IMPORTANT INFORMATION

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

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase
• Patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in the chronic phase (CP) after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
• Pediatric patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy
• Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene rearrangements as determined with an FDA-approved test
• Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-KIT mutation as determined with an FDA-approved test or with c-KIT mutational status unknown
• Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have 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 complete gross resection of KIT (CD117)-positive GIST

Important Safety Information

• GLEEVEC is often associated with edema and, occasionally, serious fluid retention. Severe fluid retention was reported in 9% to 13.1% and 2.5% to 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 were observed in 182 (11.1%) GIST patients and 1.5% to 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. In a study of patients with newly diagnosed Ph+ CML in chronic phase comparing GLEEVEC and nilotinib, severe (grade 3 or 4) fluid retention occurred in 2.5% of patients receiving GLEEVEC and in 3.9% of patients receiving nilotinib. Effusions or pulmonary edema were observed in 2.1% (none were grade 3 or 4) of patients in the GLEEVEC arm and 2.2% (0.7% grade 3 or 4) of patients in the nilotinib arm
• GLEEVEC is often associated with edema and, occasionally, serious fluid retention. Severe fluid retention was reported in 9% to 13.1% and 2.5% to 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 were observed in 182 (11.1%) GIST patients and 1.5% to 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. In a study of patients with newly diagnosed Ph+ CML in chronic phase comparing GLEEVEC and nilotinib, severe (grade 3 or 4) fluid retention occurred in 2.5% of patients receiving GLEEVEC and in 3.9% of patients receiving nilotinib. Effusions or pulmonary edema were observed in 2.1% (none were grade 3 or 4) of patients in the GLEEVEC arm and 2.2% (0.7% grade 3 or 4) of patients in the nilotinib arm
• 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)
• Congestive heart failure and left ventricular dysfunction (LVD) have been reported. Most patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. In a phase 3 study of patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and LVD occurred in 0.7% of GLEEVEC patients vs 0.9% of IFN+Ara-C patients. In a study of newly diagnosed Ph+ CML patients in chronic phase comparing GLEEVEC and nilotinib, cardiac failure was observed in 1.1% and 2.2% of patients, respectively, and severe (grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Patients with cardiac disease, 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 of GLEEVEC vs IFN+Ara-C, 1.8% of patients had grade 3/4 hemorrhage. In a study with newly diagnosed Ph+ CML patients in the chronic phase comparing GLEEVEC and nilotinib, GI hemorrhage occurred in 1.4% and 2.9% of patients, respectively. None of these events were grade 3 or 4 in the GLEEVEC arm; 0.7% were grade 3 or 4 in the nilotinib arm
• In the phase 3 unresectable or metastatic GIST studies, ~13% of patients reported grade 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) and/or intratumoral hemorrhages. GI tumor sites may have been the source of GI hemorrhages. In addition, gastric antral vascular ectasia has been reported in postmarketing experience
• GLEEVEC is sometimes associated with GI irritation. There have been rare reports, including fatalities, of GI perforation
• In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cardiogenic shock and left ventricular dysfunction have been associated with HES cell degranulation upon 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 12 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
• Fetal harm can occur when administered to a pregnant woman. Test pregnancy status in females of reproductive potential prior to GLEEVEC initiation. Advise sexually active females of reproductive potential to avoid pregnancy and use effective contraception (methods that result in <1% pregnancy rates) when taking GLEEVEC and for 14 days after stopping GLEEVEC. Advise women to avoid breastfeeding during treatment and for 1 month after the last dose because of the potential for serious adverse reactions in breastfed infants. If pregnancy occurs while taking GLEEVEC, apprise the patient 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 for 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. Advise patients that they may experience side effects such as dizziness, blurred vision, or somnolence during treatment with GLEEVEC. Caution is recommended when driving a car or operating machinery
• A decline in renal function may occur in patients receiving GLEEVEC. Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure
• In Ph+ CML trials,^* severe (grades 3/4) lab abnormalities included neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (~5%). Severe (grades 3/4) adverse reactions experienced by Ph+ CML patients who received GLEEVEC in clinical studies included hemorrhage (1.8%-19%), fluid retention (eg, pleural effusion, pulmonary edema, and ascites) (2.5%-11%), superficial edema (1.5%-6%), and musculoskeletal pain (2%-9%).† 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 an additional study of patients with Ph+ CML in chronic phase comparing GLEEVEC and nilotinib, severe (grades 3/4) adverse reactions and those with rates greater than 1% were diarrhea (4%), nausea (2%), and rash (2%)
• In HES/CEL patients, instances of grade 3 leukopenia, neutropenia, lymphopenia, and anemia were reported
• For DFSP, severe (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 (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/d; 800 mg/d), 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 grades 3 and above
• In the adjuvant GIST study comparing 12 months of GLEEVEC vs placebo treatment (GLEEVEC; placebo), severe (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 (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
• CYP3A4 is the major enzyme responsible for the metabolism of GLEEVEC. Concomitant administration of GLEEVEC and strong CYP3A4 inducers may reduce total exposure of GLEEVEC; consider alternative agents. Concomitant administration of GLEEVEC and strong CYP3A4 inhibitors may result in a significant GLEEVEC exposure increase. Grapefruit juice should be avoided because it may increase plasma concentrations of GLEEVEC. GLEEVEC will also increase plasma concentrations of other CYP3A4 metabolized drugs (eg, triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc). Use caution when administering GLEEVEC with CYP3A4 and CYP2D6 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin.
• 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

