b'DO NOT RE-SIZEDO NOT RE-SIZEAd unit Project # must match this project # 000-000000US-VENC-200072Table 8. New or Worsening Laboratory Abnormalities with VENCLEXTATable 10 describes common laboratory abnormalities reported throughoutLactationReported in 40% (All Grades) or 10% (Grade 3 or 4) of Patientstreatment that were new or worsening from baseline.Risk Summarywith AML Treated with VENCLEXTA in Combination with AzacitidineTable 10. New or Worsening Laboratory Abnormalities withThere are no data on the presence of VENCLEXTA in human milk, the or DecitabineVENCLEXTA Reported in 40% (All Grades) or 10% (Grade 3 or 4)effects of VENCLEXTA on the breastfed child, or the effects of VENCLEXTA VENCLEXTA inVENCLEXTA inof Patients with AML Treated with VENCLEXTA in Combination withon milk production. Venetoclax was present in the milk when administered Combination withCombination withLow-Dose Cytarabineto lactating rats (see Data). Azacitidine Decitabine VENCLEXTA Because many drugs are excreted in human milk and because the Laboratory(N = 67) (N = 13) (N = 61) potential for serious adverse reactions in a breastfed child from Abnormality Laboratory Abnormality VENCLEXTA is unknown, advise nursing women to discontinue AllGrade 3AllGrade 3All GradesaGrade 3 or 4abreastfeeding during treatment with VENCLEXTA. Gradesaor 4aGradesaor 4a(%) (%) Data(%) (%) (%) (%) Hematology Animal DataHematology Thrombocytopenia 100 96 Venetoclax was administered (single dose; 150 mg/kg oral) to lactating Neutropenia 100 100 100 100 Neutropenia 96 96 rats 8 to 10 days parturition. Venetoclax in milk was 1.6 times lower than in plasma. Parent drug (venetoclax) represented the majority of the total Leukopenia 100 98 100 100 Leukopenia 96 96 drug-related material in milk, with trace levels of three metabolites. Thrombocytopenia 91 78 83 83 Lymphopenia 93 66 Females and Males of Reproductive PotentialLymphopenia 88 73 100 92 Anemia 61 59 VENCLEXTA may cause fetal harm [see Warnings and Precautions and Use in Specific Populations]. Anemia 57 57 69 69 Chemistry Pregnancy TestingChemistry Hyperglycemia 85 8 Conduct pregnancy testing in females of reproductive potential before Hyperglycemia75 12 69 0 Hypocalcemia 79 16 initiation ofVENCLEXTA [see Use in Specific Populations]. Hyponatremia 62 11 ContraceptionHypocalcemia58 7 85 0 Advise females of reproductive potential to use effective contraception Hypoalbuminemia 52 4 38 8 Hyperbilirubinemia 57 3 during treatment with VENCLEXTA and for at least 30 days after the last Hypokalemia 49 7 46 0 Hypoalbuminemia 59 5 dose [see Use in Specific Populations]. Hypokalemia 56 20 InfertilityHyponatremia 49 4 38 0 Hypophosphatemia 51 21 Based on findings in animals, male fertility may be compromised by Hypophosphatemia 46 15 23 8 treatment with VENCLEXTA. Hypomagnesemia 46 0 Pediatric UseHyperbilirubinemia 45 9 46 15 Blood creatinine increased 46 3 Safety and effectiveness have not been established in pediatric patients. Hypomagnesemia 21 0 54 8 Blood bicarbonate decreased 41 0 Juvenile Animal Toxicity DataaIncludes laboratory abnormalities that were new or worsening, oraIncludes laboratory abnormalities that were new or worsening, orIn a juvenile toxicology study, mice were administered venetoclax at 10, worsening from baseline unknown.worsening from baseline unknown.30, or 100 mg/kg/day by oral gavage from 7 to 60 days of age. Clinical signs of toxicity included decreased activity, dehydration, skin pallor, and VENCLEXTA in Combination with Low-Dose Cytarabine Tumor Lysis Syndrome hunched posture at 30 mg/kg/day. In addition, mortality and body weight The most common adverse reactions (30%) of any grade were nausea,Tumor lysis syndrome is an important risk when initiating treatment ineffects occurred at 100 mg/kg/day. Other venetoclax-related effectsthrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea,patients with AML. The incidence of TLS was 3% (2/61) with VENCLEXTAwere reversible decreases in lymphocytes at 10 mg/kg/day; a dose offatigue, constipation, and dyspnea.in combination with low-dose cytarabine with implementation of dose10 mg/kg/day is approximately 0.06 times the clinical dose of 400 mg onSerious adverse reactions were reported in 95% of patients. The mostramp-up schedule in addition to standard prophylaxis and monitoringa mg/m2 basis for a 20 kg child. frequent serious adverse reactions (5%) were febrile neutropenia, sepsismeasures. All events were laboratory TLS, and all patients were able toGeriatric Use(excluding fungal), hemorrhage, pneumonia (excluding fungal), andreach the target dose.Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphomadevice-related infection.DRUG INTERACTIONS Of the 352 patients with previously treated CLL/SLL evaluated for safety The incidence of fatal adverse drug reactions was 4.9% within 30 days ofEffects of Other Drugs on VENCLEXTA from 3 open-label trials of VENCLEXTA monotherapy, 57% (201/352) were starting treatment with no reaction having an incidence of 2%.Strong or Moderate CYP3A Inhibitors or P-gp Inhibitors 65 years of age and 18% (62/352) were 75 years of age. Discontinuations due to adverse reactions occurred in 33% of patients.Concomitant use with a strong or moderate CYP3A inhibitor or a P-gpNo clinically meaningful differences in safety and effectiveness were The most frequent adverse reactions leading to drug discontinuation (2%)inhibitor increases venetoclax C maxand AUC inf , which may increaseobserved between older and younger patients in the combination and were hemorrhage and sepsis (excluding fungal).VENCLEXTA toxicities, including the risk of TLS [see Warnings andmonotherapy studies. Dosage interruptions due to adverse reactions occurred in 52% of patients.Precautions].Acute Myeloid LeukemiaThe most frequent adverse reactions leading to dose interruption (5%)Concomitant use with a strong CYP3A inhibitor at initiation and duringOf the 67 patients treated with VENCLEXTA in combination with azacitidine were thrombocytopenia, neutropenia, and febrile neutropenia.the ramp-up phase in patients with CLL/SLL is contraindicated [seein the clinical trial, 96% were 65 years of age and 50% were75 years Dosage reductions due to adverse reactions occurred in 8% of patients.Contraindications].of age. Of the 13 patients treated with VENCLEXTA in combination with The most frequent adverse reaction leading to dose reduction (2%) wasIn patients with CLL/SLL taking a steady daily dosage (after ramp-updecitabine in the clinical trial, 100% were 65 years of age and 26% thrombocytopenia.phase), consider alternative medications or adjust VENCLEXTA dosage andwere75 years of age. Of the 61 patients treated with VENCLEXTA in Adverse reactions reported in patients with newly-diagnosed AMLclosely monitor for signs of VENCLEXTA toxicities.combination with low-dose cytarabine, 97% were 65 years of age and receiving VENCLEXTA in combination with low-dose cytarabine areIn patients with AML, adjust VENCLEXTA dosage and closely monitor for66% were 75 years of age. presented in Table 9.signs of VENCLEXTA toxicities.The efficacy and safety data presented in the Adverse Reactions and Table 9. Adverse Reactions Reported in 30% (All Grades) orResume the VENCLEXTA dosage that was used prior to concomitant useClinical Studies sections were obtained from these patients [see Adverse 5% (Grade 3) of Patients with AML Treated with VENCLEXTA inwith a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 daysReactions]. There are insufficient patient numbers to show differences in Combination with Low-Dose Cytarabineafter discontinuation of the inhibitor.safety and effectiveness between geriatric and younger patients. VENCLEXTA Avoid grapefruit products, Seville oranges, and starfruit during treatmentRenal Impairmentwith VENCLEXTA, as they contain inhibitors of CYP3A.Due to the increased risk of TLS, patients with reduced renal function Adverse Reaction by Body System (N = 61) Strong or Moderate CYP3A Inducers (CLcr 80 mL/min, calculated by Cockcroft-Gault formula) require more All GradesGrade 3intensive