In a trial of imatinib mesylate versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib mesylate arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the imatinib mesylate arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience.
Imatinib mesylate is sometimes associated with GI irritation. Imatinib mesylate tablets should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.
In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib mesylate therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate.
Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1 to 2 mg/kg) for one to two weeks concomitantly with imatinib mesylate at the initiation of therapy.
Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of imatinib mesylate. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib mesylate therapy after resolution or improvement of the bullous reaction. In these instances, imatinib mesylate was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.
Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib mesylate. Monitor TSH levels in such patients.
Imatinib mesylate can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib mesylate and for 14 days after stopping imatinib mesylate. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1) ].
Growth retardation has been reported in children and pre-adolescents receiving imatinib mesylate. The long term effects of prolonged treatment with imatinib mesylate on growth in children are unknown. Therefore, monitor growth in children under imatinib mesylate treatment [see Adverse Reactions (6.1) ].
Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, ALL, and eosinophilic leukemia receiving imatinib mesylate. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions. Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib mesylate.
Motor vehicle accidents have been reported in patients receiving imatinib mesylate. Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with imatinib mesylate. Recommend caution when driving a car or operating machinery.
A decline in renal function may occur in patients receiving imatinib mesylate. Median estimated glomerular filtration rate (eGFR) values in patients on imatinib mesylate 400 mg daily for newly-diagnosed CML (four randomized trials) declined from a baseline value of 85 ml/min/1.73m2 (N=1190) to 75 ml/min/1.73m2 at 12 months (N=1082) and 69 ml/min/1.73m2 at 60 months (N=549). Evaluate renal function prior to initiating imatinib mesylate and monitor during therapy, with attention to risk factors for renal dysfunction, such as pre-existing renal impairment, diabetes mellitus, hypertension, and congestive heart failure.
The following serious adverse reactions are described elsewhere in the labeling:
· Fluid Retention and Edema [see Warnings and Precautions (5.1)]
· Hematologic Toxicity [see Warnings and Precautions (5.2)]
· Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions (5.3)]
· Hepatotoxicity [see Warnings and Precautions (5.4)]
· Hemorrhage [see Warnings and Precautions (5.5)]
· Gastrointestinal Disorders [see Warnings and Precautions (5.6)]
· Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions (5.7)]
· Dermatologic Toxicities [see Warnings and Precautions (5.8)]
· Hypothyroidism [see Warnings and Precautions (5.9)]
· Growth Retardation in Children and Adolescents [see Warnings and Precautions (5.11)]
· Tumor Lysis Syndrome [see Warnings and Precautions (5.12)]
· Renal Toxicity [ see Warnings and Precautions (5.14 )]
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.
|All Grades||CTC Grades 3/4|
|Preferred Term||Imatinib Mesylate N=551 (%)||IFN+Ara−C N=533 (%)||Imatinib Mesylate N=551 (%)||IFN+Ara−C N=533 (%)|
|− Superficial Edema||59.9||9.6||1.5||0.4|
|− Other Fluid Retention Reactions †||6.9||1.9||1.3||0.6|
|Rash and Related Terms||40.1||26.1||2.9||2.4|
|– GI Hemorrhage||1.6||1.1||0.5||0.2|
|– CNS Hemorrhage||0.2||0.4||0||0.4|
|Upper Respiratory Tract Infection||21.2||8.4||0.2||0.4|
|Patients with Newly Diagnosed Ph+ CML-CP|
|imatinib mesylate 400 mg once daily N=280||nilotinib 300 mg twice daily N=279||imatinib mesylate 400 mg once daily N=280||nilotinib 300 mg twice daily N=279|
|Body System and Preferred Term||All Grades (%)||CTC Grades † 3/4 (%)|
|Skin and subcutaneous tissue disorders||Rash||19||38||2||<1|
|Abdominal pain upper||14||18||<1||1|
|Nervous system disorders||Headache||23||32||<1||3|
|General disorders and administration-site conditions||Fatigue||20||23||1||1|
|Musculoskeletal and connective tissue disorders||Myalgia||19||19||<1||<1|
|Pain in extremity||16||15||<1||<1|
|Respiratory, thoracic and mediastinal disorders||Cough||13||17||0||0|
|Infections and infestations||Nasopharyngitis||21||27||0||0|
|Upper respiratory tract infection||14||17||0||<1|
|Eye disorders||Eyelid edema||19||1||<1||0|
|Myeloid Blast Crisis (n=260) %||Accelerated Phase (n=235) %||Chronic Phase, IFN Failure (n=532) %|
|Preferred Term||All Grades||Grade 3/4||All Grades||Grade 3/4||All Grades||Grade 3/4|
|-Other Fluid Retention Reactions †||22||6||15||4||7||2|
|– CNS Hemorrhage||9||7||3||3||2||1|
|– GI Hemorrhage||8||4||6||5||2||0.4|
|Upper Respiratory Tract Infection||3||0||12||0.4||19||0|
Hematologic and Biochemistry Laboratory Abnormalitie
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.
