b'DO NOT RE-SIZEDO NOT RE-SIZE Ad unit Project # must match this project # 000-000000US-VENC-210309Table 4. New or Worsening Clinically Important LaboratoryTable 6 presents laboratory abnormalities reported throughout treatment(10%). Among patients who achieved bone marrow clearance of leukemia, Abnormalities (10%) in Patients Treated with VEN+R in MURANO that were new or worsening from baseline. The most common (5%)53% underwent dose interruptions for absolute neutrophil countGrade 4 laboratory abnormalities observed with VENCLEXTA monotherapy(ANC) 500/microliter. VENCLEXTA +Bendamustinewere hematologic laboratory abnormalities, including neutropenia (33%),Table 7 presents adverse reactions identified in VIALE-A.Rituximab (N+ Rituximab (Nleukopenia (11%), thrombocytopenia (15%), and lymphopenia (9%). Table 7. Adverse Reactions (10%) in Patients with AML Who Laboratory Abnormality = 194) = 188) Table 6. New or Worsening Laboratory Abnormalities in 40% (AllReceived VEN+AZA with a Difference Between Arms of 5% for All AllGradeAllGradeGrades) or 10% (Grade 3 or 4) of Patients with Previously TreatedGrades or 2% for Grade 3 or 4 Reactions Compared with PBO+AZA Gradesa3 or 4Gradesa3 or 4CLL/SLL Who Received VENCLEXTA Monotherapy in VIALE-A(%) (%) (%) (%) VENCLEXTA (N = 352) VENCLEXTA +Placebo + Hematology Laboratorya AzacitidineAzacitidine Leukopenia 89 46 81 35 Abnormality All Grades (%) Grade 3 or 4 (%) Adverse Reaction(N = 283) (N = 144) Lymphopenia 87 56 79 55 Hematology AllGradeAllGradeLeukopenia 89 42 Grades3 or 4Grades3 or 4Neutropenia 86 64 84 59 (%) (%) (%) (%) Anemia 50 12 63 15Neutropenia 87 63 Gastrointestinal disorders Thrombocytopenia 49 15 60 20Lymphopenia 74 40Nausea 44 2 35 1 Anemia 71 26Diarrheaa 43 5 33 3ChemistryThrombocytopenia 64 31Vomitingb 30 2 23 1 Blood creatinine increased 77 1 78 1Stomatitisc 18 1 13 0 Hypocalcemia 62 5 51 2 Chemistry d Hypocalcemia 87 12Abdominal pain 18 1 13 0 Hyperuricemia 36 36 33 33 Blood and lymphatic system disorders Hyperkalemia 24 3 19 2Hyperglycemia 67 7Febrile neutropenia 42 42 19 19aIncludes laboratory abnormalities that were new or worsening, or with Hyperkalemia 59 5 Musculoskeletal and connective tissue disordersworsening from baseline unknown. AST increased 53 3Musculoskeletal paine 36 2 28 1Grade 4 laboratory abnormalities that developed in 2% of patients treated Hypoalbuminemia 49 2 General disorders and administration site conditionswith VEN+R included neutropenia (31%), lymphopenia (16%), leukopenia Hypophosphatemia 45 11Fatiguef 31 6 23 2(6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%), hypoglycemia (2%), and hypermagnesemia (2%). Hyponatremia 40 9Edemag 27 1 19 0VENCLEXTA as MonotherapyaIncludes laboratory abnormalities that were new or worsening, orVascular disordersThe safety of VENCLEXTA was evaluated in pooled data from threeworsening from baseline unknown. Hemorrhageh 27 7 24 3single-arm trials (M13-982, M14-032, and M12-175). Patients receivedImportant Adverse Reactions in CLL/SLLHypotensioni 12 5 8 3VENCLEXTA 400 mg orally once daily after completing the ramp-up phase (N=352). The median duration of treatment with VENCLEXTA at the time ofTumor Lysis Syndrome Metabolism and nutrition disordersdata analysis was 14.5 months (range: 0 to 50 months). Fifty-two percentTumor lysis syndrome is an important identified risk when initiating Decreased appetitej 25 4 17 1of patients received VENCLEXTA for more than 60 weeks. VENCLEXTA.Skin and subcutaneous tissue disordersIn the pooled dataset, the median age was 66 years (range: 28 to 85CLL14Rashk25 1 15 0years), 93% were White, and 68% were male. The median number of priorThe incidence of TLS was 1% (3/212) in patients treated with VEN+G therapies was 3 (range: 0 to 15). [see Warnings and Precautions]. All three events of TLS resolved and didInfections and infestationsSerious adverse reactions were reported in 52% of patients, with thenot lead to withdrawal from the trial. Obinutuzumab administration was Sepsisl (excluding fungal) 22 22 16 14most frequent (5%) being pneumonia (9%), febrile neutropenia (5%),delayed in two cases in response to the TLS events. Urinary tract infectionm 16 6 9 6and sepsis (5%). Fatal adverse reactions that occurred in the absenceMURANOof disease progression and within 30 days of venetoclax treatment wereRespiratory, thoracic and mediastinal disordersreported in 2% of patients in the VENCLEXTA monotherapy studies, mostThe incidence of TLS was 