b'BRIEF SUMMARY OF PRESCRIBING INFORMATION In this pooled safety population, the most common adverse reactions (30%), including laboratory abnormalities,Permanent discontinuation of BRUKINSA due to an adverse reaction occurred in 2% of patients in Cohort 1 andAdverse reactions lead to treatment discontinuation in 6% of patients, dose reduction in 2.3%, and dose FOR BRUKINSA (zanubrutinib) included neutrophil count decreased (42%), upper respiratory tract infection (39%), platelet count decreased (34%),included hemorrhage (1 patient), neutropenia and neutrophil count decreased (1 patient); in Cohort 2, permanentinterruption in 34%. The leading cause of dose modification was respiratory tract infections (13%).SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION hemorrhage (30%), and musculoskeletal pain (30%). discontinuation of BRUKINSA due to an adverse reaction occurred in 7% of patients and included subduralTable 7 summarizes selected adverse reactions in BGB-3111-214 and BGB-3111-AU-003.Mantle Cell Lymphoma (MCL) hemorrhage (1 patient) and diarrhea (1 patient). 1 INDICATIONS AND USAGE Dosage interruptions of BRUKINSA due to an adverse reaction occurred in 32% of patients in Cohort 1 andTable 7: Adverse Reactions Occurring in 10% Patients with MZL Who Received BRUKINSA 1.1 Mantle Cell Lymphoma The safety of BRUKINSA was evaluated in 118 patients with MCL who received at least one prior therapy in 29% in Cohort 2. Adverse reactions which required dosage interruption in 2% of patients includedBody System Adverse Reaction BRUKINSA (N=88)BRUKINSA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received atin two single-arm clinical trials, BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120] neutropenia, vomiting, hemorrhage, thrombocytopenia, and pneumonia in Cohort 1. Adverse reactions leadingAll GradesGrade 3[see Clinical Studies (14.1)]. The median age of patients who received BRUKINSA in studies BGB-3111-206 to dosage interruption in 2 patients in Cohort 2 included pneumonia and pyrexia.least one prior therapy. and BGB-3111-AU-003 was 62 years (range: 34 to 86), 75% were male, 75% were Asian, 21% were White, (%) or 4 (%)This indication is approved under accelerated approval based on overall response rate [see Clinical Studiesand 94% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior lines of therapy (range: 1 to 4).Dose reductions of BRUKINSA due to an adverse reaction occurred in 11% of patients in Cohort 1 and in 7% in Cohort 2.Infections and infestations Upper respiratory tract infectiona 26 3.4(14.1)]. Continued approval for this indication may be contingent upon verification and description of clinicalThe BGB-3111-206 trial required a platelet count 75 x 109/L and an absolute neutrophil count 1 x 109/LAdverse reactions which required dose reductions in 2% of patients included neutropenia in Cohort 1. Adversebbenefit in a confirmatory trial. independent of growth factor support, hepatic enzymes 2.5 x upper limit of normal, total bilirubin 1.5 x ULN.reaction leading to dose reduction occurred in 2 patients in Cohort 2 (each with one event: diarrhea and pneumonia). Urinary tract infection 11 2.31.2 Waldenstrms Macroglobulinemia The BGB-3111-AU-003 trial required a platelet count 50 x 109/L and an absolute neutrophil count 1 x 109/LTable 5 summarizes the adverse reactions in Cohort 1 in ASPEN. Pneumoniac,d 10 6BRUKINSA is indicated for the treatment of adult patients with Waldenstrms macroglobulinemia (WM) [seeindependent of growth factor support, hepatic enzymes 3 x upper limit of normal, total bilirubin 1.5 x ULN.Table 5: Adverse Reactions (10%) Occurring in Patients with WM Who Received BRUKINSA in Cohort 1Gastrointestinal disorders Diarrheae 25 3.4 Clinical Studies (14.2)]. Both trials required a CLcr 30 mL/min. Both trials excluded patients with prior allogeneic hematopoietic stemBody System Adverse Reaction BRUKINSA (N=101) Ibrutinib (N=98) Abdominal painf 14 2.3cell transplant, exposure to a BTK inhibitor, known infection with HIV, and serologic evidence of active hepatitis 1.3 Marginal Zone Lymphoma B or hepatitis C infection, and patients requiring strong CYP3A inhibitors or strong CYP3A inducers. PatientsAll GradesGrade 3 All GradesGrade 3 Nausea 13 0BRUKINSA is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphomareceived BRUKINSA 160 mg twice daily or 320 mg once daily. Among patients receiving BRUKINSA, 79% were(%) or 4 (%) (%) or 4 (%) Skin and subcutaneous tissue disorders Bruisingg 24 0(MZL) who have received at least