The data described below reflect exposure to SPRYCEL in 911 patients with leukemia from 1 Phase I and 5 Phase II clinical studies. The median duration of therapy was 6 months (range 0–19 months).
The majority of SPRYCEL-treated patients experienced adverse drug reactions at some time. Drug was discontinued for adverse drug reactions in 6% of patients in chronic phase CML, 5% in accelerated phase CML, 11% in myeloid blast phase CML, and 6% in lymphoid blast phase CML or Ph+ ALL.
The most frequently reported adverse events included fluid retention events such as pleural effusion; gastrointestinal events including diarrhea, nausea, abdominal pain and vomiting; and bleeding events.
The most frequently reported serious adverse events (SAEs) included pyrexia (9%), pleural effusion (8%), febrile neutropenia (7%), gastrointestinal bleeding (6%), pneumonia (6%), thrombocytopenia (5%), dyspnea (4%), anemia (3%), cardiac failure (3%), and diarrhea (2%).
All treatment-emergent adverse events (excluding laboratory abnormalities), regardless of relationship to study drug, that were reported in at least 10% of the patients in SPRYCEL clinical studies are shown in Table 4.
Table 4: Adverse Events Reported ≥10% in Clinical Studies
|All Grades||Grades 3/4 ||Grades 3/4 ||Grades 3/4 ||Grades 3/4||Grades 3/4|
|Percent (%) of Patients|
|a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, ejection fraction decreased, and left ventricular failure.|
|b Includes erythema, exfoliative rash, generalized erythema, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, systemic lupus erythematosus rash, urticaria vesiculosa, drug eruption, and rash vesicular.|
| Superficial Edema||36||1||0||2||3||2|
| Pleural Effusion||22||5||3||3||14||8|
| Other Fluid Retention||14||5||4||4||12||3|
| Generalized Edema||5||1||<1||0||2||1|
| Congestive Hearta|
| Pericardial Effusion||4||1||<1||1||3||0|
| Pulmonary Edema||4||1||1||2||0||1|
| CNS Bleeding||2||1||0||1||2||2|
| Infection (including |
bacterial, viral, fungal,
|Upper Respiratory Tract|
bacterial, viral, and
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 CML or Ph+ ALL than in chronic phase CML. 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 and/or reduction; permanent discontinuation of treatment occurred in 1% of patients.
Grade 3 or 4 elevations of transaminases or bilirubin and Grade 3 or 4 hypocalcemia 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 CML and Ph+ ALL. Elevations in transaminases 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.
Table 5: CTC Grades 3/4 Laboratory Abnormalities in Clinical Studies
|Myeloid Blast Phase|
|Lymphoid Blast |
|Percent (%) of Patients|
|CTC grades: neutropenia (Grade 3 ≥0.5–1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia|
|(Grade 3 ≥10–50 × 109/L, Grade 4 <10 × 109/L); anemia (hemoglobin ≥65–80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit 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).|
| Thrombocytopenia ||48||83||82||83|
| Elevated SGPT (ALT)||1||4||7||11|
| Elevated SGOT (AST)||1||2||5||8|
| Elevated Bilirubin||<1||1||5||8|
| Elevated Creatinine||0||2||1||1|
Additional Data From Clinical Trials
The following treatment-emergent adverse events, regardless of relationship to study drug, were reported in patients in the SPRYCEL clinical studies at a frequency of <10%. These events are presented by frequency category. Frequent adverse events are those occurring in 1%–<10% of patients and infrequent adverse events are those occurring in 0.1%–<1% of patients. Infrequent events are included on the basis of clinical relevance.
Gastrointestinal Disorders: Frequent – dyspepsia, oral soft tissue disorder, gastritis, colitis, anal fissure, dysphagia; Infrequent – esophagitis, upper gastrointestinal ulcer, ileus, pancreatitis.
General Disorders and Administration Site Conditions: Frequent – malaise; Infrequent – temperature intolerance.
Skin and Subcutaneous Tissue Disorders: Frequent – hyperhidrosis, alopecia, dry skin, acne, urticaria, dermatitis (including eczema), photosensitivity reaction, nail disorder, pigmentation disorder; Infrequent – skin ulcer, acute febrile neutrophilic dermatosis, bullous conditions, palmar-plantar erythrodysesthesia syndrome.
Respiratory, Thoracic, and Mediastinal Disorders: Frequent – lung infiltration, pneumonitis, asthma; Infrequent – bronchospasm, acute respiratory distress syndrome.
Nervous System Disorders: Frequent – dysgeusia, somnolence, syncope, tremor, convulsion; Infrequent – amnesia, cerebrovascular accident, transient ischemic attack, reversible posterior leukoencephalopathy syndrome.
Blood and Lymphatic System Disorders: Frequent – pancytopenia; Infrequent – coagulopathy, aplasia pure red cell.
Musculoskeletal and Connective Tissue Disorders: Frequent – muscle inflammation, muscular weakness, musculoskeletal stiffness; Infrequent – tendonitis, rhabdomyolysis.
Investigations: Frequent – blood creatine phosphokinase increased, troponin increased; Infrequent – platelet aggregation abnormal.
Infections and Infestations: Frequent – herpes virus infection, sepsis (including fatal outcomes), enterocolitis infection.
Metabolism and Nutrition Disorders: Frequent – appetite disturbances, hyperuricemia; Infrequent – hypoalbuminemia.
Cardiac Disorders: Frequent – palpitations, angina pectoris, cardiomegaly, myocardial infarction; Infrequent – pericarditis, ventricular tachycardia, acute coronary syndrome, myocarditis.
Eye Disorders: Frequent – conjunctivitis, dry eye.
Vascular Disorders: Frequent – flushing, hypotension, hypertension; Infrequent – livedo reticularis.
Psychiatric Disorders: Frequent – insomnia, depression, anxiety, confusional state, affect lability; Infrequent – libido decreased.
Reproductive System and Breast Disorders: Frequent – gynecomastia; Infrequent – menstruation irregular.
Injury, Poisoning, and Procedural Complications: Frequent – contusion.
Ear and Labyrinth Disorders: Frequent – tinnitus, vertigo.
Hepatobiliary Disorders: Infrequent – cholecystitis, hepatitis, cholestasis.
Renal and Urinary Disorders: Frequent – urinary frequency, renal failure; Infrequent – proteinuria.
Neoplasms Benign, Malignant and Unspecified: Frequent – tumor lysis syndrome.
Immune System Disorders: Infrequent – hypersensitivity.