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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Myelosuppression [see Warnings and Precautions (5.1) ] Seizures [see Warnings and Precautions (5.2 )] Hepatic Veno-Occlusive Disease (HVOD) [see Warnings and Precautions (5.3 ) ] Embryo-fetal Toxicity [see Warnings and Precautions (5.4) ] Cardiac Tamponade [see Warnings and Precautions (5.5 )] Bronchopulmonary Dysplasia [see Warnings and Precautions (5.6) ] Cellular Dysplasia [see Warnings and Precautions (5.7) ] Most common adverse reactions (incidence > 60%) were: myelosuppression, nausea, stomatitis, vomiting, anorexia, diarrhea, insomnia, fever, hypomagnesemia, abdominal pain, anxiety, headache, hyperglycemia and hypokalemia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. Adverse reaction information is primarily derived from the clinical study (N=61) of Busulfan Injection and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review. In the Busulfan Injection allogeneic stem cell transplantation clinical trial, all patients were treated with Busulfan 0.8 mg per kg as a two-hour infusion every six hours for 16 doses over four days, combined with cyclophosphamide 60 mg per kg x2 days. Ninety-three percent (93%) of evaluable patients receiving this dose of Busulfan maintained an AUC less than 1,500 µM•min for dose 9, which has generally been considered the level that minimizes the risk of HVOD. Table 1 lists the non-hematologic adverse reactions events through Bone Marrow Transplantation (BMT) Day +28 at a rate greater than or equal to 20% in patients treated with Busulfan Injection prior to allogeneic hematopoietic cell transplantation. Table 1: Summary of the Incidence (greater than or equal to 20%) of Non-Hematologic Adverse Reactions through BMT Day +28 in Patients who Received Busulfan Injection Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation 1. Includes all reported adverse reactions regardless of severity (toxicity grades 1-4) Non-Hematological Adverse Reactions 1 Percent Incidence BODY AS A WHOLE Fever 80 Headache 69 Asthenia 51 Chills 46 Pain 44 Edema General 28 Allergic Reaction 26 Chest Pain 26 Inflammation at Injection Site 25 Back Pain 23 CARDIOVASCULAR SYSTEM Tachycardia 44 Hypertension 36 Thrombosis 33 Vasodilation 25 DIGESTIVE SYSTEM Nausea 98 Stomatitis (Mucositis) 97 Vomiting 95 Anorexia 85 Diarrhea 84 Abdominal Pain 72 Dyspepsia 44 Constipation 38 Dry Mouth 26 Rectal Disorder 25 Abdominal Enlargement 23 METABOLIC AND NUTRITIONAL SYSTEM Hypomagnesemia 77 Hyperglycemia 66 Hypokalemia 64 Hypocalcemia 49 Hyperbilirubinemia 49 Edema 36 SGPT Elevation 31 Creatinine Increased 21 NERVOUS SYSTEM Insomnia 84 Anxiety 72 Dizziness 30 Depression 23 RESPIRATORY SYSTEM Rhinitis 44 Lung Disorder 34 Cough 28 Epistaxis 25 Dyspnea 25 SKIN AND APPENDAGES Rash 57 Pruritus 28 Additional Adverse Reactions by Body System Hematologic : Prolonged prothrombin time Gastrointestinal: Esophagitis, ileus, hematemesis, pancreatitis, rectal discomfort Hepatic: Alkaline phosphatase increases, jaundice, hepatomegaly Graft-versus-host disease: Graft-versus-host disease. There were 3 deaths (5%) attributed to GVHD. Edema: Hypervolemia, or documented weight increase Infection: Infection, pneumonia (fatal in one patient and life-threatening in 3% of patients) Cardiovascular: Arrhythmia, atrial fibrillation, ventricular extrasystoles, third degree heart block, thrombosis (all episodes were associated with the central venous catheter), hypotension, flushing and hot flashes, cardiomegaly, ECG abnormality, left-sided heart failure, and pericardial effusion Pulmonary : Hyperventilation, alveolar hemorrhage (fatal in 3%), pharyngitis, hiccup, asthma, atelectasis, pleural effusion, hypoxia, hemoptysis, sinusitis, and interstitial fibrosis (fatal in a single case) Neurologic: Cerebral hemorrhage, coma, delirium, agitation, encephalopathy, confusion, hallucinations, lethargy, somnolence Renal: BUN increased, dysuria, oliguria, hematuria, hemorrhagic cystitis Skin: Alopecia, vesicular rash, maculopapular rash, vesiculo-bullous rash, exfoliative dermatitis, erythema nodosum, acne, skin discoloration Metabolic: Hypophosphatemia, hyponatremia Other Events: Injection site pain, myalgia, arthralgia, ear disorder 6.2 Postmarketing Experience 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. The following adverse reactions have been identified during post-approval use of Busulfan Injection: Blood and Lymphatic System Disorders : febrile neutropenia Gastrointestinal Disorders : tooth hypoplasia Metabolism and Nutrition Disorders : tumor lysis syndrome Vascular Disorders : thrombotic microangiopathy (TMA) Infections and Infestations : severe bacterial, viral (e.g., cytomegalovirus viremia) and fungal infections; and sepsis. 6.3 Oral Busulfan Literature Review A literature review identified four randomized, controlled trials that evaluated a high-dose oral busulfan-containing conditioning regimen for allogeneic bone marrow transplantation in the setting of CML [see Clinical Studies (14) ] . The safety outcomes reported in those trials are summarized in Table 2 below for a mixed population of hematological malignancies (AML, CML, and ALL). Table 2: Summary of safety analyses from the randomized, controlled trials utilizing a high dose oral busulfan-containing conditioning regimen that were identified in a literature review. 1. TRM = Transplantation Related Mortality 2. VOD = Veno-Occlusive Disease of the liver 3. GVHD = Graft versus Host Disease Clift CML Chronic Phase TRM 1 VOD 2 GVHD 3 Pulmonary Hemorrhagic Seizure Cystitis Death No Report Acute≥Grade 2 1 death from No Report No Report ≤100d =35% Idiopathic =4.1% Chronic=41% Interstitial (3/73) (30/73) Pneumonitis And 1 death from Pulmonary Fibrosis Devergie CML Chronic Phase TRM VOD GVHD Pulmonary Hemorrhagic Seizure Cystitis 38% 7.7% (5/65) Acute≥Grade 2 Interstitial 10.8% (7/65) No Report Deaths=4.6% =41% Pneumonitis= (3/65) (24/59 at risk) 16.9% (11/65) Ringden CML, AML, ALL TRM VOD GVHD Pulmonary Hemorrhagic Seizure Cystitis 28% 12% Acute≥Grade 2 Interstitial 24% 6% GVHD=26% Pneumonitis Chronic GVHD =14% =45% Blume CML, AML, ALL TRM VOD GVHD Pulmonary Hemorrhagic Seizure Cystitis No Report Deaths Acute≥Grade 2 No Report No Report No Report =4.9% GVHD=22% (13/58 at risk) Chronic GVHD =31% (14/45 at risk)