prophylaxis and monitoring to reduce the risk of TLS when (%) (%) Concomitant use with a strong CYP3A inducer decreases venetoclax C max initiating treatment with VENCLEXTA [see Warnings and Precautions]. and AUC inf , which may decrease VENCLEXTA efficacy. Avoid concomitantNo dose adjustment is recommended for patients with mild or moderate Blood and lymphatic system disorders use of VENCLEXTA with strong CYP3A inducers or moderate CYP3Arenal impairment (CLcr30 mL/min. A recommended dose has not been Thrombocytopeniaa 59 59 inducers.determined for patients with severe renal impairment (CLcr 30 mL/min) a Effect of VENCLEXTA on Other Drugs or patients on dialysis. Neutropenia 46 46 Warfarin Hepatic ImpairmentFebrile neutropenia 46 44 Concomitant use of VENCLEXTA increases warfarin C maxand AUC inf , whichNo dose adjustment is recommended for patients with mild (Child-Pugh A) Anemiaa 26 26 may increase the risk of bleeding. Closely monitor international normalizedor moderate (Child-Pugh B) hepatic impairment. ratio (INR) in patients using warfarin concomitantly with VENCLEXTA.Reduce the dose of VENCLEXTA for patients with severe hepatic Gastrointestinal disorders P-gp Substrates impairment (Child-Pugh C); monitor these patients more closely for signs Nausea 64 2 Concomitant use of VENCLEXTA increases C maxand AUC infof P-gpof toxicity. substrates, which may increase toxicities of these substrates. AvoidOVERDOSAGEDiarrhea 44 3 concomitant use of VENCLEXTA with a P-gp substrate. If a concomitantThere is no specific antidote for VENCLEXTA. For patients who experience Constipation 33 0 use is unavoidable, separate dosing of the P-gp substrate at least 6 hoursoverdose, closely monitor and provide appropriate supportive treatment; before VENCLEXTA.during ramp-up phase interrupt VENCLEXTA and monitor carefully for signs General disorders and administration site conditions USE IN SPECIFIC POPULATIONS and symptoms of TLS along with other toxicities. Based on venetoclax Fatiguea 44 10 Pregnancy large volume of distribution and extensive protein binding, dialysis is Infections and infestations Risk Summary unlikely to result in significant removal of venetoclax.a There are no available data on VENCLEXTA use in pregnant women toManufactured and Marketed by: Sepsis 20 18 inform a drug-associated risk of major birth defects and miscarriage.AbbVie Inc. Pneumoniaa 18 16 Based on toxicity observed in mice, VENCLEXTA may cause fetal harmNorth Chicago, IL 60064 when administered to pregnant women. In mice, venetoclax was fetotoxicand Device related infection 13 11 at exposures 1.2 times the human clinical exposure based on AUC at aMarketed by: Urinary tract infection 8 7 human dose of 400 mg daily. Advise pregnant women of the potentialGenentech USA, Inc. Metabolic and nutritional disorders risk to a fetus.A Member of the Roche Group The estimated background risk of major birth defects and miscarriage forSouth San Francisco, CA 94080-4990Decreased appetitea 28 7 the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk 2016-2020 AbbVie Inc. Respiratory disorders in the U.S. general population of major birth defects is 2% to 4% and of 2016-2020 Genentech, Inc.Dyspneaa 31 3 miscarriage is 15% to 20% of clinically recognized pregnancies.Ref: 20064248-R1Revised: May 2020Vascular disorders DataAnimal data LAB-3834 MASTERHemorrhagea 49 15 In embryo-fetal development studies, venetoclax was administered to Hypotensiona 21 7 pregnant mice and rabbits during the period of organogenesis. In mice, venetoclax was associated with increased post-implantation loss and Hypertension 15 8 decreased fetal body weight at 150 mg/kg/day (maternal exposuresUS-VENC-200072 Adverse reactions graded using NCI Common Terminology Criteria forapproximately 1.2 times the human AUC exposure at a dose of 400 mg Adverse Events version 4.0.daily). No teratogenicity was observed in either the mouse or the rabbit. aIncludes multiple adverse reaction terms.20064248-R1 Venclexta PB-7.5 x 10.5(3).indd 3 07 Jul 2020 12:41 PM'