patients(treatment-naveCLL/SLLn=162,relapsed/ Females and Males of Reproductive Potential: Pregnancy Testing: Verify refractory CLL/SLL n=646, relapsed/refractory MCL n=370, and WM n=106)pregnancy status in females of reproductive potential prior to initiating were analyzed. The median treatment duration was 51 months (range, 0.2 toIMBRUVICA.98 months) for CLL/SLL, 11 months (range, 0 to 87 months) for MCL, and 47Contraception: Females: IMBRUVICA can cause fetal harm when administered months (range, 0.3 to 61 months) for WM. The cumulative rate of hypertensionto pregnant women [see Use in Specific Populations]. Advise females of increased over time. The prevalence for Grade 3 or greater hypertension wasreproductive potential to use effective contraception during treatment with 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); theIMBRUVICA and for 1 month after the last dose.overall incidence for the 5-year period was 11%.Males: Advise males with female partners of reproductive potential to use Postmarketing Experience: The following adverse reactions have beeneffective contraception during treatment with IMBRUVICA and for 1 month identified during postapproval use of IMBRUVICA. Because these reactionsfollowing the last dose.arereportedvoluntarilyfromapopulationofuncertainsize,itisnotPediatric Use: The safety and effectiveness of IMBRUVICA in pediatric always possible to reliably estimate their frequency or establish a causalpatients has not been established. relationship to drug exposure. Geriatric Use: Of the 1,124 patients in clinical studies of IMBRUVICA, 64% were Hepatobiliary disorders: hepatic failure including acute and/or fatal 65 years of age, while 23% were 75 years of age. No overall differences in events, hepatic cirrhosis effectiveness were observed between younger and older patients. Anemia Respiratory disorders: interstitial lung disease (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension, Metabolic and nutrition disorders: tumor lysis syndrome and atrial fibrillation occurred more frequently among older patients treated Immune system disorders: anaphylactic shock, angioedema, urticaria with IMBRUVICA.Skin and subcutaneous tissue disorders: Stevens-Johnson SyndromeHepaticImpairment:AvoiduseofIMBRUVICAinpatientswithsevere (SJS), onychoclasis, panniculitis, neutrophilic dermatoses hepatic impairment (Child-Pugh class C). The safety of IMBRUVICA has not Infections: hepatitis B reactivation been evaluated in patients with mild to severe hepatic impairment by Child-Nervous system disorders: peripheral neuropathy Pugh criteria.Date: November 17, 2021 1:03 PM Brand: IMBRUVICAColors: KFile Name: PRC-07705a_868128_v1 Size: 7.875" x 10.75"page 7 (Left Hand Page)Customer Code: PRC-07705a Description: Living Longer Without ProgressionWe Are Alexander #: 868128 Pub: U.S. Medicine Directory'