Important Safety Information

• GLEEVEC is often associated with edema and, occasionally, serious fluid retention. Severe fluid retention was reported in 9%-13.1% and 2.5%-11% of patients taking GLEEVEC for GIST and CML, respectively. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life threatening, and be advised to report any rapid, unexpected weight gain. The probability of edema tended to be increased among older patients (>65 years) or those taking higher doses of GLEEVEC. Severe edema and superficial edema was observed in 182 (11.1%) GIST patients and 1.5%-6% in CML patients, respectively. If severe fluid retention occurs, manage with diuretic therapy and withhold GLEEVEC until the event has resolved, and then resume depending on the initial severity of the event
• Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (eg, every 2-3 months). Dose reduction, treatment interruption, or in rare cases discontinuation of treatment may be required for severe neutropenia or thrombocytopenia (see full Prescribing Information for dose adjustment recommendations)
• Severe congestive heart failure and left ventricular dysfunction have been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac disease or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated
• Hepatotoxicity, occasionally severe, may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of GLEEVEC. Assess liver function before initiation of treatment and monthly thereafter, or as clinically indicated. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment. If severe hepatotoxicity occurs, GLEEVEC should be withheld until the event has resolved and then resumed depending on the initial severity of the event
• When GLEEVEC is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended
• In the newly diagnosed CML trial, 1.8% of patients had hemorrhage (NCI Grades 3/4)
• In the Phase 3 unresectable or metastatic GIST studies, 13% of patients reported hemorrhage (NCI Grades 3/4) at any site. In the Phase 2 unresectable or metastatic GIST study, 5% of patients were reported to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds; therefore, GI symptoms should be monitored at the start of therapy
• In patients with hypereosinophilic syndrome and cardiac involvement, cardiogenic shock and left ventricular dysfunction have been associated with initiation of GLEEVEC. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporarily withholding GLEEVEC. MDS /MPD disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should, therefore, be considered in patients with HES/CEL and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for 1-2 weeks concomitantly with GLEEVEC should be considered at the initiation of therapy
• Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose, with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction
• Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients
• Consider potential toxicities—specifically liver, kidney, and cardiac toxicity—and immunosuppression from long-term use
• Fetal harm can occur when administered to a pregnant woman. Therefore, women of reproductive potential should be advised not to become pregnant while taking GLEEVEC tablets and to avoid breastfeeding while taking GLEEVEC because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use highly effective contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus
• Growth retardation has been reported in children and preadolescents receiving GLEEVEC. The long-term effects of prolonged treatment with GLEEVEC on growth in children are unknown; therefore, monitoring of growth in children taking GLEEVEC is recommended
• Cases of tumor lysis syndrome (TLS), including fatal cases, have been reported. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of GLEEVEC
• Motor vehicle accidents involving patients receiving GLEEVEC have been reported. Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision, or somnolence during treatment with GLEEVEC. Caution should be recommended when driving a car or operating machinery
• In Ph+ CML trials,* severe (NCI Grades 3/4) lab abnormalities—including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (~ 5%)—and severe (NCI Grades 3/4) adverse experiences, including hemorrhage (1.8%-19%), fluid retention (eg, pleural effusion, pulmonary edema, and ascites) (2.5%-11%) and superficial edema (1.5%-6%), and musculoskeletal pain (2%-9%) were reported among patients receiving GLEEVEC. Severe fluid retention appears to be dose related, was more common in the advanced phase studies (where the dosage was 600 mg/day), and is more common in the elderly
• In HES/CEL patients, instances of Grade 3 leukopenia, neutropenia, lymphopenia, and anemia were reported
• For DFSP, severe (NCI Grades 3/4) lab abnormalities included anemia (17%), thrombocytopenia (17%), neutropenia (8%), and increased creatinine (8%)
• In the Phase 2 unresectable or metastatic GIST trial (400 mg/d; 600 mg/d), severe (NCI Grades 3/4) lab abnormalities—including anemia (3%; 9%) and neutropenia (10%; 11%)—were reported among patients receiving GLEEVEC. In Phase 3 unresectable or metastatic GIST trials (400 mg/day; 800 mg/day), the most frequently reported adverse reactions included abdominal pain (14%; 12%), edema (9%; 13%), fatigue (12%; 12%), nausea (9%; 8%), vomiting (9%; 8%), diarrhea (8%; 9%), rash (8%; 9%), myalgia (6%; 4%), anemia (5%; 6%), and anorexia (7%; 5%). The percentages listed represent NCI Grades 3 and above
• In the adjuvant GIST study comparing 12 months of GLEEVEC vs placebo treatment (GLEEVEC; placebo), severe (NCI Grades 3 and above) lab abnormalities included increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), decreased neutrophil count (3%; 1%), and decrease in hemoglobin (1%; 0%); severe (NCI Grades 3 and above reported at rates >1%) adverse reactions included abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2%; 1%), nausea (2%; 1%), vomiting (2%; 1%), decreased white blood cell count (1%; 0%), and periorbital edema (1%; 0%). The frequencies of these reported lab abnormalities and severe adverse reactions were similar in a study comparing 12 vs 36 months of GLEEVEC treatment (12 mo; 36 mo), except for liver enzyme AST (2%; 3%), decreased neutrophil count (5%; 5%), decreased white blood cell count (2%; 3%), pain (1%; 3%), infection (2%; 3%), and blurred vision (1%; 1%), which were higher among patients receiving 36 months of adjuvant treatment with GLEEVEC*
• There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation
• GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Significant reductions in imatinib concentrations may occur when GLEEVEC is administered concomitantly with agents that are strong CYP3A4 inducers such as rifampin, St. John's wort, and enzyme-inducing anti-epileptic drugs, eg, phenytoin. The concomitant use of strong CYP3A4 inducers should be avoided. If patients must be administered a strong CYP3A4 inducer, the dosage of GLEEVEC should be increased by at least 50%, and clinical response should be carefully monitored. Caution is recommended when GLEEVEC is administered with CYP3A4 inhibitors such as ketoconazole, with CYP2D6 substrates that have a narrow therapeutic window, or with CYP3A4 substrates that have a narrow therapeutic window. Other examples of commonly used drugs that may significantly interact with GLEEVEC include acetaminophen, warfarin, erythromycin, and metoprolol. Grapefruit juice should also be avoided in patients taking GLEEVEC. (Please see full Prescribing Information for other potential drug interactions)
• Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose; future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. GLEEVEC should be used with caution in patients with severe renal impairment