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adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (> 50%) are neutropenia, thrombocytopenia, anemia, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eisai, Inc. at 1-888-274-2378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia. Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention in the Phase 3 Trials in the Dacogen Arm: Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests. Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia. Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis. Discussion of Adverse Reactions Information Dacogen was studied in 3 single-arm studies (N = 66, N = 98, N = 99) and 1 controlled supportive care study (N = 83 Dacogen, N = 81 supportive care ). The data described below reflect exposure to Dacogen in 83 patients in the MDS trial. In the trial, patients received 15 mg/m 2 intravenously every 8 hours for 3 days every 6 weeks. The median number of Dacogen cycles was 3 (range 0 to 9). Table 1 presents all adverse events regardless of causality occurring in at least 5% of patients in the Dacogen group and at a rate greater than supportive care. Table 1 Adverse Events Reported in ≥ 5% of Patients in the Dacogen Group and at a Rate Greater than Supportive Care in Phase 3 MDS Trial Dacogen N = 83 (%) Supportive Care N = 81 (%) Blood and lymphatic system disorders Neutropenia 75 (90) 58 (72) Thrombocytopenia 74 (89) 64 (79) Anemia NOS 68 (82) 60 (74) Febrile neutropenia 24 (29) 5 (6) Leukopenia NOS 23 (28) 11 (14) Lymphadenopathy 10 (12) 6 (7) Thrombocythemia 4 (5) 1 (1) Cardiac disorders Pulmonary edema NOS 5 (6) 0 (0) Eye disorders Vision blurred 5 (6) 0 (0) Gastrointestinal disorders Nausea 35 (42) 13 (16) Constipation 29 (35) 11 (14) Diarrhea NOS 28 (34) 13 (16) Vomiting NOS 21 (25) 7 (9) Abdominal pain NOS 12 (14) 5 (6) Oral mucosal petechiae 11 (13) 4 (5) Stomatitis 10 (12) 5 (6) Dyspepsia 10 (12) 1 (1) Ascites 8 (10) 2 (2) Gingival bleeding 7 (8) 5 (6) Hemorrhoids 7 (8) 3 (4) Loose stools 6 (7) 3 (4) Tongue ulceration 6 (7) 2 (2) Dysphagia 5 (6) 2 (2) Oral soft tissue disorder NOS 5 (6) 1 (1) Lip ulceration 4 (5) 3 (4) Abdominal distension 4 (5) 1 (1) Abdominal pain upper 4 (5) 1 (1) Gastro-esophageal reflux disease 4 (5) 0 (0) Glossodynia 4 (5) 0 (0) General disorders and administrative site disorders Pyrexia 44 (53) 23 (28) Edema peripheral 21 (25) 13 (16) Rigors 18 (22) 14 (17) Edema NOS 15 (18) 5 (6) Pain NOS 11 (13) 5 (6) Lethargy 10 (12) 3 (4) Tenderness NOS 9 (11) 0 (0) Fall 7 (8) 3 (4) Chest discomfort 6 (7) 3 (4) Intermittent pyrexia 5 (6) 3 (4) Malaise 4 (5) 1 (1) Crepitations NOS 4 (5) 1 (1) Catheter site erythema 4 (5) 1 (1) Catheter site pain 4 (5) 0 (0) Injection site swelling 4 (5) 0 (0) Hepatobiliary disorders Hyperbilirubinemia 12 (14) 4 (5) Infections and infestations Pneumonia NOS 18 (22) 11 (14) Cellulitis 10 (12) 6 (7) Candidal infection NOS 8 (10) 1 (1) Catheter related infection 7 (8) 0 (0) Urinary tract infection NOS 6 (7) 1 (1) Staphylococcal infection 6 (7) 0 (0) Oral candidiasis 5 (6) 2 (2) Sinusitis NOS 4 (5) 2 (2) Bacteremia 4 (5) 0 (0) Injury, poisoning and procedural complications Transfusion reaction 6 (7) 3 (4) Abrasion NOS 4 (5) 1 (1) Investigations Cardiac murmur NOS 13 (16) 9 (11) Blood alkaline phosphatase NOS increased 9 (11) 7 (9) Aspartate aminotransferase increased 8 (10) 7 (9) Blood urea increased 8 (10) 1 (1) Blood lactate dehydrogenase increased 7 (8) 5 (6) Blood albumin decreased 6 (7) 0 (0) Blood bicarbonate increased 5 (6) 1 (1) Blood chloride decreased 5 (6) 1 (1) Protein total decreased 4 (5) 3 (4) Blood bicarbonate decreased 4 (5) 1 (1) Blood bilirubin