ADVERSE REACTIONS
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
Preferred Term |
|---|
All Patients
(n=911) | Chronic
Phase
(n=488) | Accelerated
Phase
(n=186) | Myeloid
Blast Phase
(n=132) | Lymphoid
Blast Phase
and
Ph+ ALL
(n=105) |
|---|
| 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. |
| Fluid Retention | 50 | 9 | 6 | 6 | 23 | 9 |
| 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
Failure/Cardiac
Dysfunction | 4 | 2 | 3 | 1 | 5 | 1 |
| Pericardial Effusion | 4 | 1 | <1 | 1 | 3 | 0 |
| Pulmonary Edema | 4 | 1 | 1 | 2 | 0 | 1 |
| Ascites | 1 | 1 | 0 | 1 | 2 | 2 |
Pulmonary
Hypertension | 1 | 0 | <1 | 1 | 2 | 0 |
| Diarrhea | 49 | 5 | 3 | 10 | 8 | 6 |
| Headache | 40 | 2 | 2 | 2 | 4 | 6 |
| Hemorrhage | 40 | 10 | 3 | 18 | 23 | 17 |
Gastrointestinal
Bleeding | 14 | 7 | 2 | 12 | 14 | 10 |
| CNS Bleeding | 2 | 1 | 0 | 1 | 2 | 2 |
| Musculoskeletal Pain | 39 | 4 | 2 | 3 | 6 | 13 |
| Pyrexia | 39 | 5 | 1 | 5 | 13 | 9 |
| Fatigue | 39 | 3 | 2 | 4 | 4 | 8 |
| Skin Rashb | 35 | 1 | 1 | 1 | 1 | 4 |
| Nausea | 34 | 1 | <1 | 0 | 5 | 2 |
| Dyspnea | 32 | 6 | 5 | 7 | 11 | 9 |
| Cough | 28 | <1 | <1 | 1 | 1 | 0 |
Infection (including
bacterial, viral, fungal,
non-specified) | 34 | 7 | 4 | 8 | 15 | 13 |
| Upper Respiratory Tract | | | | | | |
| Infection/Inflammation | 26 | 1 | 1 | 1 | 5 | 1 |
| Abdominal Pain | 25 | 2 | 1 | 2 | 4 | 6 |
| Pain | 26 | 2 | <1 | 1 | 5 | 4 |
| Vomiting | 22 | 1 | 1 | 2 | 2 | 2 |
| Anorexia | 19 | 1 | <1 | 2 | 2 | 3 |
| Asthenia | 19 | 3 | 1 | 4 | 6 | 5 |
| Arthralgia | 19 | 1 | 1 | 0 | 3 | 2 |
Mucosal Inflammation
(including
mucositis/stomatitis) | 16 | 1 | <1 | 0 | 4 | 1 |
| Dizziness | 14 | <1 | <1 | 0 | 0 | 0 |
| Weight Decreased | 14 | 1 | <1 | 1 | 1 | 0 |
| Constipation | 14 | <1 | <1 | 0 | 1 | 0 |
| Chest Pain | 13 | 1 | <1 | 0 | 4 | 3 |
Neuropathy (including
peripheral neuropathy) | 13 | 1 | 1 | 1 | 0 | 0 |
| Myalgia | 12 | 1 | 0 | 1 | 2 | 2 |
| Abdominal Distention | 11 | 0 | 0 | 0 | 0 | 0 |
| Weight Increased | 11 | 1 | <1 | 1 | 1 | 1 |
| Arrhythmia | 11 | 2 | 2 | 1 | 2 | 3 |
| Chills | 11 | <1 | 0 | 1 | 0 | 0 |
| Pruritus | 11 | 0 | 0 | 0 | 0 | 0 |
Pneumonia (including
bacterial, viral, and
fungal) | 11 | 6 | 3 | 8 | 11 | 10 |
| Febrile Neutropenia | 9 | 8 | 2 | 11 | 17 | 20 |
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 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 | Chronic Phase
(n=488) | Accelerated Phase
(n=186) | Myeloid Blast Phase
(n=132) | Lymphoid Blast
Phase and
Ph+ ALL
(n=105) |
|---|
| 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). |
| Hematology Parameters |
|---|
| Neutropenia | 49 | 74 | 83 | 81 |
| Thrombocytopenia | 48 | 83 | 82 | 83 |
| Anemia | 18 | 70 | 70 | 51 |
| Biochemistry Parameters |
|---|
| Hypophosphatemia | 11 | 13 | 23 | 21 |
| Hypocalcemia | 2 | 9 | 20 | 15 |
| 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.
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