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adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (≥10%) in patients with newly diagnosed chronic phase CML included myelosuppression, fluid retention, diarrhea, headache, musculoskeletal pain, and rash. Most common adverse reactions (≥20%) in patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The following adverse reactions are discussed in greater detail in other sections of the labeling: Myelosuppression [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . Bleeding related events [see Warnings and Precautions (5.2) ] . Fluid retention [see Warnings and Precautions (5.3) ] . QT prolongation [see Warnings and Precautions (5.4) ] . Congestive heart failure, left ventricular dysfunction, and myocardial infarction [see Warnings and Precautions (5.5) ] . Pulmonary Arterial Hypertension [see Warnings and Precautions (5.6) ] . 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. The data described below reflect exposure to SPRYCEL in clinical studies including 258 patients with newly diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL. In the newly diagnosed chronic phase CML trial, the median duration of therapy was 18 months; the median average daily dose was 99 mg. In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 years follow-up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median duration of treatment with SPRYCEL 100 mg once daily was 24 months (range 1–33 months). The median duration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid blast CML. The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of SPRYCEL-treated patients. Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reaction were 15% in chronic phase CML, 16% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reaction was lower in patients treated with 100 mg once daily than in patients treated with other dosing regimens (10% and 16%, respectively). The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash. Pleural effusions were reported in 31 patients (see Table 2). The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%). The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%). 6.1 Chronic Myeloid Leukemia (CML) Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of patients are shown in Table 2 for newly diagnosed patients with chronic phase CML and Table 3 for CML patients with resistance or intolerance to prior imatinib therapy. Table 2: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic Phase CML All Grades Grade 3/4 SPRYCEL (n=258) Imatinib (n=258) SPRYCEL (n=258) Imatinib (n=258) Preferred Term Percent (%) of Patients a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage. Fluid retention 23 43 1 1 Pleural effusion 12 0 <1 0 Superficial localized edema 10 36 0 <1 Generalized edema 3 7 0 0 Congestive heart failure/ cardiac dysfunction a 2 1 <1 <1 Pericardial effusion 2 <1 <1 0 Pulmonary hypertension 1 0 0 0 Pulmonary edema <1 0 0 0 Diarrhea 18 19 <1 1 Headache 12 10 0 0 Musculoskeletal pain 12 16 0 <1 Rash b 11 17 0 1 Nausea 9 21 0 0 Fatigue 8 11 <1 0 Myalgia 6 12 0 0 Hemorrhage c 6 5 1 1 Gastrointestinal bleeding 2 <1 1 0 Other bleeding d 5 5 0 1 CNS bleeding 0 <1 0 <1 Vomiting 5 10 0 0 Muscle inflammation 4 19 0 <1 Table 3: Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant to Prior Imatinib Therapy 100 mg Once Daily 140 mg Once Daily Chronic (n=165) Accelerated (n=157) Myeloid Blast (n=74) Lymphoid Blast (n=33) Preferred Term All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Percent (%) of Patients a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. Fluid Retention 34 4 35 8 34 7 21 6 Superficial localized edema 18 0 18 1 14 0 3 0 Pleural effusion 18 2 21 7 20 7 21 6 Generalized edema 3 0 1 0 3 0 0 0 Pericardial effusion 2 1 3 1 0 0 0 0 Congestive heart failure/ cardiac dysfunction a 0 0 0 0 4 0 0 0 Pulmonary edema 0 0 1 0 4 3 0 0 Headache 33 1 27 1 18 1 15 3 Diarrhea 27 2 31 3 20 5 18 0 Fatigue 24 2 19 2 20 1 9 3 Dyspnea 20 2 20 3 15 3 3 3 Musculoskeletal pain 19 2 11 0 8 1 0 0 Nausea 18 1 19 1 23 1 21 3 Skin rash b 17 2 15 0 16 1 21 0 Myalgia 13 0 7 1 7 1 3 0 Arthralgia 12 1 10 0 5 1 0 0 Infection (including bacterial, viral, fungal, and non-specified) 12 1 10 6 14 7 9 0 Abdominal pain 12 1 6 0 8 3 3 0 Hemorrhage 11 1 26 8 19 9 24 9 Gastrointestinal bleeding 2 1 8 6 9 7 9 3 CNS bleeding 0 0 1 1 0 0 3 3 Vomiting 7 1 11 1 12 0 15 0 Pyrexia 5 1 11 2 18 3 6 0 Febrile neutropenia 1 1 4 4 12 12 12 12 Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 4 and 5). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions (5.1) ] . Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation. Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 4. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters. Table 4: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed Chronic Phase CML SPRYCEL (n=258) Imatinib (n=258) Percent (%) of Patients CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 9 /L, Grade 4 <0.5 × 10 9 /L); thrombocytopenia (Grade 3 ≥25–<50 × 10 9 /L, Grade 4 <25 × 10 9 /L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). Hematology Parameters Neutropenia 22 20 Thrombocytopenia 19 10 Anemia 11 7 Biochemistry Parameters Hypophosphatemia 5 24 Hypokalemia 0 2 Hypocalcemia 3 2 Elevated SGPT (ALT) <1 1 Elevated SGOT (AST) <1 1 Elevated Bilirubin 1 0 Elevated Creatinine <1 1 Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of SPRYCEL are shown by disease phase in Table 5. Table 5: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance or Intolerance to Prior Imatinib Therapy Advanced Phase CML Chronic Phase CML 140 mg Once Daily 100 mg Once Daily (n=165) Accelerated Phase (n=157) Myeloid Blast Phase (n=74) Lymphoid Blast Phase (n=33) Percent (%) of Patients CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 9 /L, Grade 4 <0.5 × 10 9 /L); thrombocytopenia (Grade 3 ≥25–<50 × 10 9 /L, Grade 4 <25 × 10 9 /L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). Hematology Parameters Neutropenia 36 58 77 79 Thrombocytopenia 23 63 78 85 Anemia 13 47 74 52 Biochemistry Parameters Hypophosphatemia 10 13 12 18 Hypokalemia 2 7 11 15 Hypocalcemia <1 4 9 12 Elevated SGPT (ALT) 0 2 5 3 Elevated SGOT (AST) <1 0 4 3 Elevated Bilirubin <1 1 3 6 Elevated Creatinine 0 2 8 0 6.2 Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) A total of 135 patients with Ph+ ALL were treated with SPRYCEL in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events, such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders, such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%). 6.3 Additional Data From Clinical Trials The following adverse reactions were reported in patients in the SPRYCEL clinical studies at a frequency of 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance. Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis; <0.1% – protein losing gastroenteropathy. General Disorders and Administration Site Conditions: 1%–<10% – asthenia, pain, chest pain, chills; 0.1%–<1% – malaise, temperature intolerance. Skin and Subcutaneous Tissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. Respiratory, Thoracic, and Mediastinal Disorders: 1%–<10% – cough, lung infiltration, pneumonitis, pulmonary hypertension; 0.1%–<1% – asthma, bronchospasm; <0.1% – acute respiratory distress syndrome. Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis. Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness; 0.1%–<1% – musculoskeletal stiffness, rhabdomyolysis; <0.1% – tendonitis. Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased. Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection; 0.1%–<1% – sepsis (including fatal outcomes). Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances; 0.1%–<1% – hyperuricemia, hypoalbuminemia. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia); <0.1% – cor pulmonale, myocarditis, acute coronary syndrome. Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1% –<1% – conjunctivitis. Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis; <0.1% – livedo reticularis. Psychiatric Disorders: 1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased. Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular. Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Neoplasms Benign, Malignant, and Unspecified: 0.1%–<1% – tumor lysis syndrome. Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum). 6.4 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of SPRYCEL. 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. Cardiac disorders: atrial fibrillation/atrial flutter Vascular disorders: thrombosis/embolism (including pulmonary embolism, deep vein thrombosis) Respiratory, thoracic, and mediastinal disorders: interstitial lung disease, pulmonary arterial hypertension