b'DO NOT RE-SIZEDO NOT RE-SIZEAd unit Project # must match this project # 000-000000US-VENC-220137Table 8. New or Worsening Laboratory Abnormalities (10%) insepsis (excluding fungal; 6%). Among patients who achieved bone marrowVENCLEXTAPlacebo + Patients with AML Who Received VEN+AZA with a Difference Betweenclearance of leukemia, 32% underwent dose interruptions for + Low-DoseLow-Dose Arms of 5% for All Grades or 2% for Grade 3 or 4 ReactionsANC 500/microliter.CytarabineCytarabineCompared with PBO+AZA in VIALE-A Table 9 presents adverse reactions identified in VIALE-C. Laboratory Abnormality AllGradeAllGrade VENCLEXTA + Placebo + Table 9. Adverse Reactions (10%) in Patients with AML WhoGrades 3 or 4 Grades 3 or 4Azacitidine Azacitidine Received VEN+LDAC with a Difference Between Arms of 5% for All(%) (%) (%) (%)Laboratory Abnormality AllGradeAllGradeGrades or 2% for Grade 3 or 4 Compared with PBO+LDAC in VIALE-CAST increased 36 6 37 1Grades3 or 4Grades3 or 4VENCLEXTA + Low- Placebo + Low-Alkaline phosphatase increased34 1 26 1(%) (%) (%) (%) Dose Cytarabine Dose CytarabineALT increased 30 426 1Hematology Adverse Reaction(N = 142) (N = 68)Sodium increased 11 3 6 1 Neutrophils decreased 98 98 88 81 AllGrade 3AllGrade 3Platelet decreased 94 88 94 80 Grades or 4 Grades or 4 The denominator used to calculate the rate varied from 38 to 68 in the (%) (%) (%) (%) PBO+LDAC arm and from 65 to 142 in the VEN+LDAC arm based on theLymphocytes decreased 91 71 72 39 Gastrointestinal disorders number of patients with at least one post-treatment value. Hemoglobin decreased 61 57 56 52 Nausea 42 1 31 0 M14-387Chemistry Diarrhea 28 3 16 0 The safety of VENCLEXTA in combination with low-dose cytarabine Bilirubin increased 53 7 40 4 (N=61) was evaluated in M14-387, a non-randomized, open- label trial of Vomiting 25 1 13 0 patients with newly diagnosed AML. At baseline, patients were Calcium decreased 51 6 39 9 Abdominal paina 15 1 9 3 75 years of age, or had comorbidities that precluded the use of intensiveSodium decreased 46 14 47 8 Stomatitisb 15 1 6 0 induction chemotherapy based on at least one of the following criteria:Alkaline phosphatase increased 42 1 29 1 baseline ECOG performance status of 2-3, severe cardiac or pulmonary Blood and lymphatic system disorders comorbidity, moderate hepatic impairment, CLcr 45 mL/min, or otherBlood bicarbonate decreased 31 1 25 0 Febrile neutropenia 32 32 29 29 comorbidity. Patients received VENCLEXTA 600 mg orally once daily after The denominator used to calculate the rate varied from 85 to 144 in thecompletion of the ramp-up phase in combination with low-dose cytarabine Infections and infestations 2PBO+AZA arm and from 125 to 283 in the VEN+AZA arm based on thec (20mg/m subcutaneously on Days 1-10 of each 28-day cycle). The safety number of patients with at least one post-treatment value. Pneumonia29 19 21 21 of VENCLEXTA in combination with low-dose cytarabine is consistent with VENCLEXTA in Combination with Azacitidine or DecitabineVascular Disorders that of VIALE-C. The safety of VENCLEXTA in combination with azacitidine (N=67) orHemorrhaged 27 8 16 1 DRUG INTERACTIONSdecitabine (N=13) was evaluated in M14-358, a non-randomized trial ofHypotensione11 5 4 1 Effects of Other Drugs on VENCLEXTApatients with newly diagnosed AML. At baseline, patients were 75 yearsMusculoskeletal and connective tissue disorders Strong or Moderate CYP3A Inhibitors or P-gp Inhibitorsof age, or had comorbidities that precluded the use of intensive inductionConcomitant use with a strong or moderate CYP3A inhibitor or a P-gp chemotherapy based on at least one of the following criteria: baselineMusculoskeletal painf 23 3 18 0 inhibitor increases venetoclax C maxand