b'DO NOT RE-SIZEDO NOT RE-SIZE Ad unit Project # must match this project # 000-000000US-VENC-210309Table 8. New or Worsening Laboratory Abnormalities (10%) ina dose interruption in 5% of patients included neutropenia (20%),VENCLEXTAPlacebo + Patients with AML Who Received VEN+AZA with a Difference Betweenthrombocytopenia (15%), pneumonia (8%), febrile neutropenia (6%), and+ Low-DoseLow-Dose Arms of 5% for All Grades or 2% for Grade 3 or 4 Reactionssepsis (excluding fungal; 6%). Among patients who achieved bone marrowCytarabine CytarabineCompared with PBO+AZA in VIALE-A clearance of leukemia, 32% underwent dose interruptions for Laboratory AbnormalityANC 500/microliter.AllGradeAllGrade VENCLEXTA +Placebo +Table 9 presents adverse reactions identified in VIALE-C. Grades3 or 4Grades3 or 4 Azacitidine Azacitidine Table 9. Adverse Reactions (10%) in Patients with AML Who(%) (%) (%) (%)Laboratory Abnormality AllGradeAllGradeReceived VEN+LDAC with a Difference Between Arms of 5% for AllChemistryGrades3 or 4Grades3 or 4Grades or 2% for Grade 3 or 4 Compared with PBO+LDAC in VIALE-CBilirubin increased61 7 38 7(%) (%) (%) (%)Albumin decreased 61 6 43 4Hematology VENCLEXTA + Placebo +Low-DoseLow-Dose Potassium decreased 56 16 4214 Neutrophils decreased 98 98 88 81 Cytarabine CytarabineCalcium decreased 53 845 13 Platelet decreased 94 88 94 80 Adverse Reaction(N = 142) (N = 68)Glucose increased 52 13 59 9 Lymphocytes decreased 91 71 72 39 AllGradeAllGrade AST increased 36 6 37 1Grades3 or 4Grades3 or 4Hemoglobin decreased 61 57 56 52 (%) (%) (%) (%)Alkaline phosphatase increased34 1 26 1Chemistry Gastrointestinal disordersALT increased 30 426 1 Bilirubin increased 53 7 40 4 Nausea 42 1 31 0Sodium increased 11 3 6 1The denominator used to calculate the rate varied from 38 to 68 in theCalcium decreased 51 6 39 9 Diarrhea 28 3 16 0 PBO+LDAC arm and from 65 to 142 in the VEN+LDAC arm based on theSodium decreased 46 14 47 8 Vomiting 25 1 13 0 number of patients with at least one post-treatment value. Alkaline phosphatase increased 42 1 29 1 Abdominal paina 15 1 9 3 M14-387 Blood bicarbonate decreased 31 1 25 0 Stomatitisb 15 1 6 0 The safety of VENCLEXTA in combination with low-dose cytarabine (N=61) was evaluated in M14-387, a non-randomized, open- label trial The denominator used to calculate the rate varied from 85 to 144 in theBlood and lymphatic system disorders of patients with newly diagnosed AML. At baseline, patients were 75 PBO+AZA arm and from 125 to 283 in the VEN+AZA arm based on theFebrile neutropenia 32 32 29 29 years of age, or had comorbidities that precluded the use of intensive number of patients with at least one post-treatment value. induction chemotherapy based on at least one of the following criteria: Infections and infestations baseline ECOG performance status of 2-3, severe cardiac or pulmonary VENCLEXTA in Combination with Azacitidine or Decitabinecomorbidity, moderate hepatic impairment, CLcr 45 mL/min, or other The safety of VENCLEXTA in combination with azacitidine (N=67) orPneumoniac29 19 21 21 comorbidity. Patients received VENCLEXTA 600 mg orally once daily after decitabine (N=13) was evaluated in M14-358, a non-randomized trial ofcompletion of the ramp-up phase in combination with low-dose cytarabine patients with newly diagnosed AML. At baseline, patients were 75 yearsVascular Disorders (20mg/m2 subcutaneously on Days 1-10 of each 28-day cycle). The safety of age, or had comorbidities that precluded the use of intensive inductionHemorrhaged 27 8 16 1 of VENCLEXTA in combination with low-dose cytarabine is consistent with chemotherapy based on at least one of the following criteria: baselineHypotensione11 5 4 1 that of VIALE-C. ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity,DRUG INTERACTIONSmoderate hepatic impairment, CLcr 45 mL/min, or other comorbidity.Musculoskeletal and connective tissue disorders Effects of Other Drugs on VENCLEXTAPatients received VENCLEXTA 400 mg orally once daily after completionfof the ramp-up phase in combination with azacitidine (75 mg/m2 eitherMusculoskeletal pain 23 3 18 0 Strong or Moderate CYP3A Inhibitors or P-gp Inhibitorsintravenously or subcutaneously on Days 1-7 of each 28-day cycle) orGeneral Disorders and Administration Site ConditionsConcomitant use with a strong or moderate CYP3A inhibitor or a P-gp decitabine (20 mg/m2 intravenously on Days 1-5 of each 28-day cycle). Fatigueg 22 2 21 0 inhibitor increases venetoclax C maxand AUC 0-INF , which may increase Azacitidine VENCLEXTA toxicities, including the risk of TLS [see Warnings and The median duration of exposure to VENCLEXTA when administered inNervous System Disorders Precautions]. combination with azacitidine was 6.5 months (range: 0.1 to 38.1 months).Headache 11 0 6 0 Concomitant use with a strong CYP3A inhibitor at initiation and during The safety of VENCLEXTA in combination with azacitidine in this trial isthe ramp-up phase in patients with CLL/SLL is contraindicated [see consistent with that of VIALE-A.aIncludes abdominal pain, abdominal pain upper, abdominal discomfort,Contraindications]. Decitabine and abdominal pain lower. In patients with CLL/SLL taking a steady daily dosage (after ramp-up The median duration of exposure to VENCLEXTA when administered inbIncludes stomatitis, mouth ulceration, aphthous ulcer, glossitis,phase), consider alternative medications or adjust VENCLEXTA dosage and combination with decitabine was 8.4 months (range: 0.5 to 39 months). mucosal inflammation, and tongue ulceration. monitor more frequently for adverse reactions. Serious adverse reactions were reported in 85% of patients who receivedcIncludes pneumonia, lung infection, lower respiratory tractIn patients with AML, adjust VENCLEXTA dosage and monitor more VENCLEXTA with decitabine, the most frequent (10%) being sepsisinfection, pneumonia fungal, lower respiratory tract infection fungal,frequently for adverse reactions. (excluding fungal; 46%), febrile neutropenia (38%), and pneumonia (31%).pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumoniaResume the VENCLEXTA dosage that was used prior to concomitant use One (8%) fatal adverse reaction of bacteremia occurred within 30 days ofcytomegaloviral, and pneumonia pseudomonal. with a strong or moderate CYP3A inhibitor or a P-gp inhibitor 2 to 3 days starting treatment. dIncludes epistaxis, conjunctival hemorrhage, hemoptysis,after discontinuation of the inhibitor. Permanent discontinuation of VENCLEXTA due to adverse reactionsgastrointestinal hemorrhage, gingival bleeding, mouth hemorrhage,Avoid grapefruit products, Seville oranges, and starfruit during treatment occurred in 38% of patients. The most frequent adverse reaction leading toupper gastrointestinal hemorrhage, hematuria, retinal hemorrhage,with VENCLEXTA, as they contain inhibitors of CYP3A. permanent discontinuation (5%) was pneumonia (8%).catheter site hemorrhage, cerebral hemorrhage, gastric hemorrhage,Strong or Moderate CYP3A InducersDosage reductions of VENCLEXTA due to adverse reactions occurred ingastritis hemorrhagic, hemorrhage intracranial, hemorrhageConcomitant use with a strong CYP3A inducer decreases venetoclax C max15% of patients. The most frequent adverse reaction leading to dosesubcutaneous, lip