"The U.S. Food and Drug Administration today approved Iclusig (ponatinib) to treat adults with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), two rare blood and bone marrow diseases."...
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.
Chronic Myeloid Leukemia
The majority of Gleevec-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% 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 for newly diagnosed CML, Table 3 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. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure.
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 and 3.
Table 2 : Adverse Reactions Reported in Newly Diagnosed CML Clinical Trial ( ≥ 10% of Gleevec Treated Patients)(1)
|Preferred Term||All Grades||CTC Grades 3/4|
|- Superficial Edema||59.9||9.6||1.5||0.4|
|- Other Fluid Retention Reactions2||6.9||1.9||1.3||0.6|
|Rash and Related Terms||40.1||26.1||2.9||2.4|
|- 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|
|(1)All adverse reactions occurring
in ≥ 10% 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 : Adverse Reactions Reported in Other CML Clinical
Trials ( ≥ 10% of All Patients in any Trial)(1)
|Preferred Term||Myeloid Blast Crisis (n=260) %||Accelerated Phase (n=235) %||Chronic Phase, IFN Failure (n=532) %|
|All Grades||Grade 3/4||All Grades||Grade 3/4||All Grades||Grade 3/4|
|-Other Fluid Retention|
|- 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|
|(1) All adverse reactions occurring
in ≥ 10% of patients are listed regardless of suspected relationship
(2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.
Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥ 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 4 and 5). 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 4 : Lab Abnormalities in Newly Diagnosed CML Clinical
|Grade 3||Grade 4||Grade 3||Grade 4|
|- 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|
|*p < 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups)|
Table 5 :Lab Abnormalities in Other CML Clinical Trials
|CTC Grades1||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) 400mg %|
|Grade 3||Grade 4||Grade 3||Grade 4||Grade 3||Grade 4|
|- Thrombocytopenia||30||33||31||13||21||< 1|
|- 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||0||2.3||0|
|- Elevated SGPT (ALT)||2.3||0.4||4.3||0||2.1||0|
|1CTC Grades: neutropenia (Grade 3 ≥ 0.5-1.0 x 109/L, Grade 4 < 0.5 x 109/L), thrombocytopenia (Grade 3 ≥ 10-50 x 109/L, Grade 4 < 10 x 109/L), anemia (hemoglobin ≥ 65-80 g/L, Grade 4 < 65 g/L), elevated creatinine (Grade 3 > 3-6 x upper limit normal range [ULN], Grade 4 > 6 x ULN), elevated bilirubin (Grade 3 > 3-10 x ULN, Grade 4 > 10 x ULN), elevated alkaline phosphatase (Grade 3 > 5-20 x ULN, Grade 4 > 20 x ULN), elevated SGOT or SGPT (Grade 3 > 5-20 x ULN, Grade 4 > 20 x ULN)|
Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5) 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
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. Although most patients experienced adverse reactions at some time during the study, the incidence of Grade 3/4 adverse reactions was low.
Adverse Reactions in Other Subpopulations
In older patients ( ≥ 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 ½ 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, which were easily manageable. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were rarely severe 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 6.
Table 6 : Adverse Reactions Reported (More than One Patient)
in MPD Patients in the Phase 2 Study ( ≥ 10% All Patients) All Grades
|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 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 7.
Table 7 : Adverse Reactions Reported in DFSP Patients in
the Phase 2 Study ( ≥ 10% All Patients) All Grades
|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 (25.0)|
|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 8.
Table 8 : Laboratory Abnormalities Reported in DFSP Patients
in the Phase 2 Study
|Grade 3||Grade 4|
|- Anemia||17 %||0 %|
|- Thrombocytopenia||17 %||0 %|
|- Neutropenia||0 %||8 %|
|- Elevated Creatinine||0 %||8 %|
|1CTC Grades: neutropenia (Grade 3 ≥ 0.5-1.0 x 109/L, Grade 4 < 0.5 x 109/L), thrombocytopenia (Grade 3 ≥ 10 - 50 x 109/L, Grade 4 < 10 x 109/L), anemia (Grade 3 ≥ 65-80 g/L, Grade 4 < 65 g/L), elevated creatinine (Grade 3 > 3-6 x upper limit normal range [ULN], Grade 4 > 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 9.
