b'DO NOT RE-SIZEDO NOT RE-SIZEAd unit Project # must match this project # 000-000000US-VENC-220137Table 4. New or Worsening Clinically Important LaboratoryTable 6 presents laboratory abnormalities reported throughout treatmentTable 7 presents adverse reactions identified in VIALE-A.Abnormalities (10%) in Patients Treated with VEN+R in MURANO that were new or worsening from baseline. The most common (5%)Table 7. Adverse Reactions (10%) in Patients with AML Who Grade 4 laboratory abnormalities observed with VENCLEXTA monotherapyReceived VEN+AZA with a Difference Between Arms of 5% for All VENCLEXTA +Bendamustine +were hematologic laboratory abnormalities, including neutropenia (33%),Grades or 2% for Grade 3 or 4 Reactions Compared with PBO+AZA Rituximab Rituximab leukopenia (11%), thrombocytopenia (15%), and lymphopenia (9%). in VIALE-ALaboratory Abnormality (N = 194) (N = 188) Table 6. New or Worsening Laboratory Abnormalities in 40% (All AllGradeAllGradeGrades) or 10% (Grade 3 or 4) of Patients with Previously TreatedAdverse ReactionVENCLEXTA +Placebo + Gradesa3 or 4 Gradesa3 or 4 CLL/SLL Who Received VENCLEXTA Monotherapy Azacitidine Azacitidine(%) (%) (%) (%) (N = 283) (N = 144)Hematology VENCLEXTA AllGrade 3AllGrade 3 (N = 352) Leukopenia 89 46 81 35 Laboratory Abnormality a Grades or 4 Grades or 4All Grades Grade 3 or 4 (%) (%) (%) (%) Lymphopenia 87 56 79 55 (%)(%) Gastrointestinal disorders Neutropenia 86 64 84 59 HematologyNausea 44 2 35 1 Anemia 50 12 63 15Leukopenia 89 42Diarrheaa 43 5 33 3 Thrombocytopenia 49 15 60 20Neutropenia 87 63Vomitingb 30 2 23 1ChemistryLymphopenia 74 40Stomatitisc 18 1 13 0 Blood creatinine increased 77 1 78 1Anemia 71 26Abdominal paind 18 1 13 0 Hypocalcemia 62 5 51 2Thrombocytopenia 64 31 Blood and lymphatic system disorders Hyperuricemia 36 36 33 33 ChemistryFebrile neutropenia 42 42 19 19 Hyperkalemia 24 3 19 2Hypocalcemia 87 12a Musculoskeletal and connective tissue disordersIncludes laboratory abnormalities that were new or worsening, or with Hyperglycemia 67 7 eworsening from baseline unknown. Hyperkalemia 59 5Musculoskeletal pain 36 2 28 1Grade 4 laboratory abnormalities that developed in 2% of patients treated AST increased 53 3 General disorders and administration site conditions fwith VEN+R included neutropenia (31%), lymphopenia (16%), leukopenia Fatigue 31 6 23 2(6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%), Hypoalbuminemia 49 2Edemag 27 1 19 0hypoglycemia (2%), and hypermagnesemia (2%). Hypophosphatemia 45 11 Vascular disordersVENCLEXTA as Monotherapy Hyponatremia 40 9 hThe safety of VENCLEXTA was evaluated in pooled data from threeaIncludes laboratory abnormalities that were new or worsening, or Hemorrhage i 27 7 24 3single-arm trials (M13-982, M14-032, and M12-175). Patients receivedworsening from baseline unknown. Hypotension 12 5 8 3VENCLEXTA 400 mg orally once daily after completing the ramp-up phaseMetabolism and nutrition disorders(N=352). The median duration of treatment with VENCLEXTA at the time ofImportant Adverse Reactions in CLL/SLLdata analysis was 14.5 months (range: 0 to 50 months). Fifty-two percentTumor Lysis SyndromeDecreased appetitej 25 4 17 1of patients received VENCLEXTA for more than 60 weeks. Tumor lysis syndrome is an important identified risk when initiatingSkin and subcutaneous tissue disordersIn the pooled dataset, the median age was 66 years (range: 28 to 85VENCLEXTA. Rashk25 1 15 0years), 93% were White, and 68% were male. The median number of priorCLL14 Infections and infestationstherapies was 3 (range: 0 to 15). The incidence of TLS was 1% (3/212) in patients treated with VEN+GlSerious adverse reactions were reported in 52% of patients, with the Sepsis (excluding fungal) 22 22 16 14most frequent (5%) being pneumonia (9%), febrile neutropenia (5%),[see Warnings and Precautions]. All three events of TLS resolved and did Urinary tract infectionm 16 6 9 6and sepsis (5%). Fatal adverse reactions that occurred in the absencenot lead to withdrawal from the trial. Obinutuzumab administration was of disease progression and within 30 days of venetoclax treatment weredelayed in two cases in response to the TLS events.Respiratory, thoracic and mediastinal disordersreported in 2% of patients in the VENCLEXTA monotherapy studies, mostMURANODyspnean 18 4 10 2often (2 patients) from septic shock.The incidence of TLS was 3% (6/194) in patients treated with VEN+R.Nervous system disordersAdverse reactions led to treatment discontinuation in 9% of patients,After 77/389 patients were enrolled in the trial, the protocol was amendedodose reduction in 13%, and dose interruption in 36%. The most frequentto incorporate the current TLS prophylaxis and monitoring measures. Dizziness 17 1 8 1adverse reactions leading to drug discontinuation were thrombocytopeniaAll events of TLS occurred during the VENCLEXTA ramp-up period andaIncludes diarrhea and colitis. and autoimmune hemolytic anemia. The most frequent adverse reactionwere resolved within two days. All six patients completed the ramp-upbIncludes vomiting and hematemesis.