AUC 0-INF , which may increase ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity,General Disorders and Administration Site ConditionsVENCLEXTA toxicities, including the risk of TLS [see Warnings and moderate hepatic impairment, CLcr 45 mL/min, or other comorbidity.Fatigueg 22 2 21 0 Precautions]. Patients received VENCLEXTA 400 mg orally once daily after completionConcomitant use with a strong CYP3A inhibitor at initiation and during of the ramp-up phase in combination with azacitidine (75 mg/m2 eitherNervous System Disorders the ramp-up phase in patients with CLL/SLL is contraindicated [see intravenously or subcutaneously on Days 1-7 of each 28-day cycle) orContraindications]. decitabine (20 mg/m2 intravenously on Days 1-5 of each 28-day cycle). Headache 11 0 6 0aIncludes abdominal pain, abdominal pain upper, abdominal discomfort,In patients with CLL/SLL taking a steady daily dosage (after ramp-up Azacitidine and abdominal pain lower. phase), consider alternative medications or adjust VENCLEXTA dosage and The median duration of exposure to VENCLEXTA when administered inbIncludes stomatitis, mouth ulceration, aphthous ulcer, glossitis,monitor more frequently for adverse reactions. combination with azacitidine was 6.5 months (range: 0.1 to 38.1 months).mucosal inflammation, and tongue ulceration. In patients with AML, adjust VENCLEXTA dosage and monitor more The safety of VENCLEXTA in combination with azacitidine in this trial iscIncludes pneumonia, lung infection, lower respiratory tractfrequently for adverse reactions. consistent with that of VIALE-A.infection, pneumonia fungal, lower respiratory tract infection fungal,Resume the VENCLEXTA dosage that was used prior to concomitant use Decitabine pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumoniawith a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days The median duration of exposure to VENCLEXTA when administered incytomegaloviral, and pneumonia pseudomonal. after discontinuation of the inhibitor. combination with decitabine was 8.4 months (range: 0.5 to 39 months). dIncludes epistaxis, conjunctival hemorrhage, hemoptysis,Avoid grapefruit products, Seville oranges, and starfruit during treatment Serious adverse reactions were reported in 85% of patients who receivedgastrointestinal hemorrhage, gingival bleeding, mouth hemorrhage,with VENCLEXTA, as they contain inhibitors of CYP3A. VENCLEXTA with decitabine, the most frequent (10%) being sepsisupper gastrointestinal hemorrhage, hematuria, retinal hemorrhage,Strong or Moderate CYP3A Inducers(excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%).catheter site hemorrhage, cerebral hemorrhage, gastric hemorrhage, One (8%) fatal adverse reaction of bacteremia occurred within 30 days ofgastritis hemorrhagic, hemorrhage intracranial, hemorrhageConcomitant use with a strong CYP3A inducer decreases venetoclax C maxstarting treatment. subcutaneous, lip hemorrhage, mucosal hemorrhage, pharyngealand AUC 0-INF , which may decrease VENCLEXTA efficacy. Avoid concomitant hemorrhage, post procedural hemorrhage, pulmonary alveolaruse of VENCLEXTA with strong CYP3A inducers or moderate CYP3A Permanent discontinuation of VENCLEXTA due to adverse reactionshemorrhage, pulmonary hemorrhage, tooth pulp hemorrhage, uterineinducers. occurred in 38% of patients. The most frequent adverse reaction leading tohemorrhage, and vascular access site hemorrhage.Effect of VENCLEXTA on Other Drugspermanent discontinuation (5%) was pneumonia (8%).e f Includes hypotension and orthostatic hypotension. WarfarinDosage reductions of VENCLEXTA due to adverse reactions occurred inIncludes back pain, arthralgia, pain in extremity, musculoskeletal 15% of patients. The most frequent