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.
In the single open-label multicenter clinical trial, a total of 438 patients were treated (CML-CP=318; CML-AP=120).
The median duration of exposure in days for CML-CP and CML-AP patients is 245 (range 1-502) and 138 (range 2-503), respectively. The median dose intensity of 797 mg/day (range 145–1149) was similar for both the chronic and accelerated phase patients and corresponded to the planned 400 mg twice daily dosing.
The median cumulative duration in days of dose interruptions for the CML-CP patients was 18 (range 1-185), and the median duration in days of dose interruptions for the CML-AP patients was 22 (range 1–163).
In CML-CP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritis, nausea, fatigue, headache, constipation, diarrhea and vomiting. The common serious drug-related adverse reactions were thrombocytopenia and neutropenia.
In CML-AP patients, the most commonly reported drug-related adverse reactions (>10%) were rash, pruritus and constipation. The common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia.
Sudden deaths and QT prolongation were reported. [ See Boxed Warning and Warnings and Precautions (5.2 and 5.3 ) ] .
Discontinuation for drug-related adverse reactions was observed in 11% of CML-CP and 8% of CML-AP patients.
Table 4 shows the percentage of patients experiencing treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in at least 10% of patients who received at least one dose of Tasigna are listed.
| CML-CP |
| CML-AP |
|Body System and Preferred Term|| All Grades |
| CTC Grades b |
3 / 4
| All Grades |
| CTC Grades b |
3 / 4
|Skin and subcutaneous tissue disorders:||Rash||33||2||28||0|
|Nervous system disorders||Headache||31||3||21||2|
|General disorders and administration site conditions||Fatigue||28||1||16||<1|
|Musculoskeletal and connective tissue disorders||Arthralgia||18||2||16||0|
|Pain in extremity||13||1||16||2|
|Respiratory, thoracic and mediastinal disorders||Cough||17||<1||13||0|
|Infections and infestations||Nasopharyngitis||16||<1||11||0|
a Excluding laboratory abnormalities
b NCI Common Terminology Criteria for Adverse Events, Version 3.0
Table 5 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.
| CML-CP |
| CML-AP |
|Grades 3/4 *||Grades 3/4 *|
|-Elevated bilirubin (total)||9%||10%|
|-Elevated SGPT (ALT)||4%||2%|
|-Elevated SGOT (AST)||1%||1%|
|-Elevated alkaline phosphatase||1%||3%|
*NCI Common Terminology Criteria for Adverse Events, version 3.0
1CML-CP: Thrombocytopenia: 11% were grade 3, 17% were grade 4
2CML-AP: Thrombocytopenia: 7% were grade 3, 30% were grade 4
3CML-AP: Neutropenia: 12% were grade 3, 25% were grade 4
The following drug-related adverse reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1% -10%), and uncommon (0.1%-1%) adverse reactions single events are captured as unknown frequency. For laboratory abnormalities, very common events (≥1/10) not included in Table 4 are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category.
Infections and Infestations: Uncommon: pneumonia, urinary tract infection, gastroenteritis, pharyngitis.
Unknown frequency: sepsis, bronchitis, herpes simplex, candidiasis.
Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia.
Unknown frequency: thrombocytosis, leukocytosis.
Endocrine Disorders: Uncommon: hyperthyroidism.
Unknown frequency: hypothyroidism, thyroiditis.
Metabolism and Nutrition Disorders: Common: hypomagnesemia, hyperkalemia, hyperglycemia, anorexia.
Uncommon: hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, dehydration, decreased appetite, increased appetite.
Unknown frequency: diabetes mellitus, hypercalcemia, hyperphosphatemia.
Psychiatric Disorders: Common: Insomnia.
Uncommon: depression, anxiety.
Unknown frequency: disorientation, confusional state.
Nervous System Disorders: Common: dizziness, paresthesia
Uncommon: intracranial hemorrhage, migraine, tremor, hypoesthesia, hyperesthesia.
Unknown frequency: brain edema, loss of consciousness, optic neuritis, peripheral neuropathy.
Eye Disorders: Uncommon: eye hemorrhage, visual acuity reduced, periorbital edema, conjunctivitis, eye irritation, dry-eye.
Unknown frequency: papilloedema, diplopia, vision blurred, photophobia, eye swelling, blepharitis, eye pain.
Ear and Labyrinth Disorders: Common: vertigo.
Unknown frequency: hearing impaired, ear pain.
Cardiac Disorders: Common: palpitations, electrocardiogram QT prolonged.
Uncommon: cardiac failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease, cardiomegaly, cardiac murmur, bradycardia.
Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, cardiac flutter, extrasysoles,
Vascular Disorders: Common: hypertension, flushing.
Uncommon: hypertensive crisis, hematoma.
Unknown frequency: shock hemorrhagic, hypotension, thrombosis.
Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, cough, dysphonia.
Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, epistaxis, pharyngolaryngeal pain, throat irritation.
Unknown frequency: pulmonary hypertension.
Gastrointestinal Disorders: Common: abdominal discomfort, dyspepsia, flatulence.
Uncommon: pancreatitis, gastrointestinal hemorrhage, melena, abdominal distension, mouth ulceration, gastroesophageal reflux, stomatitis, dry mouth.
Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus.
Hepatobiliary Disorders: Uncommon: hepatitis.
Unknown frequency: hepatotoxicity, hepatomegaly, jaundice.
Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, alopecia, erythema, hyperhidrosis, dry skin.
Uncommon: exfoliative rash, ecchymosis, swelling face.
Unknown frequency: erythema nodosum, skin ulcer, petechiae, photosensitivity.
Musculoskeletal and Connective Tissue Disorders: Common: musculoskeletal chest pain, musculoskeletal pain.
Uncommon: muscular weakness.
Unknown frequency: Arthritis, joint swelling.
Renal and Urinary Disorders: Uncommon: dysuria, micturition urgency, nocturia, pollakiuria.
Unknown frequency: renal failure, hematuria, urinary incontinence.
Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction.
General Disorders and Administration Site Conditions: Common: pyrexia.
Uncommon: chest pain, face edema, gravitational edema, influenza-like illness, chills, malaise.
Investigations: Very common: lipase increased.
Common: blood amylase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood glucose increased, weight decreased, weight increased.
Uncommon: blood lactate dehydrogenase increased, blood glucose decreased, blood creatinine increased, blood urea increased.
Unknown frequency: troponin increased, blood potassium decreased, blood bilirubin unconjugated increased.