decreased 4 (5) 1 (1) Metabolism and nutrition disorders Hyperglycemia NOS 27 (33) 16 (20) Hypoalbuminemia 20 (24) 14 (17) Hypomagnesemia 20 (24) 6 (7) Hypokalemia 18 (22) 10 (12) Hyponatremia 16 (19) 13 (16) Appetite decreased NOS 13 (16) 12 (15) Anorexia 13 (16) 8 (10) Hyperkalemia 11 (13) 3 (4) Dehydration 5 (6) 4 (5) Musculoskeletal and connective tissue disorders Arthralgia 17 (20) 8 (10) Pain in limb 16 (19) 8 (10) Back pain 14 (17) 5 (6) Chest wall pain 6 (7) 1 (1) Musculoskeletal discomfort 5 (6) 0 (0) Myalgia 4 (5) 1 (1) Nervous system disorders Headache 23 (28) 11 (14) Dizziness 15 (18) 10 (12) Hypoesthesia 9 (11) 1 (1) Psychiatric disorders Insomnia 23 (28) 11 (14) Confusional state 10 (12) 3 (4) Anxiety 9 (11) 8 (10) Renal and urinary disorders Dysuria 5 (6) 3 (4) Urinary frequency 4 (5) 1 (1) Respiratory, thoracic and Mediastinal disorders Cough 33 (40) 25 (31) Pharyngitis 13 (16) 6 (7) Crackles lung 12 (14) 1 (1) Breath sounds decreased 8 (10) 7 (9) Hypoxia 8 (10) 4 (5) Rales 7 (8) 2 (2) Postnasal drip 4 (5) 2 (2) Skin and subcutaneous tissue disorders Ecchymosis 18 (22) 12 (15) Rash NOS 16 (19) 7 (9) Erythema 12 (14) 5 (6) Skin lesion NOS 9 (11) 3 (4) Pruritis 9 (11) 2 (2) Alopecia 7 (8) 1 (1) Urticaria NOS 5 (6) 1 (1) Swelling face 5 (6) 0 (0) Vascular disorders Petechiae 32 (39) 13 (16) Pallor 19 (23) 10 (12) Hypotension NOS 5 (6) 4 (5) Hematoma NOS 4 (5) 3 (4) Discussion of Clinically Important Adverse Reactions In the controlled trial using Dacogen dosed at 15 mg/m 2 , administered by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days, the highest incidence of Grade 3 or Grade 4 adverse events in the Dacogen arm were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%). Bone marrow suppression was the most frequent cause of dose reduction, delay and discontinuation. Six patients had fatal events associated with their underlying disease and myelosuppression (anemia, neutropenia, and thrombocytopenia) that were considered at least possibly related to drug treatment [See Warnings and Precautions ( 5.1 ) ]. Of the 83 Dacogen-treated patients, 8 permanently discontinued therapy for adverse events; compared to 1 of 81 patients in the supportive care arm. In a single-arm MDS study (N=99) Dacogen was dosed at 20 mg/m 2 intravenous, infused over one hour daily for 5 consecutive days of a 4 week cycle. Table 2 presents all adverse events regardless of causality occurring in at least 5% of patients. Table 2 Adverse Events Reported in ≥ 5% of Patients in a Single-arm Study* Dacogen N = 99 (%) Blood and lymphatic system disorders Anemia 31 (31%) Febrile neutropenia 20 (20%) Leukopenia 6 (6% ) Neutropenia 38 (38% ) Pancytopenia 5 (5% ) Thrombocythemia 5 (5% ) Thrombocytopenia 27 (27%) Cardiac disorders Cardiac failure congestive 5 (5% ) Tachycardia 8 (8% ) Ear and labyrinth disorders Ear pain 6 (6% ) Gastrointestinal disorders Abdominal pain 14 (14%) Abdominal pain upper 6 (6% ) Constipation 30 (30%) Diarrhea 28 (28%) Dyspepsia 10 (10%) Dysphagia 5 (5% ) Gastro-esophageal reflux disease 5 (5% ) Nausea 40 (40%) Oral pain 5 (5% ) Stomatitis 11 (11%) Toothache 6 (6% ) Vomiting 16 (16%) General disorders and administration site conditions Asthenia 15 (15%) Chest pain 6 (6% ) Chills 16 (16%) Fatigue 46 (46%) Mucosal inflammation 9 (9% ) Edema 5 (5% ) Edema peripheral 27 (27%) Pain 5 (5% ) Pyrexia 36 (36%) Infections and infestations Cellulitis 9 (9% ) Oral candidiasis 6 (6% ) Pneumonia 20 (20%) Sinusitis 6 (6% ) Staphylococcal bacteremia 8 (8% ) Tooth abscess 5 (5% ) Upper respiratory tract infection 10 (10%) Urinary tract infection 7 (7% ) Injury, poisoning and procedural complications Contusion 9 (9% ) Investigations Blood bilirubin increased 6 (6% ) Breath sounds abnormal 5 (5% ) Weight decreased 9 (9% ) Metabolism and nutrition disorders Anorexia 23 (23%) Decreased appetite 8 (8% ) Dehydration 8 (8% ) Hyperglycemia 6 (6% ) Hypokalemia 12 (12%) Hypomagnesemia 5 (5% ) Musculoskeletal and connective tissue disorders Arthralgia 17 (17%) Back pain 18 (18%) Bone pain 6 (6% ) Muscle spasms 7 (7% ) Muscular weakness 5 (5% ) Musculoskeletal pain 5 (5% ) Myalgia 9 (9% ) Pain in extremity 18 (18%) Nervous system disorders Dizziness 21 (21%) Headache 23 (23%) Psychiatric disorders Anxiety 9 (9% ) Confusional state 8 (8% ) Depression 9 (9% ) Insomnia 14 (14%) Respiratory, thoracic and mediastinal disorders Cough 27 (27%) Dyspnea 29 (29%) Epistaxis 13 (13%) Pharyngolaryngeal pain 8 (8% ) Pleural effusion 5 (5% ) Sinus congestion 5 (5% ) Skin and subcutaneous tissue disorders Dry skin 8 (8% ) Ecchymosis 9 (9% ) Erythema 5 (5% ) Night sweats 5 (5% ) Petechiae 12 (12%) Pruritus 9 (9% ) Rash 11 (11%) Skin lesion 5 (5% ) Vascular disorders Hypertension 6 (6% ) Hypotension 11 (11%) * In this single arm study, investigators reported adverse events based on clinical signs and symptoms rather than predefined laboratory abnormalities. Thus not all laboratory abnormalities were recorded as adverse events. Discussion of Clinically Important Adverse Reactions In the single-arm study (N=99) when Dacogen was dosed at 20 mg/m 2 intravenous, infused over one hour daily for 5 consecutive days, the highest incidence of Grade 3 or Grade 4 adverse events were neutropenia (37%), thrombocytopenia (24%) and anemia (22%). Seventy-eight percent of patients had dose delays, the median duration of this delay was 7 days and the largest percentage of delays were due to hematologic toxicities. Hematologic toxicities and infections were the most frequent causes of dose delays and discontinuation. Eight patients had fatal events due to infection and/or bleeding (seven of which occurred in the clinical setting of myelosuppression) that were considered at least possibly related to drug treatment. Nineteen of 99 patients permanently discontinued therapy for adverse events. No overall difference in safety was detected between patients > 65 years of age and younger patients in these myelodysplasia trials. No significant gender differences in safety or efficacy were detected. Patients with renal or hepatic dysfunction were not studied. Insufficient numbers of non-white patients were available to draw conclusions in these clinical trials. Serious Adverse Events that occurred in patients receiving Dacogen regardless of causality, not previously reported in Tables 1 and 2 include: Blood and Lymphatic System Disorders: myelosuppression, splenomegaly. Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia. Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage. General Disorders and Administrative Site Conditions: chest pain, catheter site hemorrhage. Hepatobiliary Disorders: cholecystitis. Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection. Injury, Poisoning and Procedural Complications: post procedural pain, post procedural hemorrhage. Nervous System Disorders: intracranial hemorrhage. Psychiatric Disorders: mental status changes. Renal and Urinary Disorders: renal failure, urethral hemorrhage. Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass. Allergic Reaction: Hypersensitivity (anaphylactic reaction) to Dacogen has been reported in a Phase 2 trial. 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of Dacogen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cases of Sweet’s Syndrome (acute febrile neutrophilic dermatosis) have been reported.