b'DO NOT RE-SIZEDO NOT RE-SIZEAd unit Project # must match this project # 000-000000US-VENC-200072VENCLEXTA +Bendamustine +Table 6. New or Worsening Laboratory Abnormalities with VENCLEXTASerious adverse reactions were reported in 85% of patients. The most RituximabRituximabMonotherapy (40% All Grades or 10% Grade 3 or 4) frequent serious adverse reactions (5%) were febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, (N = 194) (N = 188) VENCLEXTA cellulitis, and localized infection. LaboratoryAlla Grade 3Alla Grade 3(N = 352) One (8%) fatal adverse drug reaction of bacteremia occurred within 30 Abnormality Gradesor 4Gradesor 4Laboratory Abnormality a days of starting treatment. (%) (%) (%) (%) All GradesGrade 3 or 4 (%) (%) Discontinuations due to adverse reactions occurred in 38% of patients. TheHyperuricemia 36 36 33 33 Hematology most frequent adverse reaction leading to drug discontinuation (5%) wasHyperkalemia 24 3 19 2 Leukopenia 89 42 pneumonia (excluding fungal). Dosage interruptions due to adverse reactions occurred in 62% of patients. aIncludes laboratory abnormalities that were new or worsening, or withNeutropenia 87 63 The most frequent adverse reactions leading to dose interruption (5%) worsening from baseline unknown.Lymphopenia 74 40 were febrile neutropenia, neutropenia, and pneumonia (excluding fungal). Grade 4 laboratory abnormalities developing in 2% of patients treatedAnemia 71 26 Dosage reductions due to adverse reactions occurred in 15% of patients. with VEN+R include neutropenia (31%), lymphopenia (16%), leukopeniaThe most frequent adverse reaction leading to dose reduction (5%) was (6%), thrombocytopenia (6%), hyperuricemia (4%), hypocalcemia (2%),Thrombocytopenia 64 31 neutropenia. hypoglycemia (2%), and hypermagnesemia (2%).Chemistry Adverse reactions reported in patients with newly-diagnosed AML using VENCLEXTA in combination with azacitidine or decitabine are presented Monotherapy Studies (M13-982, M14-032, and M12-175) Hypocalcemia 87 12 in Table 7. The safety of single agent VENCLEXTA at the 400 mg recommended dailyHyperglycemia 67 7 Table 7. Adverse Reactions Reported in 30% (All Grades) or dose following a dose ramp-up schedule is based on pooled data from three single-arm trials (M13-982, M14-032, and M12-175). In the pooledHyperkalemia 59 5 5% (Grade 3) of Patients with AML Treated with VENCLEXTA in dataset, consisting of 352 patients with previously treated CLL or SLL, theAST increased 53 3 Combination with Azacitidine or Decitabine median age was 66 years (range: 28 to 85 years), 93% were white, andVENCLEXTA inVENCLEXTA in 68% were male. The median number of prior therapies was 3 (range: 0 toHypoalbuminemia 49 2 Combination withCombination with 15). The median duration of treatment with VENCLEXTA at the time of dataHypophosphatemia 45 11 Azacitidine Decitabine analysis was 14.5 months (range: 0 to 50 months). Fifty-two percent ofHyponatremia 40 9 Adverse Reaction by(N = 67) (N = 13)patients received VENCLEXTA for more than 60 weeks.Body SystemFatal adverse reactions that occurred in the absence of diseaseaIncludes laboratory abnormalities that were new or worsening, orAll GradesGrade 3All GradesGrade 3 progression and within 30 days of venetoclax treatment were reported inworsening from baseline unknown.