|CTC Grades||Imatinib Mesylate N=551 %||IFN+Ara−C N=533 %|
|Grade 3||Grade 4||Grade 3||Grade 4|
|Hematology Parameters *|
|− Neutropenia *||13.1||3.6||20.8||4.5|
|− Thrombocytopenia *||8.5||0.4||15.9||0.6|
|− Elevated Creatinine||0||0||0.4||0|
|− Elevated Bilirubin||0.9||0.2||0.2||0|
|− Elevated Alkaline Phosphatase||0.2||0||0.8||0|
|− Elevated SGOT /SGPT||4.7||0.5||7.1||0.4|
|imatinib mesylate 400 mg once-daily N=280 (%)||nilotinib 300 mg twice-daily N=279 (%)|
|Elevated bilirubin (total)||<1||4|
|Elevated SGPT (ALT)||3||4|
|Elevated SGOT (AST)||1||1|
|Elevated alkaline phosphatase||<1||0|
|Myeloid Blast Crisis (n=260) 600 mg n=223 400 mg n=37 %||Accelerated Phase (n=235) 600 mg n=158 400 mg n=77 %||Chronic Phase, IFN Failure (n=532) 400 mg %|
|CTC Grades *||Grade 3||Grade 4||Grade 3||Grade 4||Grade 3||Grade 4|
|− Elevated Creatinine||1.5||0||1.3||0||0.2||0|
|− Elevated Bilirubin||3.8||0||2.1||0||0.6||0|
|− Elevated Alkaline Phosphatase||4.6||0||5.5||0.4||0.2||0|
|− Elevated SGOT (AST)||1.9||0||3||0||2.3||0|
|− Elevated SGPT (ALT)||2.3||0.4||4.3||0||2.1||0|
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
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.
In Combination with Multi-agent Chemotherapy
Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n=92) were assigned to receive imatinib mesylate and treated in 5 successive cohorts. Imatinib mesylate exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.
The safety of imatinib mesylate given in combination with intensive chemotherapy was evaluated by comparing the incidence of grade 3 and 4 adverse events, neutropenia (less than 750/mcL) and thrombocytopenia (less than 75,000/mcL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive imatinib mesylate. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without imatinib mesylate. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with imatinib mesylate and 647 without imatinib mesylate. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included imatinib mesylate are presented in Table 8.
Table 8: Adverse Reactions Reported More Frequently in Patients Treated with Study Drug (greater than 5%) or in Cycles with Study Drug (greater than 1%)
|Adverse Event Grade 3 and 4 Adverse Events||Per Patient Incidence Ph+ ALL With Imatinib Mesylate N=92 n (%)||Per Patient Incidence Ph- ALL With Imatinib Mesylate N=65 n (%)||Per Patient Per Cycle Incidence With Imatinib Mesylate* N=778 n (%)||Per Patient Per Cycle Incidence No Imatinib Mesylate** N=647 n (%)|
|Nausea and/or Vomiting||15 (16)||6 (9)||28 (4)||8 (1)|
|Hypokalemia||31 (34)||16 (25)||72 (9)||32(5)|
|Pneumonitis||7 (8)||1 (1)||7(1)||1(< 1)|
|Pleural effusion||6 (7)||0||6 (1)||0|
|Abdominal Pain||8 (9)||2 (3)||9 (1)||3(< 1)|
|Anorexia||10 (11)||3 (5)||19 (2)||4 (1)|
|Hemorrhage||11 (12)||4 (6)||17 (2)||8 (1)|
|Hypoxia||8 (9)||2 (3)||12 (2)||2 (< 1)|
|Myalgia||5 (5)||0||4 (1)||1 (< 1)|
|Stomatitis||15 (16)||8 (12)||22 (3)||14 (2)|
|Diarrhea||8 (9)||3 (5)||12 (2)||3 (< 1)|
|Rash / Skin Disorder||4 (4)||0||5 (1)||0|
|Infection||49 (53)||32 (49)||131 (17)||92 (14)|
|Hepatic (transaminase and/or bilirubin)||52 (57)||38 (58)||172 (22)||113 (17)|
|Hypotension||10 (11)||5 (8)||16 (2)||6 (1)|
|Neutropenia (< 750/mcL)||92 (100)||63 (97)||556 (71)||218 (34)|
|Thrombocytopenia (< 75,000/mcL)||90 (92)||63 (97)||431 (55)||329 (51)|
*Defined as the frequency of AEs per patient per treatment cycles that included imatinib mesylate (includes patients with Ph+ ALL that received cycles with imatinib mesylate).
**Defined as the frequency of AEs per patient per treatment cycles that did not include imatinib mesylate includes patients with Ph+ ALL that received cycles without imatinib mesylate as well as all patients with Ph- ALL who did not receive imatinib mesylate in any treatment cycle).
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 DiseasesAdverse 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.
|Preferred Term||N=7 n (%)|
|Muscle Cramp||3 (42.9)|
|Periorbital Edema||2 (28.6)|
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 ProtuberansAdverse 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.
|Preferred term||N=12 n (%)|
|Periorbital Edema||4 (33.3)|
|Face Edema||2 (16.7)|
|Edema Peripheral||4 (33.3)|
|Eye Edema||4 (33.3)|
|Lacrimation Increased||3 (25)|
|Dyspnea Exertional||2 (16.7)|
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.
|CTC Grades *||Grade 3 %||Grade 4 %|
|– Elevated Creatinine||0||8|
Adverse Reactions from Multiple Clinical Trials
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
Estimated 1% to 10%: flushing, hemorrhage
Estimated 0.1% to 1%: hypertension, hypotension, peripheral coldness, Raynaud’s phenomenon, hematoma, subdural hematoma
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
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
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
Estimated 0.1%–1%: hypothyroidism, hyperthyroidism
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
1 Including some fatalities
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