(5%) leading to dose reductions or interruptions was neutropenia (8%).and reached the recommended daily dose of 400 mg of VENCLEXTA. NocIncludes stomatitis, mouth ulceration, mucosal inflammation, cheilitis, clinical TLS was observed in patients who followed the current 5-weekaphthous ulcer, glossitis, and tongue ulceration.Table 5 presents adverse reactions identified in these trials. ramp-up schedule and TLS prophylaxis and monitoring measures. RatesdIncludes abdominal pain, abdominal pain upper, abdominal discomfort, Table 5. Adverse Reactions Reported in 10% (All Grades) or 5%of laboratory abnormalities relevant to TLS for patients treated with VEN+Rand abdominal pain lower.(Grade 3) of Patients with Previously Treated CLL/SLL Who Receivedare presented in Table 4.eIncludes arthralgia, back pain, pain in extremity, musculoskeletal VENCLEXTA MonotherapyMonotherapy Studies (M13-982 and M14-032) pain, bone pain, myalgia, neck pain, non-cardiac chest pain, arthritis, In 168 patients with CLL treated according to recommendations describedmusculoskeletal chest pain, musculoskeletal stiffness, spinal pain, and VENCLEXTA in sections 2.1 and 2.2, the rate of TLS was 2%. All events either metmusculoskeletal discomfort. fAdverse Reaction(N = 352) laboratory TLS criteria (laboratory abnormalities that met 2 of theg Includes fatigue and asthenia.All Grades Grade 3 following within 24 hours of each other: potassium 6 mmol/L, uric acidIncludes edema peripheral, edema, generalized edema, eyelid edema, face edema, penile edema, periorbital edema, and swelling.(%)(%) 476 mol/L, calcium 1.75 mmol/L, or phosphorus 1.5 mmol/L), orhwere reported as TLS events. The events occurred in patients who had aIncludes epistaxis, hematuria, conjunctival hemorrhage, hemoptysis, Blood and lymphatic system disorders lymph node(s) 5 cm and/or absolute lymphocyte count (ALC) 25 x 109/L.hemorrhoidal hemorrhage, gingival bleeding, mouth hemorrhage, Neutropeniaa 50 45 All events resolved within 5 days. No TLS with clinical consequenceshemorrhage intracranial, vaginal hemorrhage, cerebral hemorrhage, a such as acute renal failure, cardiac arrhythmias, or sudden death and/orgastrointestinal hemorrhage, muscle hemorrhage, skin hemorrhage, Anemia 33 18 seizures was observed in these patients. All patients had CLcrupper gastrointestinal hemorrhage, anal hemorrhage, eye hemorrhage, Thrombocytopeniaa 29 20 50 mL/min. Laboratory abnormalities relevant to TLS were hyperkalemiagastritis hemorrhagic, hemorrhage, hemorrhage urinary tract, Lymphopeniaa 11 7 (17% all Grades, 1% Grade 3), hyperphosphatemia (14% all Grades,hemorrhagic diathesis, hemorrhagic stroke, hemorrhagic vasculitis, 2% Grade 3), hypocalcemia (16% all Grades, 2% Grade 3), andlower gastrointestinal hemorrhage, mucosal hemorrhage, penile Febrile neutropenia 6 6 hyperuricemia (10% all Grades, 1% Grade 3).hemorrhage, post procedural hemorrhage, rectal hemorrhage, retinal Gastrointestinal disorders In the initial Phase 1 dose-finding trials, which had shorter (2-3 week)hemorrhage, shock hemorrhagic, soft tissue hemorrhage, subdural Diarrhea 43 3 ramp-up phase and higher starting doses, the incidence of TLS was 13%hemorrhage, tongue hemorrhage, urethral hemorrhage, vessel puncture (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and site hemorrhage, vitreous hemorrhage, and wound hemorrhage. iNausea 42 1 3 events of acute renal failure, 1 requiring dialysis. After this experience,j Includes hypotension and orthostatic hypotension.Abdominal paina 18 3 TLS risk assessment, dosing regimen, TLS prophylaxis and monitoringk Includes decreased appetite and hypophagia.Includes rash, rash maculo-papular, rash macular, drug eruption, Vomiting 16 1 measures were revised.rash papular, rash pustular, eczema, rash erythematous, rash pruritic, Constipation 16 