adverse reaction leading to dosepain, myalgia, neck pain, non-cardiac chest pain, arthritis, bone pain,Concomitant use of VENCLEXTA increases warfarin C maxand AUC 0-INF , reduction (5%) was neutropenia (15%).musculoskeletal chest pain, and spinal pain. which may increase the risk of bleeding. Monitor international normalized Dosage interruptions of VENCLEXTA due to adverse reactions occurredgIncludes fatigue and asthenia. ratio (INR) more frequently in patients using warfarin concomitantly with in 69% of patients. The most frequent adverse reactions leading to doseOther clinically important adverse reactions (All Grades) at 10% that didVENCLEXTA. interruption (10%) were neutropenia (38%), febrile neutropenia (23%),not meet criteria for Table 9 or 10% are presented below: P-gp Substratesleukopenia (15%), and pneumonia (15%).Hepatobiliary disorders: cholecystitis/cholelithiasisa (1%) Concomitant use of VENCLEXTA increases C maxand AUC 0-INFof P-gp The most common adverse reactions (30%) were febrile neutropeniab substrates, which may increase toxicities of these substrates. Avoid Infections and infestations: sepsis (excluding fungal; 15%), urinary tractconcomitant use of VENCLEXTA with a P-gp substrate. If a concomitant (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%),infectionc (8%) use is unavoidable, separate dosing of the P-gp substrate at least 6 hours dizziness (54%), nausea (54%), abdominal pain (46%), diarrhea (46%), pneumonia (46%), sepsis (excluding fungal; 46%), cough (38%), pyrexiaMetabolism and nutrition disorders: decreased appetite (19%), tumorbefore VENCLEXTA. (31%), hypotension (31%), oropharyngeal pain (31%), edema (31%),lysis syndrome (6%) USE IN SPECIFIC POPULATIONSand vomiting (31%). The most common laboratory abnormalities (30%)Nervous system disorders: dizzinessd (9%)Pregnancywere neutrophils decreased (100%), lymphocytes decreased (100%),Respiratory, thoracic, and mediastinal disorders: dyspneae (10%) Risk Summarywhite blood cells decreased (100%), platelets decreased (92%), calciumInvestigations: weight decreased (9%). Based on findings in animals and its mechanism of action, VENCLEXTA decreased (85%), hemoglobin decreased (69%), glucose increaseda may cause embryo-fetal harm when administered to a pregnant woman. (69%), magnesium decreased (54%), potassium decreased (46%),Includes cholecystitis and cholecystitis acute. bilirubin increased (46%), albumin decreased (38%), alkaline phosphatasebIncludes sepsis, bacteremia, septic shock, neutropenic sepsis,There are no available data on VENCLEXTA use in pregnant women to increased (38%), sodium decreased (38%), ALT increased (31%),staphylococcal bacteremia, streptococcal bacteremia, bacterial sepsis,inform a drug-associated risk. Administration of venetoclax to pregnant creatinine increased (31%), and potassium increased (31%).Escherichia bacteremia, pseudomonal bacteremia, and staphylococcalmice during the period of organogenesis was fetotoxic at exposuresVENCLEXTA in Combination with Low-Dose Cytarabine sepsis.1.2 times the human exposure at the recommended dose of 400 mg daily VIALE-C cIncludes urinary tract infection and escherichia urinary tract infection. based on AUC. Advise pregnant women of the potential risk to a fetus. d The estimated background risk of major birth defects and miscarriage for The safety of VENCLEXTA in combination with low-dose cytarabineIncludes dizziness and vertigo. the indicated population is unknown. All pregnancies have a background (VEN+LDAC) (N=142) versus placebo with low-dose cytarabine (PBO+LDAC)eIncludes dyspnea and dyspnea exertional. risk of birth defect, loss, or other adverse outcomes. In the U.S. general (N=68) was evaluated in VIALE-C, a