INDICATION STATEMENT

GLEEVEC^® (imatinib mesylate) tablets are indicated for the treatment of:

• Newly diagnosed adult patients with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP)
• Patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in CP after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia (Ph+ ALL)
• Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene rearrangements
• Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-KIT mutation or with c-KIT mutational status unknown
• Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase–negative or unknown
• Adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP)
• Patients with KIT (CD117)–positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST)
• Adjuvant treatment of adult patients following resection of KIT (CD117)–positive GIST

Important Safety Information

• GLEEVEC is often associated with edema and occasionally severe fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening.
• 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 (for example, every 2-3 months).
• Dose adjustments may be necessary due to hematologic adverse reactions, hepatotoxicity, and other nonhematologic adverse reactions.
• In Ph+ CML trials,* severe (NCI Grades 3/4) lab abnormalities—including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (approx 5%)—and severe adverse reactions (NCI Grades 3/4), 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 Phase 3 unresectable or metastatic GIST trials (400 mg/day; 800 mg/day) severe (NCI Grades 3/4/5) lab abnormalities—including anemia (5%; 6%) and neutropenia (3%; 4%)—and severe adverse reactions (NCI Grades 3/4/5), including abdominal pain (14%; 12%), fluid retention and edema (9%; 13%), fatigue (12%; 12%), nausea (9%; 8%), vomiting (9%; 8%), diarrhea (8%; 9%), rash (8%; 9%), and myalgia (6%; 4%) were reported among patients receiving GLEEVEC.
• In the adjuvant treatment of GIST trials (GLEEVEC; placebo) severe (NCI Grades 3 and above) lab abnormalities—increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), and decrease in hemoglobin (1%; 0%)—and severe adverse reactions (NCI Grades 3 and above), including abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2% to 1%), nausea (2%; 1%), vomiting (2%; 1%), and periorbital edema (1%; 0%) were reported among patients receiving adjuvant treatment of GLEEVEC.
• Severe congestive heart failure and left ventricular dysfunction have occasionally 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 failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.
• Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.
• Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose, and 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.
• In the newly diagnosed CML trial, 2% of patients had (NCI Grades 3/4) hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 13% of patients reported (NCI Grades 3/4) hemorrhage 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.
• There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation.
• In patients with HES and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of therapy with 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 childbearing potential should be advised to not become pregnant while taking GLEEVEC tablets and to avoid breast-feeding while taking GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use adequate contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus.
• GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of GLEEVEC should increase by at least 50% and clinical response should be carefully monitored in patients receiving GLEEVEC with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with GLEEVEC include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions.)
• For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.

Common Adverse Reactions to GLEEVEC Tablets

• The majority of adult patients with Ph+ CML who received GLEEVEC in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all Grades) were superficial edema (60%-74%), nausea (50%-73%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), rash and related terms (36%-47%), muscle cramps (28%-62%), and vomiting (23%-58%).*^†
• The adverse reactions and safety profile for Ph+ ALL, MDS/MPD, ASM, and HES/CEL were generally similar to the safety profile for Ph+ CML.^†
• The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea, vomiting, diarrhea, myalgia, muscle cramps, and rash, which were easily manageable. Superficial edemas were also a common finding in all studies and were described primarily as periorbital or lower-limb edemas. However, these edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of GLEEVEC. ^†
• Frequently reported adverse reactions (all Grades) in the seven MDS/MPD patients assessed were nausea (57%); diarrhea and muscle cramps (43% each); anemia, fatigue, arthralgia, and periorbital edema (29% each). ^†
• All ASM patients experienced at least 1 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.^†
• All HES/CEL patients experienced at least 1 adverse reaction, the most common being gastrointestinal, cutaneous, and musculoskeletal disorders. Hematologic abnormalities were also frequent, with instances of Grade 3 leukopenia, neutropenia, lymphopenia, and anemia. ^†
• Frequently reported adverse reactions (all Grades) in the 12 patients with DFSP assessed included nausea and fatigue (42% each); periorbital, peripheral and eye edema (33% each); diarrhea, vomiting, rash, lacrimation increase, and anemia (25% each); face edema, pyrexia, exertional dyspnea, rhinitis, and anorexia (17% each). ^†
• The majority of patients who received GLEEVEC in the Phase 3 unresectable or metastatic GIST study experienced adverse reactions at some time. The most frequently reported adverse reactions (400 mg/day; 800 mg/day) (all Grades) were edema (77%; 86%), fatigue (69%; 75%), nausea (58%; 65%), diarrhea (56%; 58%), abdominal pain (57%; 55%), rash and related terms (56%; 70%), vomiting (37%; 41%), and muscle cramps (32%; 30%). Therapy with GLEEVEC was discontinued for adverse reactions in 5% of patients at both dose levels studied. ^†
• In the adjuvant treatment of GIST trials, the majority of both GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (GLEEVEC; placebo) (all Grades) diarrhea (60%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), and abdominal pain (21%; 22%).^†
• In the adjuvant GIST trial, drug was discontinued for adverse reactions in 17% of GLEEVEC- and 3% of placebo-treated patients. 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. ^†
• Supportive care may help management of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary.
• GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation. GLEEVEC tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.
• Patients should be informed to take GLEEVEC exactly as prescribed, not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose.

*Numbers indicate the range of percentages in 4 studies among adult patients with newly diagnosed Ph+ CML and patients in BC, AP, and CP after failure of interferon-alpha therapy.

^†For more detailed study information, please see full Prescribing Information.

Please see full Prescribing Information for additional Important Safety Information.