3% (6/194) in patients treated with VEN+R. Dyspnean 18 4 10 2often (2 patients) from septic shock.After 77/389 patients were enrolled in the trial, the protocol was amended Adverse reactions led to treatment discontinuation in 9% of patients,to incorporate the current TLS prophylaxis and monitoring measures.Nervous system disordersdose reduction in 13%, and dose interruption in 36%. The most frequentAll events of TLS occurred during the VENCLEXTA ramp-up period and Dizzinesso 17 1 8 1adverse reactions leading to drug discontinuation were thrombocytopeniawere resolved within two days. All six patients completed the ramp-upaIncludes diarrhea and colitis. and autoimmune hemolytic anemia. The most frequent adverse reactionand reached the recommended daily dose of 400 mg of VENCLEXTA. NobIncludes vomiting and hematemesis.(5%) leading to dose reductions or interruptions was neutropenia (8%).clinical TLS was observed in patients who followed the current 5-weekcIncludes stomatitis, mouth ulceration, mucosal inflammation, cheilitis, ramp-up schedule and TLS prophylaxis and monitoring measures. Rates Table 5 presents adverse reactions identified in these trials. of laboratory abnormalities relevant to TLS for patients treated with VEN+Raphthous ulcer, glossitis, and tongue ulceration.Table 5. Adverse Reactions Reported in 10% (All Grades) or 5%are presented in Table 4.dIncludes abdominal pain, abdominal pain upper, abdominal discomfort, (Grade 3) of Patients with Previously Treated CLL/SLL Who ReceivedMonotherapy Studies (M13-982 and M14-032) and abdominal pain lower.VENCLEXTA MonotherapyIn 168 patients with CLL treated according to recommendations describedeIncludes arthralgia, back pain, pain in extremity, musculoskeletal pain, bone pain, myalgia, neck pain, non-cardiac chest pain, arthritis, VENCLEXTA in sections 2.1 and 2.2, the rate of TLS was 2%. All events either metmusculoskeletal chest pain, musculoskeletal stiffness, spinal pain, and (N = 352) laboratory TLS criteria (laboratory abnormalities that met 2 of themusculoskeletal discomfort.Adverse Reaction following within 24 hours of each other: potassium 6 mmol/L, uric acidfIncludes fatigue and asthenia.All GradesGrade 3 476 mol/L, calcium 1.75 mmol/L, or phosphorus 1.5 mmol/L),gIncludes edema peripheral, edema, generalized edema, eyelid edema, (%)(%) or were reported as TLS events. The events occurred in patients whoface edema, penile edema, periorbital edema, and swelling. had a lymph node(s) 5 cm and/or absolute lymphocyte count (ALC)hBlood and lymphatic system disorders 25 x 109/L. All events resolved within 5 days. No TLS with clinicalIncludes epistaxis, hematuria, conjunctival hemorrhage, hemoptysis, Neutropeniaa 50 45 consequences such as acute renal failure, cardiac arrhythmias, orhemorrhoidal hemorrhage, gingival bleeding, mouth hemorrhage, hemorrhage intracranial, vaginal hemorrhage, cerebral hemorrhage, Anemiaa 33 18 sudden death and/or seizures was observed in these patients. All patientsgastrointestinal hemorrhage, muscle hemorrhage, skin hemorrhage, a had CLcr 50 mL/min. Laboratory abnormalities relevant to TLS wereupper gastrointestinal hemorrhage, anal hemorrhage, eye hemorrhage, Thrombocytopenia 29 20 hyperkalemia (17% all Grades, 1% Grade 3), hyperphosphatemia (14%gastritis hemorrhagic, hemorrhage, hemorrhage urinary tract, Lymphopeniaa 11 7 all Grades, 2% Grade 3), hypocalcemia (16% all Grades, 2% Grade 3),hemorrhagic diathesis, hemorrhagic stroke, hemorrhagic vasculitis, Febrile neutropenia 6 6 and hyperuricemia (10% all Grades, 1% Grade 3).lower gastrointestinal hemorrhage, mucosal hemorrhage, penile Gastrointestinal disorders In the initial Phase 1 dose-finding trials, which had shorter (2-3 week)hemorrhage, post procedural hemorrhage, rectal hemorrhage, retinal ramp-up phase and higher starting doses, the incidence of TLS was 13%hemorrhage, shock hemorrhagic, soft tissue hemorrhage, subdural Diarrhea 43 3 (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and hemorrhage, tongue hemorrhage, urethral hemorrhage, vessel puncture Nausea 42 1 3 events of acute renal failure, 1 requiring dialysis. After this experience,site hemorrhage, vitreous hemorrhage, and wound hemorrhage. Abdominal paina 18 3 TLS risk assessment, dosing regimen, TLS prophylaxis and monitoringi j Includes hypotension and orthostatic hypotension.measures were revised.Includes decreased appetite and hypophagia.Vomiting 16 1 Acute Myeloid Leukemia