one antiCD20-based regimen. exposed for 6 months or longer, and 68% were exposed for greater than one year. Infections and infestations Upper respiratory tract infectiona 44 0 40 2 Rashh 21 0This indication is approved under accelerated approval based on overall response rate [see Clinical StudiesFatal events within 30 days of the last dose of BRUKINSA occurred in 8 (7%) of 118 patients with MCL. FatalPneumoniab 12 4 26 10 Musculoskeletal and connective (14.3)]. Continued approval for this indication may be contingent upon verification and description of clinicalcases included pneumonia in 2 patients and cerebral hemorrhage in one patient. tissue disorders Musculoskeletal paini 27 1.1benefit in a confirmatory trial. Serious adverse reactions were reported in 36 patients (31%). The most frequent serious adverse reactions thatUrinary tract infection 11 0 13 21.4 Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma occurred were pneumonia (11%) and hemorrhage (5%). Gastrointestinal disorders Diarrhea 22 3 34 2 Vascular disorders Hemorrhagej23 1.1BRUKINSA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or smallOf the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverseNausea 18 0 13 1 General disorders Fatiguek 21 2.3lymphocytic lymphoma (SLL) [see Clinical Studies (14.4)]. reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumoniaConstipation 16 0 7 0 Respiratory, thoracic and l4 CONTRAINDICATIONS(3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B). Vomiting 12 0 14 1 mediastinal disorders Cough 10 0None. Table 3 summarizes the adverse reactions in BGB-3111-206 and BGB-3111-AU-003. General disordersFatiguec 31 1 25 1 a Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, tonsillitis, rhinitis, viral upper Table 3: Adverse Reactions (10%) in Patients Receiving BRUKINSA in BGB-3111-206 and respiratory tract infection.5 WARNINGS AND PRECAUTIONS Pyrexia 16 4 13 2 bUrinary tract infection includes urinary tract infection, cystitis, Escherichia urinary tract infection, pyelonephritis, cystitis.BGB-3111-AU-003 Trials c5.1 Hemorrhage Body System Adverse Reaction Percent of PatientsEdema peripheral 12 0 20 0Pneumonia includes COVID-19 pneumonia, pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection,d d organizing pneumonia.Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with(N=118) Skin and subcutaneous tissueBruising 20 0 34 0 Includes 2 fatalities from COVID-19 pneumonia.BRUKINSA monotherapy. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage,All GradesGrade 3 ordisorders Rashe 29 0 32 0 e f Diarrhea includes diarrhea and diarrhea hemorrhagic.hematuria, and hemothorax was reported in 3.6% of patients treated with BRUKINSA monotherapy in clinicalAbdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort.trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae,% Higher % Pruritus 11 1 6 0 gBruising includes contusion, ecchymosis, increased tendency to bruise, post procedural contusion.occurred in 30% of patients. Infections and infestations Upper respiratory tract infectiona 39 0 Musculoskeletal and connectivef h Rash includes rash, rash maculo-papular, rash pruritic, dermatitis, dermatitis allergic, dermatitis atopic, dermatitis contact, drug reaction Musculoskeletal pain 45 9 39 1 with eosinophilia and systemic symptoms, erythema, photosensitivity reaction, rash erythematous, rash papular, seborrheic dermatitis.Pneumoniab 15 10c tissue disorders iMusculoskeletal pain includes back pain, arthralgia, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal chest pain, Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the riskUrinary tract infection 11 0.8 Muscle spasms 10 0 28 1 j bone pain, musculoskeletal discomfort, neck pain. Hemorrhage includes epistaxis, hematuria, hemorrhoidal hemorrhage, hematoma, hemoptysis, conjunctival hemorrhage, diarrheaof hemorrhage. Skin and subcutaneous tissue disorders Rashd 36 0 Nervous system disorders Headache 18 1 14 1 hemorrhagic, hemorrhage urinary tract, mouth hemorrhage, pulmonary hematoma, subcutaneous hematoma, gingival bleeding, Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any gradeBruisinge 14 0 Dizziness 13 1 12 0 k melena, upper gastrointestinal hemorrhage.occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre and post surgery depending upon theRespiratory, thoracic andCough 16 0 18 0 l Fatigue includes fatigue, lethargy, asthenia.type of surgery and the risk of bleeding. Gastrointestinal disorders Diarrhea 23 0.8 mediastinal disorders Cough includes cough and productive