"The U.S. Food and Drug Administration today expanded the approved use of Imbruvica (ibrutinib) for chronic lymphocytic leukemia (CLL) patients who have received at least one previous therapy.
CLL is a rare blood and bone marrow disease"...
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.
The following serious adverse reactions are described elsewhere in the labeling:
- Fluid Retention and Edema [see WARNINGS AND PRECAUTIONS]
- Hematologic Toxicity [see WARNINGS AND PRECAUTIONS]
- Congestive Heart Failure and Left Ventricular Dysfunction [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Hemorrhage [see WARNINGS AND PRECAUTIONS]
- Gastrointestinal Disorders [see WARNINGS AND PRECAUTIONS]
- Hypereosinophilic Cardiac Toxicity [see WARNINGS AND PRECAUTIONS]
- Dermatologic Toxicities [see WARNINGS AND PRECAUTIONS]
- Hypothyroidism [see WARNINGS AND PRECAUTIONS]
- Growth Retardation in Children and Adolescents [see WARNINGS AND PRECAUTIONS]
- Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
- Impairments Related to Driving and Using Machinery [see WARNINGS AND PRECAUTIONS]
Chronic Myeloid Leukemia
The majority of Gleevec-treated patients experienced adverse reactions at some time. Gleevec was discontinued due to drug-related adverse reactions in 2.4% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec versus IFN+Ara-C, and in 12.5% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec and nilotinib. Gleevec 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 Gleevec [see DOSAGE AND ADMINISTRATION]. The frequency of severe superficial edema was 1.5%–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 Gleevec 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 Gleevec treated patients are shown in Tables 2, 3, and 4.
Table 2: Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial in the Gleevec versus IFN+Ara-C Study (greater than or equal to 10% of Gleevec Treated Patients)(1)
|All Grades||CTC Grades 3/4|
|Other Fluid Retention Reactions2||6.9||1.9||1.3||0.6|
|Rash and Related Terms||40.1||26.1||2.9||2.4|
|Upper Respiratory Tract Infection||21.2||8.4||0.2||0.4|
|(1)All adverse reactions occurring in greater than or equal to10% of Gleevec treated patients are listed regardless of suspected relationship to treatment.
(2)Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.
Table 3: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP in the Gleevec versus nilotinib Study (greater than or equal to 10% in Gleevec 400 mg Once-Daily or nilotinib 300 mg Twice-Daily Groups) 60-Month Analysisa
|Patients with Newly Diagnosed Ph+ CML-CP|
|Body System and Preferred Term||All Grades (%)||CTC Gradesb 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|
|aExcluding laboratory abnormalities
bNCI Common Terminology Criteria for Adverse Events, Version 3.0
Table 4: Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (greater than or equal to 10% of All Patients in any Trial)(1)
|Myeloid Blast Crisis||Accelerated Phase||Chronic Phase, IFN Failure|
|Preferred Term||All Grades||Grade 3/4||All Grades||Grade 3/4||All Grades||Grade 3/4|
|Other Fluid Retention Reactions (2)||22||6||15||4||7||2|
|Upper Respiratory Tract Infection||3||0||12||0.4||19||0|
|(1) All adverse reactions occurring in greater than or equal to10% of patients are listed regardless of suspected relationship to treatment.
(2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.
Hematologic And Biochemistry Laboratory Abnormalities
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 Gleevec, but in rare cases require permanent discontinuation of treatment.
Table 5: Laboratory Abnormalities in Newly Diagnosed CML Clinical Trial (Gleevec versus IFN+Ara-C)
|CTC Grades||Grade 3||Grade 4||Grade 3||Grade 4|
|Elevated Alkaline Phosphatase||0.2||0||0.8||0|
|Elevated SGOT /SGPT||4.7||0.5||7.1||0.4|
|*p less than 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups)|
Table 6: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (Gleevec versus nilotinib)
|Gleevec 400 mg
|nilotinib 300 mg
|Elevated bilirubin (total)||<1||4|
|Elevated SGPT (ALT)||3||4|
|Elevated SGOT (AST)||1||1|
|Elevated alkaline phosphatase||<1||0|
|*NCI Common Terminology Criteria for Adverse Events, version 3.0|
Table 7: Laboratory Abnormalities in Other CML Clinical Trials
|Myeloid Blast Crisis
|Chronic Phase, IFN Failure
|600 mg n=223
400 mg n=37
|600 mg n=158
400 mg n=77
|CTC Grades1||Grade 3||Grade 4||Grade 3||Grade 4||Grade 3||Grade 4|
|Elevated Alkaline Phosphatase||4.6||0||5.5||0.4||0.2||0|
|Elevated SGOT (AST)||1.9||0||3.0||0||2.3||0|
|Elevated SGPT (ALT)||2.3||0.4||4.3||0||2.1||0|
|1CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 109/L), anemia (hemoglobin greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3–10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN), elevated SGOT or SGPT (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN)|
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 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.