hemorrhage, mucosal hemorrhage, pharyngealand AUC 0-INF , which may decrease VENCLEXTA efficacy. Avoid concomitant reduction (5%) was neutropenia (15%).hemorrhage, post procedural hemorrhage, pulmonary alveolaruse of VENCLEXTA with strong CYP3A inducers or moderate CYP3A hemorrhage, pulmonary hemorrhage, tooth pulp hemorrhage, uterine Dosage interruptions of VENCLEXTA due to adverse reactions occurredhemorrhage, and vascular access site hemorrhage.inducers. in 69% of patients. The most frequent adverse reactions leading to doseeIncludes hypotension and orthostatic hypotension. Effect of VENCLEXTA on Other Drugsinterruption (10%) were neutropenia (38%), febrile neutropenia (23%),fIncludes back pain, arthralgia, pain in extremity, musculoskeletalWarfarinleukopenia (15%), and pneumonia (15%).pain, myalgia, neck pain, non-cardiac chest pain, arthritis, bone pain,Concomitant use of VENCLEXTA increases warfarin C maxand AUC 0-INF , The most common adverse reactions (30%) were febrile neutropeniamusculoskeletal chest pain, and spinal pain. which may increase the risk of bleeding. Monitor international normalized (69%), fatigue (62%), constipation (62%), musculoskeletal pain (54%),gIncludes fatigue and asthenia. ratio (INR) more frequently in patients using warfarin concomitantly with dizziness (54%), nausea (54%), abdominal pain (46%), diarrhea (46%),VENCLEXTA. pneumonia (46%), sepsis (excluding fungal; 46%), cough (38%), pyrexiaOther clinically important adverse reactions (All Grades) at 10% that didP-gp Substrates(31%), hypotension (31%), oropharyngeal pain (31%), edema (31%),not meet criteria for Table 9 or 10% are presented below:and vomiting (31%). The most common laboratory abnormalities (30%)a Concomitant use of VENCLEXTA increases C maxand AUC 0-INFof P-gp Hepatobiliary disorders: cholecystitis/cholelithiasis (1%) substrates, which may increase toxicities of these substrates. Avoid were neutrophils decreased (100%), lymphocytes decreased (100%),bwhite blood cells decreased (100%), platelets decreased (92%), calciumInfections and infestations: sepsis (excluding fungal; 15%), urinary tractconcomitant use of VENCLEXTA with a P-gp substrate. If a concomitant decreased (85%), hemoglobin decreased (69%), glucose increasedinfectionc (8%) use is unavoidable, separate dosing of the P-gp substrate at least 6 hours (69%), magnesium decreased (54%), potassium decreased (46%),Metabolism and nutrition disorders: decreased appetite (19%), tumorbefore VENCLEXTA. bilirubin increased (46%), albumin decreased (38%), alkaline phosphataselysis syndrome (6%) USE IN SPECIFIC POPULATIONSincreased (38%), sodium decreased (38%), ALT increased (31%),Nervous system disorders: dizzinessd (9%)Pregnancycreatinine increased (31%), and potassium increased (31%).Respiratory, thoracic, and mediastinal disorders: dyspneae (10%) Risk SummaryVENCLEXTA in Combination with Low-Dose Cytarabine Investigations: weight decreased (9%). Based on findings in animals and its mechanism of action, VENCLEXTA VIALE-C aIncludes cholecystitis and cholecystitis acute.may cause embryo-fetal harm when administered to a pregnant woman. The safety of VENCLEXTA in combination with low-dose cytarabinebIncludes sepsis, bacteremia, septic shock, neutropenic sepsis,There are no available data on VENCLEXTA use in pregnant women to (VEN+LDAC) (N=142) versus placebo with low-dose cytarabinestaphylococcal bacteremia, streptococcal bacteremia, bacterial sepsis,inform a drug-associated risk. Administration of venetoclax to pregnant (PBO+LDAC) (N=68) was evaluated in VIALE-C, a double-blind randomizedEscherichia bacteremia, pseudomonal