b'IMBRUVICA (ibrutinib)IMBRUVICA (ibrutinib) Table 5: Adverse Reactions Reported in10% of Patients in theHELIOS: Adverse reactions described below in Table 7 reflect exposure IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2to IMBRUVICA + BR with a median duration of 14.7 months and exposure IMBRUVICA Chlorambucil to placebo + BR with a median of 12.8 months in HELIOS in patients with (N=135) (N=132) previously treated CLL/SLL.AllGrade 3AllGrade 3Table 7: Adverse Reactions Reported in at Least 10% of Patients and at Least Body System Grades or HigherGrades or Higher2% Greater in the IMBRUVICA Arm in Patients with CLL/SLL in HELIOSAdverse Reaction (%) (%) (%) (%) IMBRUVICA + BR Placebo + BRGastrointestinal disorders (N=287) (N=287)Diarrhea 42 4 17 0 AllGrade 3AllGrade 3 Nausea 22 1 39 1 Body System Grades or HigherGrades or Higher Constipation 16 1 16 0 Adverse Reaction (%) (%) (%) (%)Blood and lymphatic system Stomatitis* 141 4 1 disordersVomiting 13 0 20 1 Neutropenia* 66 61 60 56Abdominal pain 13 3 11 1 Thrombocytopenia* 34 16 26 16Dyspepsia 11 0 2 0 Gastrointestinal disordersMusculoskeletal andDiarrhea 36 2 23 1connective tissue disordersAbdominal pain 12 1 8 1Musculoskeletal pain*36420 0Arthralgia 161 7 1 Skin and subcutaneous tissue Muscle spasms 11 0 5 0 disordersGeneral disorders andRash*32 4 25 1administration site conditionsBruising*20 1 8 1Fatigue 30 1 38 5 Musculoskeletal and Peripheral edema 19 1 9 0 connective tissue disordersPyrexia 17 0 14 2 Musculoskeletal pain*29 2 20 0Respiratory, thoracic andMuscle spasms12 1 5 0mediastinal disorders General disorders and Cough 22 0 15 0 administration site conditionsDyspnea 10 1 10 0 Pyrexia 25 4 22 2Skin and subcutaneousVascular disorderstissue disorders Hemorrhage* 19 2 9 1Rash* 21 4 12 2 Hypertension*11 5 5 2Bruising* 19 0 7 0 Infections and infestationsEye disorders Bronchitis 13 2 10 3Dry eye 17 0 5 0 Skin infection*10 3 6 2Lacrimation increased 13 0 6 0 Metabolism and nutrition Vision blurred 13 0 8 0 disordersVisual acuity reduced 11 0 20 Hyperuricemia 10 2 6 0Infections and infestations The body system and individual ADR terms are sorted in descending frequency Upper respiratory tract17 2 17 2 order in the IMBRUVICA arm. infection * Includes multiple ADR terms Skin infection* 152 3 1 1 used for frequency above 0 and below 0.5%Pneumonia* 14 8 7 4 Includes 2 events of hemorrhage with fatal outcome in the IMBRUVICA arm Urinary tract infections 10 1 8 1 and 1 event of neutropenia with a fatal outcome in the placebo + BR arm.Vascular disorders Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA+BR and 2% of patients treated with placebo + BR. The frequencyHypertension* 14 4 1 0 of Grade 3 and 4 atrial fibrillation was 3% in patients treated with IMBRUVICA+BR Nervous system disorders and 1% in patients treated with placebo+BR.Headache12 1 10 2 iLLUMINATE: Adverse reactions described below in Table 8 reflect exposure Dizziness 11 0 12 1 to IMBRUVICA + obinutuzumab with a median duration of 29.3 months and exposure to chlorambucil + obinutuzumab with a median of 5.1 months in Investigations iLLUMINATE in patients with previously untreated CLL/SLL.Weight decreased 10 0 12 0 Table 8: Adverse Reactions Reported in at Least 10% of Patients in the Subjects with multiple events for a given ADR term are counted once onlyIMBRUVICA Arm in Patients with CLL/SLL in iLLUMINATEfor each ADR term.IMBRUVICA +Chlorambucil + The body system and individual ADR terms are sorted in descending frequencyObinutuzumab Obinutuzumaborder in the IMBRUVICA arm. (N=113) (N=115)* Includes multiple ADR termsAllGrade 3AllGrade 3 Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities inBody System Grades or HigherGradesor Higher Patients with CLL/SLL in RESONATE-2 Adverse Reaction (%) (%) (%) (%)IMBRUVICAChlorambucilBlood and lymphatic system (N=135) (N=132) disordersAll GradesGrade 3 or 4All GradesGrade 3 or 4 Neutropenia* 48 39 64 48(%) (%) (%) (%)Thrombocytopenia* 36 19 28 11Neutrophils Decreased 55 28 67 31Anemia 17 4 25 8Platelets Decreased 47 7 58 14 Skin and subcutaneous tissue Hemoglobin Decreased 36 0 39 2 disorders Treatment-emergent Grade 4 thrombocytopenia (1% in the IMBRUVICA arm Rash* 36 3 11 0vs 3% in the chlorambucil arm) and neutropenia (11% in the IMBRUVICA arm Bruising* 32 3 3 0vs 12% in the chlorambucil arm) occurred in patients.'