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 9 :Number (%) of Patients with Adverse Reactions where
Frequency is ≥ 10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable
and/or Malignant Metastatic GIST Clinical Trials
|Reported or Specified Term||Imatinib 400 mg N=818||Imatinib 800 mg N=822|
|All Grades %||Grades 3/4/5 %||All Grades %||Grades 3/4/5 %|
|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 10.
Table 10 : Laboratory Abnormalities in the Phase 2 Unresectable
and/or Malignant Metastatic GIST Trial
|CTC Grades1||400 mg (n=73) %||600 mg (n=74) %|
|Grade 3||Grade 4||Grade 3||Grade 4|
|- Elevated Creatinine||0||0||3||0|
|- Reduced Albumin||3||0||4||0|
|- Elevated Bilirubin||1||0||1||3|
|- 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 ≥ 0.5-1.0 x 109/L, Grade 4 < 0.5 x 109/L), thrombocytopenia (Grade 3 ≥ 10 - 50 x 109/L, Grade 4 < 10 x 109/L), anemia (Grade 3 ≥ 65-80 g/L, Grade 4 < 65 g/L), elevated creatinine (Grade 3 > 3-6 x upper limit normal range [ULN], Grade 4 > 6 x ULN), elevated bilirubin (Grade 3 > 3-10 x ULN, Grade 4 > 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 > 5-20 x ULN, Grade 4 > 20 x ULN), albumin (Grade 3 < 20 g/L)|
Adjuvant Treatment of GIST
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.
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 11.
Table 11: Adverse Reactions Reported in the Adjuvant GIST
Trial ( ≥ 5% of Gleevec Treated Patients)(1)
|Preferred Term||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 ≥ 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.|
Additional Data from Multiple Clinical Trials
The following adverse reactions have been reported during clinical trials of Gleevec.
Estimated 1%-10%: flushing, hemorrhage
Clinical Laboratory Tests:
Estimated 0.1%-1%: blood CPK increased, blood LDH increased,
Estimated 0.01%-0.1%: blood amylase increased
Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae
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, erythema multiforme, leucocytoclastic vasculitis
General Disorders and Administration Site Conditions:
Estimated 1%-10%: weakness, anasarca, chills
Estimated 0.1%-1%: malaise
Estimated 1%-10%: pancytopenia, febrile neutropenia
Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1
Estimated 0.01%-0.1%: angioedema Infections:
Estimated 0.01%-0.1%: fungal infection
Metabolic and Nutritional:
Estimated 1%-10%: weight decreased
Estimated 1%-10%: joint swelling
Estimated 0.1%-1%: joint and muscle stiffness
Estimated 0.01%-0.1%: muscular weakness, arthritis
Estimated 1%-10%: paresthesia, hypesthesia
Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis
Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain
Respiratory: Estimated 1%-10%: epistaxis
Estimated 0.1%-1%: pleural effusion
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.
Nervous system disorders: cerebral edema1
Eye disorders: vitreous hemorrhage
Vascular disorders: thrombosis/embolism, anaphylactic shock
Respiratory, thoracic and mediastinal disorders: acute respiratory failure1, interstitial lung disease
Skin and subcutaneous tissue disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome
Musculoskeletal and connective tissue disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children
1Including some fatalities
Read the Gleevec (imatinib mesylate) Side Effects Center for a complete guide to possible side effects »
Agents Inducing CYP3A Metabolism
Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p < 0.05) decreased mean Cmax and AUC.
Similar findings were observed in patients receiving 400-1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED's decreased by 73% compared to patients not receiving EIAED.
Concomitant administration of Gleevec and St. John's Wort led to a 30% reduction in the AUC of imatinib.
Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Gleevec doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers. [see DOSAGE AND ADMINISTRATION].
Agents Inhibiting CYP3A Metabolism
There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Gleevec with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations.
Interactions with Drugs Metabolized by CYP3A4
Gleevec increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Gleevec. Particular caution is recommended when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus).
Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).
Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.
Interactions with Drugs Metabolized by CYP2D6
Gleevec increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Gleevec has a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.
Interaction with Acetaminophen
In vitro, Gleevec inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 μM) . Co-administration of Gleevec (400 mg/day for eight days) with acetaminophen (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Gleevec pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of Gleevec at doses > 400 mg/day or the chronic use of concomitant acetaminophen and Gleevec.
Last reviewed on RxList: 2/21/2013
This monograph has been modified to include the generic and brand name in many instances.
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