double-blind randomized trial inTable 10 describes laboratory abnormalities identified in VIALE-C. population, the estimated background risk of major birth defects and patients with newly diagnosed AML. At baseline, patients were 75 yearsTable 10. New or Worsening Laboratory Abnormalities (10%) inmiscarriage in clinically recognized pregnancies is 2% to 4% and 15% to of age, or had comorbidities that precluded the use of intensive inductionPatients with AML Who Received VEN+LDAC with Difference Between20%, respectively. chemotherapy based on at least one of the following criteria: baselineArms of 5% for All Grades or 2% for Grade 3 or 4 ReactionsDataECOG performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, CLcr 45 mL/min, or other comorbidity.Compared with PBO+LDAC in VIALE-C Animal dataPatients were randomized to receive VENCLEXTA 600 mg orally once dailyVENCLEXTAPlacebo +In embryo-fetal development studies, venetoclax was administered to after completion of a 4-day ramp-up phase in combination with low-dose+ Low-DoseLow-Dosepregnant mice and rabbits during the period of organogenesis. In mice, cytarabine (20 mg/m2 subcutaneously once daily on Days 1-10 of eachCytarabineCytarabine venetoclax was associated with increased post-implantation loss and 28-day cycle) or placebo in combination with low-dose cytarabine. AmongLaboratory Abnormality decreased fetal body weight at 150 mg/kg/day (maternal exposures patients who received VEN+LDAC, the median duration of exposure toAllGradeAllGradeapproximately 1.2 times the human exposure at the recommended dose VENCLEXTA was 3.9 months (range: 0.1 to 17.1 months).Grades 3 or 4 Grades 3 or 4 of 400 mg once daily). No teratogenicity was observed in either the mouse Serious adverse reactions were reported in 65% of patients who received(%) (%) (%) (%) or the rabbit. VEN+LDAC, with the most frequent (10%) being pneumonia (17%), febrileHematology Lactationneutropenia (16%), and sepsis (excluding fungal; 12%). Fatal adverse Platelets decreased97 95 92 90 Risk Summaryreactions occurred in 23% of patients who received VEN+LDAC, with Neutrophils decreased 95 92 82 71 There are no data on the presence of VENCLEXTA in human milk or the the most frequent (5%) being pneumonia (6%) and sepsis (excludingeffects on the breastfed child or milk production. Venetoclax was present fungal; 7%).Lymphocytes decreased 92 69 65 24 in the milk when administered to lactating rats (see Data). Adverse reactions led to permanent discontinuation of VENCLEXTA in Hemoglobin decreased 63 57 57 54 Because of the potential for serious adverse reactions in a breastfed child, 25% of patients, dose reductions in 9%, and dose interruptions in 63%.Chemistry advise women not to breastfeed during treatment with VENCLEXTA and for The most frequent adverse reaction (2%) which resulted in permanent1 week after the last dose. discontinuation of VENCLEXTA was pneumonia (6%). Adverse reactions Bilirubin increased61 7 38 7which required a dose reduction in 1% of patients were pneumonia (1%) Albumin decreased 61 6 43 4 Dataand thrombocytopenia (1%), and the adverse reactions which required Potassium decreased 56 16 4214 Animal Dataa dose interruption in 5% of patients included neutropenia (20%),Venetoclax was administered (single dose; 150 mg/kg oral) to lactating thrombocytopenia (15%), pneumonia (8%), febrile neutropenia (6%), and Calcium decreased 53 845 13 rats 8 to 10 days post-parturition. Venetoclax in milk was 1.6 times lowerGlucose increased 52 13 59 9 than in plasma. Parent drug (venetoclax) represented the majority of the total drug-related material in milk, with trace levels of three metabolites. 20070720 Venclexta PB-7.5 x 10.5(3.5).indd 3 /29/Jun2022 2:29 PM'