cough.5.2 Infections Constipation 13 0 Dyspnea 14 0 7 0 Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included peripheral neuropathy, Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurredVascular disorders Hypertension 12 3.4 Vascular disorders Hemorrhageg 42 4 43 9 second primary malignancies, dizziness, edema, headache, petechiae, purpura, and atrial fibrillation or flutter. in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infectionsHemorrhagef11 3.4c Hypertension 14 9 19 14 Table 8 summarizes select laboratory abnormalities.occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients.aUpper respiratory tract infection includes upper respiratory tract infection, laryngitis, nasopharyngitis, sinusitis, rhinitis, viral upper Infections due to hepatitis B virus (HBV) reactivation have occurred. Musculoskeletal and connective Musculoskeletal paing 14 3.4 respiratory tract infection, pharyngitis, rhinovirus infection, upper respiratory tract congestion. Table 8: Select Laboratory Abnormalities (20%) that Worsened from Baseline in Patients with MZLtissue disorders bPneumonia includes lower respiratory tract infection, lung infiltration, pneumonia, pneumonia aspiration, pneumonia viral.aConsider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections accordingRespiratory, thoracic and cFatigue includes asthenia, fatigue, lethargy. Laboratory Abnormality BRUKINSAto standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever orCough 12 0 dBruising includes all related terms containing bruise, contusion, or ecchymosis.other signs and symptoms of infection and treat appropriately. a mediastinal disorders eRash includes all related terms rash, maculo-papular rash, erythema, rash erythematous, drug eruption, dermatitis allergic, dermatitis atopic,All Grades (%) Grade 3 or 4 (%) b Upper respiratory tract infection includes upper respiratory tract infection, upper respiratory tract infection viral. f rash pruritic, dermatitis, photodermatoses, dermatitis acneiform, stasis dermatitis, vasculitic rash, eyelid rash, urticaria, skin toxicity.Hematologic abnormalities5.3 CytopeniasPneumonia includes pneumonia, pneumonia fungal, pneumonia cryptococcal, pneumonia streptococcal, atypical pneumonia, lung Musculoskeletal pain includes back pain, arthralgia, pain in extremity, musculoskeletal pain, myalgia, bone pain, spinal pain, Grade 3 or 4 cytopenias, including neutropenia (22%), thrombocytopenia (8%), and anemia (7%) based on laboratoryc infection, lower respiratory tract infection, lower respiratory tract infection bacterial, lower respiratory tract infection viral. gmusculoskeletal chest pain, neck pain, arthritis, musculoskeletal discomfort.Neutrophils decreased 43 15Includes fatal adverse reaction.Hemorrhage includes epistaxis, hematuria, conjunctival hemorrhage, hematoma, rectal hemorrhage, periorbital hemorrhage, measurements, developed in patients treated with BRUKINSA monotherapy [see Adverse Reactions (6.1)]. Grade 4d mouth hemorrhage, post procedural hemorrhage, hemoptysis, skin hemorrhage, hemorrhoidal hemorrhage, ear hemorrhage, eyePlatelets decreased 33 10Rash includes all related terms containing rash.neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% of patients. eBruising includes all related terms containing bruise, bruising, contusion, ecchymosis. hemorrhage, hemorrhagic diathesis, periorbital hematoma, subdural hemorrhage, wound hemorrhage, gastric hemorrhage, lowerLymphocytes decreased 32 8Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or fHemorrhage includes all related terms containing hemorrhage, hematoma. gastrointestinal hemorrhage, spontaneous hematoma, traumatic hematoma, traumatic intracranial hemorrhage, tumor hemorrhage, gMusculoskeletal pain includes musculoskeletal pain, musculoskeletal discomfort, myalgia, back pain, arthralgia, arthritis. retinal hemorrhage, hematochezia, diarrhea hemorrhagic, hemorrhage, melena, post-procedural hematoma, subdural hematoma,Hemoglobin decreased 26 6discontinue treatment as warranted [see Dosage and Administration (2.4)]. Treat using growth factor oranal hemorrhage, hemorrhagic disorder, pericardial hemorrhage, postmenopausal hemorrhage, stoma site hemorrhage, subarachnoid transfusions, as needed. Other clinically significant adverse reactions that occurred in 10% of patients with mantle cell lymphoma includehemorrhage. Chemistry abnormalities5.4 Second Primary Malignancies major hemorrhage (defined asGrade 3 hemorrhage or CNS hemorrhage of any grade) (5%), and headache (4.2%). Clinically