Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions (5.3)]
Growth Retardation in Children and Adolescents [see Warnings and Precautions (5.11)]
Impairments Related to Driving and Using Machinery [see Warnings and Precautions (5.13)]
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.
Chronic Myeloid Leukemia
The majority of imatinib mesylate-treated patients experienced adverse reactions at some time. Imatinib mesylate was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate versus IFN+Ara-C, and in 12.5% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib. Imatinib mesylate was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon- alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis.
The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of imatinib mesylate [see Dosage and Administration (2.13)]. The frequency of severe superficial edema was 1.5% to 6%.
A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting imatinib mesylate treatment and using diuretics or other appropriate supportive care measures. These reactions may be serious or life threatening.
Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the imatinib mesylate treated patients are shown in Tables 2, 3, and 4.
Hematologic and Biochemistry Laboratory Abnormalitie</span>
Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.
In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 5, 6, and 7). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.
These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib mesylate, but may require permanent discontinuation of treatment.
Hepatotoxicity
Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 6 and 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure.
Adverse Reactions in Pediatric Population
Single agent therapy
The overall safety profile of pediatric patients treated with imatinib mesylate in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Most patients experienced adverse reactions at some time during the study. The incidence of Grade 3/4 events across all types of adverse reactions was 75%; the events with the highest Grade 3/4 incidence in CML pediatric patients were mainly related to myelosuppression.
Adverse Reactions in Other Subpopulations
In older patients (greater than or equal to 65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.
Acute Lymphoblastic Leukemia
The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps and rash. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were reported as Grade 3/4 events in 6.3% of the patients and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of imatinib mesylate.
Myelodysplastic/Myeloproliferative Diseases
Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib mesylate for MDS/MPD in the Phase 2 study, are shown in Table 9.
Aggressive Systemic Mastocytosis
All ASM patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued imatinib mesylate due to drug-related adverse reactions or abnormal laboratory values.
Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia
The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of imatinib mesylate observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia.
Dermatofibrosarcoma Protuberans
Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with imatinib mesylate for DFSP in the Phase 2 study are shown in Table 10.
Clinically relevant or severe laboratory abnormalities in the 12 patients treated with imatinib mesylate for DFSP in the Phase 2 study are presented in Table 11.
Adverse Reactions from Multiple Clinical Trials</span>
Cardiac Disorders:
Estimated 1% to 10%: palpitations, pericardial effusion
Estimated 0.1% to 1%: congestive cardiac failure, tachycardia, pulmonary edema
Estimated 0.01% to 0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris
Vascular Disorders:
Estimated 1% to 10%: flushing, hemorrhage
Estimated 0.1% to 1%: hypertension, hypotension, peripheral coldness, Raynaud’s phenomenon, hematoma, subdural hematoma
Investigations:
Estimated 1% to 10%: blood CPK increased, blood amylase increased
Estimated 0.1% to 1%: blood LDH increased
Skin and Subcutaneous Tissue Disorders:
Estimated 1% to 10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura
Estimated 0.1% to 1%: exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme
Estimated 0.01% to 0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis
Gastrointestinal Disorders:
Estimated 1% to 10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis
Estimated 0.1% to 1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis
Estimated 0.01% to 0.1%: colitis, ileus, inflammatory bowel disease
General Disorders and Administration Site Conditions:
Estimated 1% to 10%: weakness, anasarca, chills
Estimated 0.1% to 1%: malaise
Blood and Lymphatic System Disorders:
Estimated 1% to 10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophilia
Estimated 0.1% to 1%: thrombocythemia, bone marrow depression, lymphadenopathy
Estimated 0.01% to 0.1%: hemolytic anemia, aplastic anemia
Hepatobiliary Disorders:
Estimated 0.1% to 1%: hepatitis, jaundice
Estimated 0.01% to 0.1%: hepatic failure and hepatic necrosis1
Immune System Disorders:
Estimated 0.01% to 0.1%: angioedema
Infections and Infestations:
Estimated 0.1% to 1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis
Estimated 0.01% to 0.1%: fungal infection
Metabolism and Nutrition Disorders:
Estimated 1% to 10%: weight decreased, decreased appetite
Estimated 0.1% to 1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia
Musculoskeletal and Connective Tissue Disorders:
Estimated 1% to 10%: joint swelling
Estimated 0.1% to 1%: joint and muscle stiffness, muscular weakness, arthritis
Nervous System/Psychiatric Disorders:
Estimated 1% to 10%: paresthesia, hypesthesia
Estimated 0.1% to 1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor
Estimated 0.01% to 0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis
Renal and Urinary Disorders:
Estimated 0.1% to 1%: renal failure acute, urinary frequency increased, hematuria, renal pain
Reproductive System and Breast Disorders:
Estimated 0.1% to 1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema
Respiratory, Thoracic and Mediastinal Disorders:
Estimated 1% to 10%: epistaxis
Estimated 0.1% to 1%: pleural effusion
Estimated 0.01% to 0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage
Eye, Ear and Labyrinth Disorders:
Estimated 1% to 10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye
Estimated 0.1% to 1%: vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract
Estimated 0.01% to 0.1%: papilledema1, glaucoma
1Including some fatalities
6.2 Postmarketing Experience
The following additional adverse reactions have been identified during post approval use of imatinib mesylate. 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.
Infections: hepatitis B virus reactivation1
Nervous System Disorders: cerebral edema1
Eye Disorders: vitreous hemorrhage
Cardiac Disorders: pericarditis, cardiac tamponade1
Vascular Disorders: thrombosis/embolism, anaphylactic shock
Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure1, interstitial lung disease
Gastrointestinal Disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation1 [see Warnings and Precautions (5.6)], diverticulitis, gastric antral vascular ectasia
Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and Connective Tissue Disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthralgia, bone pain)
Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst
1Including some fatalities
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