(%) (%) (%) (%)2% of patients in the VENCLEXTA monotherapy studies, most commonlyImportant Adverse Reactions(2 patients) from septic shock. Serious adverse reactions were reportedBlood and lymphatic system disordersin 52% of patients, with the most frequent (5%) being pneumonia (9%),Tumor Lysis Syndromefebrile neutropenia (5%), and sepsis (5%).Tumor lysis syndrome is an important identified risk when initiatingThrombocytopeniaa 49 45 54 54Adverse reactions led to treatment discontinuation in 9% of patients,VENCLEXTA.Neutropeniaa 49 49 38 38dose reduction in 13%, and dose interruption in 36%. The most frequentCLL14adverse reactions leading to drug discontinuation were thrombocytopeniaThe incidence of TLS was 1% (3/212) in patients treated with VEN+GFebrile neutropenia 36 36 69 69and autoimmune hemolytic anemia. The most frequent adverse reaction[see Warnings and Precautions]. All three events of TLS resolved and didAnemiaa 30 30 15 15(5%) leading to dose reductions or interruptions was neutropenia (8%).not lead to withdrawal from the study. Obinutuzumab administration was Adverse reactions identified in these trials of single-agent VENCLEXTA aredelayed in two cases in response to the TLS events.Gastrointestinal disorderspresented in Table 5.MURANO Nausea 58 1 46 0Table 5. Adverse Reactions Reported in 10% (All Grades) or 5%In the open-label randomized phase 3 study, the incidence of TLS wasDiarrhea 54 3 38 8(Grade 3) of Patients with Previously Treated CLL/SLL (VENCLEXTA3% (6/194) in patients treated with VEN+R. After 77/389 patients were Monotherapy)enrolled in the study, the protocol was amended to incorporate the currentConstipation 49 3 62 0VENCLEXTA TLS prophylaxis and monitoring measures. All events of TLS occurredVomitinga 40 0 23 0during the VENCLEXTA ramp-up period and were resolved within two days. Adverse Reaction by Body(N = 352) All sixpatients completed the ramp-up and reached the recommendedAbdominal paina 22 4 46 0System All GradesGrade 3daily dose of 400 mg of VENCLEXTA. No clinical TLS was observed inGeneral disorders and administration site conditions(%) (%) patients who followed the current 5-week ramp-up schedule and TLSaprophylaxis and monitoring measures. Rates of laboratory abnormalitiesPeripheral edema 46 1 31 0Blood and lymphatic system disorders relevant to TLS for patients treated with VEN+R are presented in Table 4.Fatiguea 36 7 62 15Neutropeniaa 50 45 Monotherapy Studies (M13-982 and M14-032)a In 168 patients with CLL treated according to recommendations, the Pyrexia 21 3 31 0Anemia 33 18 rate of TLS was 2%. All events either met laboratory TLS criteriaCachexia 0 0 8 8Thrombocytopeniaa 29 20 (laboratory abnormalities that met 2 of the following within 24 hours a of each other: potassium 6 mmol/L, uric acid 476 mol/L, calciumMultiple organ6 6 0 0Lymphopenia 11 7 1.75 mmol/L, or phosphorus 1.5 mmol/L); or were reported as TLSdysfunction syndrome Febrile neutropenia 6 6 events. The events occurred in patients who had a lymph node(s) 5 cmInfections and infestationsand/or ALC 25 x 109/L. All events resolved within 5 days. No TLS with Gastrointestinal disorders clinical consequences such as acute renal failure, cardiac arrhythmias orPneumonia (excluding Diarrhea 43 3 sudden death and/or seizures was observed in these patients. All patientsfungal)a 27 25 46 31had CLcr 50 mL/min. Laboratory abnormalities relevant to TLS wereSepsis (excluding Nausea 42 1 hyperkalemia (17% all Grades, 1% Grade 3), hyperphosphatemia (14% allfungal)a 13 13 46 46Abdominal paina 18 3 Grades, 2% Grade 3), hypocalcemia (16% all Grades, 2% Grade 3), and hyperuricemia (10% all Grades, 1% Grade 3).Urinary tract infection16 6 23 0Vomiting 16 1 In the initial Phase 1 dose-finding trials, which had shorter (2-3 week)Cellulitis 6 0 15 8Constipation 16 1 ramp-up phase and higher starting doses, the incidence of TLS was 13% (10/77; 5 laboratory TLS, 5 clinical TLS), including 2 fatal events and Localized infection 0 0 8 8Mucositisa 13 1 3 events of acute renal failure, 1 requiring dialysis. After this experience,Musculoskeletal and connective tissue disordersGeneral disorders and administration site conditions TLS risk assessment, dosing regimen, TLS prophylaxis and