kIncludes rash, rash maculo-papular, rash macular, drug eruption, Constipation 16 1 VENCLEXTA in Combination with Azacitidinerash papular, rash pustular, eczema, rash erythematous, rash pruritic, Mucositisa 13 1 The safety of VENCLEXTA in combination with azacitidine (VEN+AZA)dermatitis acneiform, rash morbilliform, dermatitis, eczema asteatotic, Infections and infestations (N=283) versus placebo in combination with azacitidine (PBO+AZA)exfoliative rash, and perivascular dermatitis. lIncludes sepsis, escherichia bacteremia, escherichia sepsis, septic Upper respiratory tract infectiona 36 1 (N=144) was evaluated in VIALE-A, a double-blind, randomized trial, inshock, bacteremia, staphylococcal bacteremia, klebsiella bacteremia, Pneumoniaa 14 8 patients with newly diagnosed AML. At baseline, patients were 75 yearsstaphylococcal sepsis, streptococcal bacteremia, enterococcal a of age or had comorbidities that precluded the use of intensive inductionbacteremia, klebsiella sepsis, pseudomonal bacteremia, pseudomonal Lower respiratory tract infection 11 2 chemotherapy based on at least one of the following criteria: baselinesepsis, urosepsis, bacterial sepsis, clostridial sepsis, enterococcal General disorders and administration site conditions ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity,sepsis, neutropenic sepsis, and streptococcal sepsis.Fatiguea 32 4 moderate hepatic impairment, CLcr 45 mL/min, or other comorbidity.mIncludes urinary tract infection, escherichia urinary tract infection, a Patients were randomized to receive VENCLEXTA 400 mg orally once dailycystitis, urinary tract infection enterococcal, urinary tract infection Edema 22 2 after completion of the ramp-up phase in combination with azacitidine2 bacterial, pyelonephritis acute, and urinary tract infection pseudomonal.Pyrexia 18 1 (75 mg/m either intravenously or subcutaneously on Days 1-7 of eachnIncludes dyspnea, dyspnea exertional, and dyspnea at rest.Musculoskeletal and connective tissue disorders 28-day cycle) or placebo in combination with azacitidine. Among patientsoIncludes dizziness and vertigo.who received VEN+AZA, the median duration of exposure to VENCLEXTA Musculoskeletal paina 29 2 was 7.6 months (range: 0.1 to 30.7 months).Other clinically important adverse reactions (All Grades) at 10% that did Arthralgia 12 1 Serious adverse reactions were reported in 83% of patients who receivednot meet criteria for Table 7 or 10% are presented below:Respiratory, thoracic, and mediastinal disorders VEN+AZA, with the most frequent (5%) being febrile neutropenia (30%),Hepatobiliary disorders: cholecystitis/cholelithiasisa (4%) Cougha 22 0 pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhageInfections and infestations: pneumoniab (33%)a (6%). Fatal adverse reactions occurred in 23% of patients who receivedMetabolism and nutrition disorders: tumor lysis syndrome (1%)Dyspnea 13 1 VEN+AZA, with the most frequent (2%) being pneumonia (4%), sepsisNervous system disorders: headachec (11%)Nervous system disorders (excluding fungal; 3%), and hemorrhage (2%). Investigations: weight decreased (13%).Headache 18 1 Adverse reactions led to permanent discontinuation of VENCLEXTA inaa 24% of patients, dose reductions in 2%, and dose interruptions in 72%.Includes cholecystitis acute, cholelithiasis, cholecystitis, and cholecystitis Dizziness 14 0 Adverse reactions which led to discontinuation of VENCLEXTA in 2% ofchronic.Skin and subcutaneous tissue disorders patients were sepsis (excluding fungal; 3%) and pneumonia (2%). ThebIncludes pneumonia, lung infection, pneumonia fungal, pneumonia Rasha 18 1 most frequent adverse reaction leading to dose reduction was pneumoniaklebsiella, atypical pneumonia, lower respiratory tract infection, pneumonia Adverse reactions graded using NCI Common Terminology Criteria for(0.7%). Adverse reactions which required a dose interruption in 5%viral, lower respiratory tract infection fungal, pneumonia hemophilus, Adverse Events version 4.0. of patients included febrile neutropenia (20%), neutropenia (20%),pneumonia pneumococcal, and pneumonia respiratory syncytial viral.aIncludes multiple adverse reaction terms. pneumonia (14%), sepsis (excluding fungal; 11%), and thrombocytopeniacIncludes headache and tension headache.Table 8 presents laboratory abnormalities identified in VIALE-A.20068717-R1 Venclexta PB-7.5 x 10.5(3.5).indd 2 /08/Nov2021 8:41 AM16-5085 US-VENC-210309 AD.indd 4 11/24/21 2:17 PM'