Adverse Reactions In Pediatric Population
Single Agent Therapy
The overall safety profile of pediatric patients treated with Gleevec 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 Gleevec and treated in 5 successive cohorts. Gleevec exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.
The safety of Gleevec 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 Gleevec. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without Gleevec. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with Gleevec and 647 without Gleevec. 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 Gleevec 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%)
|Per Patient Incidence Ph+ALL With Gleevec||Per Patient Incidence Ph- ALL No Gleevec||Per Patient Per Cycle Incidence With Gleevec*||Per Patient Per Cycle Incidence No Gleevec**|
|Grade 3 and 4 Adverse Events|
|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 Gleevec (includes patients with Ph+ ALL that received cycles with Gleevec
**Defined as the frequency of AEs per patient per treatment cycles that did not include Gleevec (includes patients with Ph+ ALL that received cycles without Gleevec as well as all patients with Ph- ALL who did not receive Gleevec 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 Gleevec.
Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec for MDS/MPD in the Phase 2 study, are shown in Table 9.
Table 9: Adverse Reactions Regardless of Relationship to Study Drug Reported (More than One Patient) in MPD Patients in the Phase 2 Study (greater than or equal to 10% All Patients) All Grades
|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 Gleevec 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 Gleevec 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.
Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with Gleevec for DFSP in the Phase 2 study are shown in Table 10.
Table 10: Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study (greater than or equal to 10% All Patients) All Grades
|Periorbital Edema||4 (33.3)|
|Face Edema||2 (16.7)|
|Edema Peripheral||4 (33.3)|
|Eye Edema||4 (33.3)|
|Lacrimation Increased||3 (25.0)|
|Dyspnea Exertional||2 (16.7)|
Clinically relevant or severe laboratory abnormalities in the 12 patients treated with Gleevec for DFSP in the Phase 2 study are presented in Table 11.
Table 11: Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study
|CTC Grades1||Grade 3
|1CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 109/L), anemia (Grade 3 greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN)|
Gastrointestinal Stromal Tumors
Unresectable And/Or Malignant Metastatic GIST
In the Phase 3 trials, the majority of Gleevec-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see DOSAGE AND ADMINISTRATION]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%).
Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 12.
Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.
Table 12: Number (%) of Patients with Adverse Reactions Regardless of Relationship to Study Drug where Frequency is Greater than or Equal to 10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials
|Imatinib 400 mg
|Imatinib 800 mg
|Reported or Specified Term||All Grades
|Fatigue/lethargy, malaise, asthenia||69.3||11.7||74.9||12.2|
|Other GI toxicity||25.2||8.1||28.1||6.6|
|Other pain (excluding tumor related pain)||20.4||5.9||20.8||5.0|
|Other dermatology/skin toxicity||17.6||5.9||20.1||5.7|
|Other constitutional symptoms||16.7||6.4||15.2||4.4|
|Infection (without neutropenia)||15.5||6.6||16.5||5.6|
|Other neurological toxicity||15.0||6.4||15.2||4.9|
|Other renal/genitourinary toxicity||14.2||6.5||13.6||5.2|
|Arthralgia (joint pain)||13.6||4.8||12.3||3.0|
|Dyspnea (shortness of breath)||13.6||6.8||14.2||5.6|
|Fever in absence of neutropenia (ANC<1.0 x 109/L)||13.2||4.9||12.9||3.4|
|Stomatitis/pharyngitis (oral/pharyngeal mucositis)||9.2||5.4||10.0||4.3|
Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 13.
Table 13: Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial
|CTC Grades1||Grade 3||Grade 4||Grade 3||Grade 4|
|Elevated Alkaline Phosphatase||0||0||3||0|
|Elevated SGOT (AST)||4||0||3||3|
|Elevated SGPT (ALT)||6||0||7||1|
|1CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 109/L, Grade 4 less than 0.5 x 109/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 109/L, Grade 4 less than 10 x 109/L), anemia (Grade 3 greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3–10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN), albumin (Grade 3 less than 20 g/L)|
Adjuvant Treatment Of GIST
In Study 1, the majority of both Gleevec and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.