monitoring measures were revised.Back pain 15 0 31 0Fatiguea 32 4 Acute Myeloid Leukemia Myalgiaa 10 0 31 0Edemaa 22 2 The safety of VENCLEXTA (400 mg daily dose) in combination withNervous system disordersPyrexia 18 1 azacitidine (n=67) or decitabine (n= 13) and VENCLEXTA (600 mg dailyadose) in combination with low-dose cytarabine (n= 61) is based on twoDizziness 28 1 46 0Infections and infestations non-randomized trials of patients with newly-diagnosed AML. The median duration of exposure for patients taking VENCLEXTA in combination withSkin and subcutaneous tissue disordersUpper respiratory tractazacitidine and decitabine was 6.5 months (range: 0.1 to 31.9 months) andRasha 33 1 31 0infectiona 36 1 8.4 months (range: 0.5 to 22.3 months), respectively. The median duration Pneumoniaa 14 8 of exposure for patients taking VENCLEXTA in combination with low doseRespiratory, thoracic and mediastinal disordersLower respiratory tractcytarabine was 3.9 months (range: 0.2 to 29.2 months).Cougha 25 0 38 0infectiona 11 2 VENCLEXTA in Combination with Azacitidine or Decitabine Hypoxia 18 6 15 0Musculoskeletal and connective tissue disorders Azacitidine Oropharyngeal pain9 0 31 0The most common adverse reactions (30%) of any grade were nausea, Musculoskeletal paina 29 2 diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage,Vascular disordersArthralgia 12 1 peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia.Hemorrhagea 46 7 46 0Serious adverse reactions were reported in 75% of patients. The most Nervous system disorders frequent serious adverse reactions (5%) were febrile neutropenia,Hypotensiona 21 6 31 0Headache 18 1 pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure,Hypertension 12 7 15 8and multiple organ dysfunction syndrome. Dizzinessa 14 0 The incidence of fatal adverse drug reactions was 1.5% within 30 days ofAdverse reactions graded using NCI Common Terminology Criteria for starting treatment. No reaction had an incidence of 2%.Adverse Events version 4.0. Respiratory, thoracic, and mediastinal disorders Discontinuations due to adverse reactions occurred in 21% of patients.aIncludes multiple adverse reaction terms.Cougha 22 0 The most frequent adverse reactions leading to drug discontinuation (2%) a were febrile neutropenia and pneumonia (excluding fungal).Table 8 describes common laboratory abnormalities reported throughout Dyspnea 13 1 treatment that were new or worsening from baseline. Skin and subcutaneous tissue disorders Dosage interruptions due to adverse reactions occurred in 61% of patients. The most frequent adverse reactions leading to dose interruption (5%) Rasha 18 1 were neutropenia, febrile neutropenia, and pneumonia (excluding fungal). Adverse reactions graded using NCI Common Terminology Criteria forDosage reductions due to adverse reactions occurred in 12% of patients. Adverse Events version 4.0.The most frequent adverse reaction leading to dose reduction (5%) was aIncludes multiple adverse reaction terms. neutropenia. DecitabineTable 6 describes common laboratory abnormalities reported throughoutThe most common adverse reactions (30%) of any grade were febrile treatment that were new or worsening from baseline. The most commonneutropenia, constipation, fatigue, thrombocytopenia, abdominal pain, (5%) Grade 4 laboratory abnormalities observed with VENCLEXTAdizziness, hemorrhage, nausea, pneumonia (excluding fungal), sepsis monotherapy were hematologic laboratory abnormalities, including(excluding fungal), cough, diarrhea, neutropenia, back pain, hypotension, neutropenia (33%), leukopenia (11%), thrombocytopenia (15%), andmyalgia, oropharyngeal pain, peripheral edema, pyrexia, and rash. lymphopenia (9%). 20064248-R1 Venclexta PB-7.5 x 10.5(3).indd 2 07 Jul 2020 12:41 PM'