relevant adverse reactions in 10% of patients who received BRUKINSA included localized infection,Glucose increased 54 4.6Second primary malignancies, including non-skin carcinoma, have occurred in 13% of patients treated withTable 4: Selected Laboratory Abnormalitiesa (20%) in Patients with MCL atrial fibrillation or atrial flutter, and hematuria. Creatinine increased 34 1.1BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer,in Studies BGB-3111-206 and BGB-3111-AU-003 Table 6 summarizes the laboratory abnormalities in ASPEN. Phosphate decreased 27 2.3reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanomaLaboratory Parameter Percent of Patients (N=118) Table 6: Select Laboratory Abnormalitiesa (20%) that Worsened from Baseline in Patients with WMCalcium decreased 23 0(1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for theWho Received BRUKINSA in Cohort 1development of second primary malignancies. All Grades (%) Grade 3 or 4 (%) b b ALT increased 22 1.15.5 Cardiac Arrhythmias Hematologic abnormalities Laboratory Abnormality BRUKINSA IbrutinibaThe denominator used to calculate the rate varied from 87 to 88 based on the number of patients with a baseline value and at least Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutterAll Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) one post-treatment value. Neutrophils decreased 45 20were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher casesLymphocytosisb 41 16 Hematologic abnormalities Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphomain 1.7% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increasedNeutrophils decreased 50 24 34 9risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients. Platelets decreased 40 7 The safety data described below reflect exposure to BRUKINSA (160 mg twice daily) in 675 patients with CLL Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chestHemoglobin decreased 27 6 Platelets decreased 35 8 39 5 from two randomized controlled clinical trials [see Clinical Studies (14.4)]. The trial required patients to be discomfort), manage appropriately [see Dosage and Administration (2.4)], and consider the risks and benefits ofChemistry abnormalities Hemoglobin decreased 20 7 20 7 unsuitable for fludarabine, cyclophosphamide, and rituximab (FCR) therapy defined as age 65 years, or age 18 continued BRUKINSA treatment. Chemistry abnormalities to 65 years with either a total Cumulative Illness Rating Scale (CIRS) 6, creatinine clearance 30 to 69 mL/min, 5.6 Embryo-Fetal Toxicity Blood uric acid increased 29 2.6 or history of serious or frequent infections. The trial excluded patients with AST or ALT 2 times the upper limit of Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman.ALT increased 28 0.9 Glucose increased 45 2.3 33 2.3 normal (ULN) or bilirubin 3 times (ULN) and patients requiring a strong CYP3A inhibitor or inducer.Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetalBilirubin increased 24 0.9 Creatinine increased 31 1 21 1 SEQUOIAtoxicity, including malformations at exposures that were 5 times higher than those reported in patients at thea Based on laboratory measurements. Calcium decreased 27 2 26 0 The safety of BRUKINSA monotherapy in patients with previously untreated CLL/SLL was evaluated in a recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSAb Asymptomatic lymphocytosis is a known effect of BTK inhibition.Potassium increased 24 2 12 0 randomized, multicenter, open-label, actively controlled trial [see Clinical Studies (14.4)]. Patients without and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week afterdeletion of chromosome 17p13.1 (17p deletion) (Cohort 1) received either BRUKINSA 160 mg twice daily until the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug,Waldenstrms Macroglobulinemia (WM) Phosphate decreased 20 3.1 18 0 disease progression or unacceptable toxicity (n=240) or bendamustine plus rituximab (BR) for 6 cycles (n=227). the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. The safety of BRUKINSA was investigated in two cohorts of Study BGB-3111-302 (ASPEN). Cohort 1 included Urate increased 16 3.2 34 6 Bendamustine was dosed at 90 mg/m2/day intravenously on the first 2 days of each cycle, and rituximab was 199 patients with MYD88 mutation (MYD88MUT) WM, randomized to and treated with either BRUKINSA (101 patients) ordosed at 375 mg/m2 on day 1 of Cycle 1 and 500 mg/m2 on day 1 of Cycles 2 to 6.6 ADVERSE REACTIONS ibrutinib (98 patients). The trial also included a non-randomized