In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the Gleevec 12-month and 36-month treatment arms, respectively. As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.
Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to Gleevec treatment in either trial.
Table 14: Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 (greater than or equal to 5% of Gleevec Treated Patients)(1)
|All CTC Grades||CTC Grade 3 and above|
|Liver enzymes (ALT) Increased||16.6||13.0||2.7||0|
|Neutrophil Count Decreased||16.0||6.1||3.3||0.9|
|White Blood Cell Count Decreased||14.5||4.3||0.6||0.3|
|Liver Enzymes (AST) Increased||12.2||7.5||2.1||0|
|Blood Creatinine Increased||11.6||5.8||0||0.3|
|Pain in Extremity||7.4||7.2||0.3||0|
|Blood Alkaline Phosphatase Increased||6.5||7.5||0||0|
|Abdominal Pain Upper||6.2||6.4||0.3||0|
|Platelet Count Decreased||5.0||3.5||0||0|
|Upper Respiratory Tract Infection||5.0||3.5||0||0|
|(1)All adverse reactions occurring in greater than or equal to 5% of patients are listed regardless of suspected relationship to treatment.
A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.
Table 15: Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and 3/4 Grades (greater than or equal to 5% of Gleevec Treated Patients) Study 2(1)
|All CTC Grades||CTC Grades 3 and above|
|Patients with at least one AE||99.0||100.0||20.1||32.8|
|Blood lactate dehydrogenase increased||43.3||60.1||0||0|
|White blood cell count decreased||34.5||47.0||2.1||3.0|
|Blood creatinine increased||30.4||44.4||0||0|
|Aspartate aminotransferase increased||30.9||37.9||1.5||3.0|
|Alanine aminotransferase increased||28.9||34.3||2.1||3.0|
|Neutrophil count decreased||24.2||33.3||4.6||5.1|
|Blood alkaline phosphatase increased||10.8||16.7||0||0.5|
|Platelet count decreased||11.3||14.1||0||0|
|Blood bilirubin increased||11.3||13.1||0||0|
|(1)All adverse reactions occurring in greater than or equal to5% of patients are listed regardless of suspected relationship to treatment.
A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category.
Additional Data From Multiple Clinical Trials
The following adverse reactions have been reported during clinical trials of Gleevec.
Estimated 1%–10%: palpitations, pericardial effusion
Estimated 0.1%–1%: congestive cardiac failure, tachycardia, pulmonary edema
Estimated 1%–10%: flushing, hemorrhage
Estimated 1%–10%: blood CPK increased, blood amylase increased
Estimated 0.1%–1%: blood LDH increased
Skin and Subcutaneous Tissue Disorders
Estimated 0.1%–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%–0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis
General Disorders And Administration Site Conditions
Estimated 1%–10%: weakness, anasarca, chills
Estimated 0.1%–1%: malaise
Blood And Lymphatic System Disorders
Estimated 1%–10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophila
Estimated 0.01%–0.1%: hepatic failure and hepatic necrosis1
Immune System Disorders
Estimated 0.01%–0.1%: angioedema
Infections And Infestations
Estimated 0.01%–0.1%: fungal infection
Metabolism And Nutrition Disorders
Estimated 1%–10%: weight decreased, decreased appetite
Musculoskeletal And Connective Tissue Disorders
Estimated 1%–10%: joint swelling
Nervous System/Psychiatric Disorders
Estimated 1%–10%: paresthesia, hypesthesia
Estimated 0.01%–0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis
Renal and Urinary Disorders
Estimated 0.1%–1%: renal failure acute, urinary frequency increased, hematuria, renal pain
Reproductive System And Breast Disorders
Respiratory, Thoracic And Mediastinal Disorders
Estimated 1%–10%: epistaxis
Estimated 0.1%–1%: pleural effusion
Eye, Ear And Labyrinth Disorders
1Including some fatalities
The following additional adverse reactions have been identified during post approval use of Gleevec. 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
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], 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)
1Including some fatalities
Read the Gleevec (imatinib mesylate) Side Effects Center for a complete guide to possible side effects
Agents Inducing CYP3A Metabolism
Concomitant administration of Gleevec and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see CLINICAL PHARMACOLOGY].
Agents Inhibiting CYP3A Metabolism
Concomitant administration of Gleevec and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice [see CLINICAL PHARMACOLOGY].
Interactions With Drugs Metabolized By CYP3A4
Gleevec will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window.
Interactions With Drugs Metabolized By CYP2D6
Use caution when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.
Read the Gleevec Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 10/24/2016
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