1 Acute Myeloid Leukemia dermatitis acneiform, rash morbilliform, dermatitis, eczema asteatotic, Mucositisa 13 1 VENCLEXTA in Combination with Azacitidineexfoliative rash, and perivascular dermatitis. lThe safety of VENCLEXTA in combination with azacitidine (VEN+AZA)Includes sepsis, escherichia bacteremia, escherichia sepsis, septic Infections and infestations (N=283) versus placebo in combination with azacitidine (PBO+AZA)shock, bacteremia, staphylococcal bacteremia, klebsiella bacteremia, Upper respiratory tract infectiona 36 1 (N=144) was evaluated in VIALE-A, a double-blind, randomized trial, instaphylococcal sepsis, streptococcal bacteremia, enterococcal Pneumoniaa 14 8 patients with newly diagnosed AML. At baseline, patients were 75 yearsbacteremia, klebsiella sepsis, pseudomonal bacteremia, pseudomonal a of age or had comorbidities that precluded the use of intensive inductionsepsis, urosepsis, bacterial sepsis, clostridial sepsis, enterococcal Lower respiratory tract infection 11 2 chemotherapy based on at least one of the following criteria: baselinesepsis, neutropenic sepsis, and streptococcal sepsis.General disorders and administration site conditions ECOG performance status of 2-3, severe cardiac or pulmonary comorbidity,mIncludes urinary tract infection, escherichia urinary tract infection, a moderate hepatic impairment, CLcr 45 mL/min, or other comorbidity.cystitis, urinary tract infection enterococcal, urinary tract infection Fatigue 32 4 bacterial, pyelonephritis acute, and urinary tract infection pseudomonal.Patients were randomized to receive VENCLEXTA 400 mg orally once dailynEdemaa 22 2 after completion of the ramp-up phase in combination with azacitidine o Includes dyspnea, dyspnea exertional, and dyspnea at rest.Pyrexia 18 1 (75 mg/m2 either intravenously or subcutaneously on Days 1-7 of eachIncludes dizziness and vertigo.Musculoskeletal and connective tissue disorders 28-day cycle) or placebo in combination with azacitidine. Among patientsOther clinically important adverse reactions (All Grades) at 10% that did a who received VEN+AZA, the median duration of exposure to VENCLEXTAnot meet criteria for Table 7 or 10% are presented below:Musculoskeletal pain 29 2 was 7.6 months (range: 0.1 to 30.7 months).Hepatobiliary disorders: cholecystitis/cholelithiasisa (4%) Arthralgia 12 1 Serious adverse reactions were reported in 83% of patients who receivedInfections and infestations: pneumoniab (33%)Respiratory, thoracic, and mediastinal disorders VEN+AZA, with the most frequent (5%) being febrile neutropenia (30%),Metabolism and nutrition disorders: tumor lysis syndrome (1%)pneumonia (22%), sepsis (excluding fungal; 19%), and hemorrhage Cougha 22 0 (6%). Fatal adverse reactions occurred in 23% of patients who receivedNervous system disorders: headachec (11%)Dyspneaa 13 1 VEN+AZA, with the most frequent (2%) being pneumonia (4%), sepsisInvestigations: weight decreased (13%).Nervous system disorders (excluding fungal; 3%), and hemorrhage (2%).aIncludes cholecystitis acute, cholelithiasis, cholecystitis, and cholecystitis Adverse reactions led to permanent discontinuation of VENCLEXTA inchronic.Headache 18 1 24% of patients, dose reductions in 2%, and dose interruptions in 72%.bDizzinessa 14 0 Adverse reactions which led to discontinuation of VENCLEXTA in 2% ofIncludes pneumonia, lung infection, pneumonia fungal, pneumonia patients were sepsis (excluding fungal; 3%) and pneumonia (2%). Theklebsiella, atypical pneumonia, lower respiratory tract infection, pneumonia Skin and subcutaneous tissue disorders most frequent adverse reaction leading to dose reduction was pneumoniaviral, lower respiratory tract infection fungal, pneumonia hemophilus, a pneumonia pneumococcal, and pneumonia respiratory syncytial viral.Rash 18 1 (0.7%). Adverse reactions which required a dose interruption in 5%cAdverse reactions graded using NCI Common Terminology Criteria forof patients included febrile neutropenia (20%), neutropenia (20%),Includes headache and tension headache.Adverse Events version 4.0.pneumonia (14%), sepsis (excluding fungal; 11%), and thrombocytopeniaTable 8 presents laboratory abnormalities identified in VIALE-A.aIncludes multiple adverse reaction terms. (10%). Among patients who achieved bone marrow clearance of leukemia, 53% underwent dose interruptions for absolute neutrophil count (ANC) 500/microliter. 20070720 Venclexta PB-7.5 x 10.5(3.5).indd 2 /29/Jun2022 2:29 PM'