arm, Cohort 2, with 26 wild type MYD88 (MYD88WT) WMBilirubin increased 12 1 33 1 Additionally, the same BRUKINSA regimen was evaluated in 111 patients with previously untreated CLL/SLL The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling: patients and 2 patients with unknown MYD88 status [see Clinical Studies (14.2)]. Based on laboratory measurements. with 17p deletion in a non-randomized single arm (Cohort 2).a b The denominator used to calculate the rate varied from 86 to 101 based on the number of patients with a baseline value Hemorrhage [see Warnings and Precautions (5.1)] Among patients who received BRUKINSA, 93% were exposed for 6 months or longer, and 89% were exposed forand at least one post-treatment value. Randomized cohort: Previously untreated CLL/SLL without 17p deletion Infections [see Warnings and Precautions (5.2)] greater than 1 year.Marginal Zone LymphomaIn patients with previously untreated CLL/SLL without 17p deletion, the median age was 70, 62% were male,Cytopenias [see Warnings and Precautions (5.3)] In Cohort 1 of the ASPEN study safety population (N=101), the median age of patients who received BRUKINSAThe safety of BRUKINSA was evaluated in 88 patients with previously treated MZL in two single-arm clinical89% were White, 2% were Asian, and 2% were Black. Most patients (93%) had an ECOG performance status was 70 years (45-87 years old); 67% were male, 86% were White, 4% were Asian and 10% were not reportedstudies, BGB-3111-214 and BGB-3111-AU-003 [see Clinical Studies (14.3)]. The trials required an absoluteof 0 to 1. Second Primary Malignancies [see Warnings and Precautions (5.4)] (unknown race). In Cohort 2 of the ASPEN study safety population (N=28), the median age of patients whoneutrophil count 1 x 109/L, platelet count 50 or 75 x 109/L and adequate hepatic function and excludedThe median duration of exposure to BRUKINSA was 26 months, with 71% exposed for more than 2 years. Cardiac Arrhythmias [see Warnings and Precautions (5.5)] received BRUKINSA was 72 (39-87 years old); 50% were male, 96% were White and 4% were not reportedpatients requiring a strong CYP3A inhibitor or inducer. Patients received BRUKINSA 160 mg twice daily (97%)Serious adverse reactions occurred in 36% of patients who received BRUKINSA. Serious adverse reactions 6.1 Clinical Trials Experience (unknown race). or 320 mg once daily (3%). The median age in both studies combined was 70 years (range: 37 to 95), 52% werethat occurred in 5% of patients were COVID-19, pneumonia, and second primary malignancy (5% each). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theIn Cohort 1, serious adverse reactions occurred in 44% of patients who received BRUKINSA. Serious adversemale, 64% were Caucasian and 19% were Asian. Most patients (92%) had an ECOG performance status of 0 to 1.Fatal adverse reactions occurred in 11 (4.6%) patients with the leading cause of death being COVID-19 (2.1%).clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreactions in 2% of patients included influenza (3%), pneumonia (4%), neutropenia and neutrophil countEighty percent received BRUKINSA for 6 months or longer, and 67% received treatment for more than one year. Adverse reactions led to permanent discontinuation of BRUKINSA in 8% of patients, dose reduction in 8%, and reflect the rates observed in practice. decreased (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%). In Cohort 2, serious adverseTwo fatal adverse reactions (2.3%) occurred within 30 days of the last dose of BRUKINSA, including myocardialdose interruption in 46%. The most common adverse reactions leading to permanent discontinuation were The data in the WARNINGS AND PRECAUTIONS reflect exposure to BRUKINSA as a single-agent in nine clinicalreactions occurred in 39% of patients. Serious adverse reactions in 2 patients included pneumonia (14%). infarction and a Covid-19related death. second primary malignancy and COVID-19. The leading causes of dose modification (5% of all patients) were trials, administered at 160 mg twice daily in 1445 patients and at 320 mg once daily in 105 patients. Among theseSerious adverse reactions occurred in 40% of patients. The most frequent serious adverse reactions wererespiratory infections (COVID-19, pneumonia) and hemorrhage.1550 patients, the median duration of exposure was 26 months, 80% of patients were exposed for at least 12pyrexia (8%) and pneumonia (7%). months, and 58% of patients were exposed for at least 24 months. 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