bacteremia, and staphylococcalmice during the period of organogenesis was fetotoxic at exposures 1.2 trial in patients with newly diagnosed AML. At baseline, patients weresepsis.times the human exposure at the recommended dose of 400 mg daily 75 years of age, or had comorbidities that precluded the use of intensivecIncludes urinary tract infection and escherichia urinary tract infection. based on AUC. Advise pregnant women of the potential risk to a fetus. induction chemotherapy based on at least one of the following criteria:d The estimated background risk of major birth defects and miscarriage for baseline ECOG performance status of 2-3, severe cardiac or pulmonaryIncludes dizziness and vertigo. the indicated population is unknown. All pregnancies have a background comorbidity, moderate hepatic impairment, CLcr 45 mL/min, or othereIncludes dyspnea and dyspnea exertional. risk of birth defect, loss, or other adverse outcomes. In the U.S. general comorbidity. Patients were randomized to receive VENCLEXTA Table 10 describes laboratory abnormalities identified in VIALE-C. population, the estimated background risk of major birth defects and 600 mg orally once daily after completion of a 4-day ramp-up phase inmiscarriage in clinically recognized pregnancies is 2% to 4% and 15% to combination with low-dose cytarabine (20 mg/m2 subcutaneously onceTable 10. New or Worsening Laboratory Abnormalities (10%) in20%, respectively. daily on Days 1-10 of each 28-day cycle) or placebo in combinationPatients with AML Who Received VEN+LDAC with Difference Between with low-dose cytarabine. Among patients who received VEN+LDAC, theArms of 5% for All Grades or 2% for Grade 3 or 4 ReactionsDatamedian duration of exposure to VENCLEXTA was 3.9 months (range: Compared with PBO+LDAC in VIALE-C Animal data0.1 to 17.1 months).In embryo-fetal development studies, venetoclax was administered to Serious adverse reactions were reported in 65% of patients who receivedVENCLEXTAPlacebo +pregnant mice and rabbits during the period of organogenesis. In mice, VEN+LDAC, with the most frequent (10%) being pneumonia (17%), febrile+ Low-DoseLow-Dosevenetoclax was associated with increased post-implantation loss and neutropenia (16%), and sepsis (excluding fungal; 12%). Fatal adverseLaboratory Abnormality Cytarabine Cytarabine decreased fetal body weight at 150 mg/kg/day (maternal exposures reactions occurred in 23% of patients who received VEN+LDAC, withAllGradeAllGradeapproximately 1.2 times the human exposure at the recommended dose the most frequent (5%) being pneumonia (6%) and sepsis (excludingGrades3 or 4Grades3 or 4of 400 mg once daily). No teratogenicity was observed in either the mouse fungal; 7%). (%) (%) (%) (%) or the rabbit. Adverse reactions led to permanent discontinuation of VENCLEXTA inHematology Lactation25% of patients, dose reductions in 9%, and dose interruptions in 63%. Platelets decreased97 95 92 90 Risk SummaryThe most frequent adverse reaction (2%) which resulted in permanentThere are no data on the presence of VENCLEXTA in human milk or the discontinuation of VENCLEXTA was pneumonia (6%). Adverse reactions Neutrophils decreased 95 92 82 71 effects on the breastfed child or milk production. Venetoclax was present which required a dose reduction in 1% of patients were pneumonia (1%) Lymphocytes decreased 92 69 65 24 in the milk when administered to lactating rats (see Data). and thrombocytopenia (1%), and the adverse reactions which required Hemoglobin decreased 63 57 57 5420068717-R1 Venclexta PB-7.5 x 10.5(3.5).indd 3 /08/Nov2021 8:41 AM16-5085 US-VENC-210309 AD.indd 5 11/24/21 2:17 PM'