Common Side Effects of GLEEVEC Tablets

• Almost all adult Ph+ CML patients who received GLEEVEC in clinical studies experienced adverse reactions at some time. In 4 Ph+ CML studies, the most frequently reported adverse reactions (all grades) and those with rates greater than 45% were superficial edema (60%-74%), nausea (50%-73%), diarrhea (43%-57%), hemorrhage (29%-57%), musculoskeletal pain (38%-49%), fatigue (39%-48%), rash and related terms (36%-47%), muscle cramps (28%-62%), and vomiting (23%-58%).† In an additional study of patients with newly diagnosed Ph+ CML in chronic phase comparing GLEEVEC and nilotinib, the most frequently reported adverse reactions (all grades) and those with rates greater than 15% were diarrhea (46%), nausea (41%), muscle spasms (34%), vomiting (27%), headache (23%), nasopharyngitis (21%), fatigue (20%), peripheral edema (20%), rash (19%), myalgia (19%), eyelid edema (19%), arthralgia (17%), back pain (17%), and pain in extremity (16%)
• 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 adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions in the Ph+ ALL studies were mild nausea, vomiting, diarrhea, myalgia, muscle cramps, and rash. Superficial edemas were also a common finding in all studies and were described primarily as periorbital or lower-limb edemas. However, 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
• Frequently reported adverse reactions (all grades) in the 7 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 GI, 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 DFSP patients assessed included nausea and fatigue (42% each); periorbital, peripheral, and eye edema (33% each); diarrhea, vomiting, rash, lacrimation increased, and anemia (25% each); face edema, pyrexia, exertional dyspnea, rhinitis, and anorexia (17% each)
• Almost all patients who received GLEEVEC in the phase 3 unresectable or metastatic GIST studies experienced adverse reactions at some time. Overall, the incidence of all grades of adverse reactions and the incidence of severe (grade 3 and above) adverse reactions were similar between the 2 treatment arms, except for edema and rash/related terms, which were reported more frequently in the 800-mg group. The most frequently reported adverse reactions (400 mg/d; 800 mg/d) (all grades) were edema (77%; 86%), fatigue (69%; 75%), nausea (58%; 65%), abdominal pain (57%; 55%), diarrhea (56%; 58%), rash and related terms (56%; 70%), vomiting (37%; 41%), myalgia (32%; 30%), anemia (32%; 35%), anorexia (31%; 36%), and arthralgia (14%; 12%). Therapy with GLEEVEC was discontinued for adverse reactions in 5% of patients studied^*
• In the adjuvant treatment of GIST studies, almost all the 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. In Study 1, comparing 12 months of GLEEVEC treatment vs placebo (all grades), these included (GLEEVEC; placebo) diarrhea (59%; 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%), abdominal pain (21%; 22%), anorexia (17%; 9%), muscle spasms (16%; 3%), white blood cell count decreased (15%; 4%), arthralgia (15%; 15%), and myalgia (12%; 12%).^* The frequencies of these reported adverse reactions were similar in Study 2, comparing 12 vs 36 months of GLEEVEC treatment (12 mo; 36 mo), except for decreased hemoglobin (72%; 80%), periorbital edema (59%; 74%), muscle spasms (31%; 49%), decreased white blood cell count (35%; 47%), pain (26%; 46%), peripheral edema (33%; 41%), rash (29%; 39%), arthralgia (9%; 17%), and myalgia (9%; 15%), which were higher among patients receiving 36 months of adjuvant treatment with GLEEVEC. Adverse reactions listed represent the most frequently reported for Study 1 with the addition of adverse reactions with higher rates in Study 2^*
• In the adjuvant GIST study comparing GLEEVEC vs placebo, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebo-treated patients. Edema, GI disturbances (nausea, vomiting, abdominal distension, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation. In the adjuvant study comparing 12 vs 36 months of GLEEVEC treatment, drug was discontinued for adverse events in 8% of patients treated for 12 months and 14% of patients treated for 36 months^*
• Supportive care may help reduce the severity of some mild to moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary
• Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered at 400 mg twice a day. For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron
• GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation
• Patients should be instructed to take GLEEVEC exactly as prescribed and 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

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

^†Numbers indicate the range of percentages in 4 studies among patients with newly diagnosed Ph+ CML, patients in blast crisis, in accelerated phase, and in the chronic phase after failure of interferon-alpha therapy.