Imatinib Mesylate

1 INDICATIONS AND USAGE Imatinib mesylate tablets are a kinase inhibitor indicated for the treatment of: • Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. ( 1.1 ) • Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy. ( 1.2 ) • Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). ( 1.3 ) • Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. ( 1.4 ) • Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. ( 1.5 ) • Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. ( 1.6 ) • Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. ( 1.7 ) • Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). ( 1.8 ) • Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). ( 1.9 ) • Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST. ( 1.10 ) 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. 1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). 1.4 Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. 1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. 1.6 Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. 1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. 1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. 1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. 1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

2 DOSAGE AND ADMINISTRATION • Adults with Ph+ CML CP ( 2.2 ): 400 mg/day • Adults with Ph+ CML AP or BC ( 2.2 ): 600 mg/day • Pediatrics with Ph+ CML CP ( 2.3 ): 340 mg/m 2 /day • Adults with Ph+ ALL ( 2.4 ): 600 mg/day • Pediatrics with Ph+ ALL ( 2.5 ): 340 mg/m 2 /day • Adults with MDS/MPD ( 2.6 ): 400 mg/day • Adults with ASM ( 2.7 ): 100 mg/day or 400 mg/day • Adults with HES/CEL ( 2.8 ): 100 mg/day or 400 mg/day • Adults with DFSP ( 2.9 ): 800 mg/day • Adults with metastatic and/or unresectable GIST ( 2.10 ): 400 mg/day • Adjuvant treatment of adults with GIST ( 2.11 ): 400 mg/day • Patients with mild to moderate hepatic impairment ( 2.12 ): 400 mg/day • Patients with severe hepatic impairment ( 2.12 ): 300 mg/day All doses of imatinib mesylate tablets should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib mesylate tablets can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400-mg tablet to reduce exposure to iron. 2.1 Drug Administration The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100-mg tablet, and 200 mL for a 400-mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s). For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. 2.2 Adult Patients With Ph+ CML CP, AP, or BC The recommended dose of imatinib mesylate tablets is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. 2.3 Pediatric Patients With Ph+ CML CP The recommended dose of imatinib mesylate tablets for children with newly diagnosed Ph+ CML is 340 mg/m 2 /day (not to exceed 600 mg). Imatinib mesylate tablets treatment can be given as a once daily dose or the daily dose may be split into two-one portion dosed in the morning and one portion in the evening. There is no experience with imatinib mesylate tablets treatment in children under 1 year of age. 2.4 Adult Patients With Ph+ ALL The recommended dose of imatinib mesylate tablets is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. 2.5 Pediatric Patients With Ph+ ALL The recommended dose of imatinib mesylate tablets to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m 2 /day (not to exceed 600 mg). Imatinib mesylate tablets treatment can be given as a once daily dose. 2.6 Adult Patients With MDS/MPD Determine PDGFRb gene rearrangements status prior to initiating treatment. The recommended dose of imatinib mesylate tablets is 400 mg/day for adult patients with MDS/MPD. 2…

5 WARNINGS AND PRECAUTIONS • Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics. ( 5.1 , 6.1 ) • Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction, dose interruption, or discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter. ( 5.2 ) • Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Monitor and treat patients with cardiac disease or risk factors for cardiac failure. ( 5.3 ) • Severe hepatotoxicity, including fatalities 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. ( 5.4 ) • Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML and with GIST. GI tumor sites may be the source of GI bleeds in GIST. ( 5.5 ) • Gastrointestinal (GI) perforations, some fatal, have been reported. ( 5.6 ) • Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of imatinib mesylate tablets in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD, and ASM). ( 5.7 ) • Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of imatinib mesylate tablets. ( 5.8 ) • Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients. ( 5.9 ) • Fetal harm can occur when administered to a pregnant woman. Apprise women of the potential harm to the fetus, and to use effective contraception. ( 5.10 , 8.1 ) • Growth retardation occurring in children and pre-adolescents receiving imatinib mesylate tablets has been reported. Close monitoring of growth in children under imatinib mesylate tablets treatment is recommended. ( 5.11 , 6.2 ) • Tumor Lysis Syndrome. Close monitoring is recommended. ( 5.12 ) • Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate tablets. Caution patients about driving a car or operating machinery. ( 5.13 ) • Renal Toxicity. A decline in renal function may occur in patients receiving imatinib mesylate tablets. Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction. ( 5.14 ) 5.1 Fluid Retention and Edema Imatinib mesylate is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1) ] . Weigh and monitor patients regularly for signs and symptoms of fluid retention. Investigate unexpected rapid weight gain carefully and provide appropriate treatment. The probability of edema was increased with higher imatinib mesylate dose and age greater than 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate. Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib mesylate for GIST [see Adverse Reactions (6.1) ] . In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib mesylate and in 3.9% of patients receiving nilotinib 300 mg twice daily. Effusions (including pleural effusion, pericardi…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS • CYP3A4 inducers may decrease imatinib mesylate tablets Cmax and area under curve (AUC). ( 2.12 , 7.1 , 12.3 ) • CYP3A4 inhibitors may increase imatinib mesylate tablets Cmax and AUC. ( 7.2 , 12.3 ) • Imatinib mesylate tablets are an inhibitor of CYP3A4 and CYP2D6 which may increase the Cmax and AUC of other drugs. ( 7.3 , 7.4 , 12.3 ) • Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin. ( 7.3 ) • Imatinib mesylate tablets may delay the clearance of methotrexate when methotrexate is used at high doses (> 500 mg/m 2 ). ( 7.5 ) 7.1 Agents Inducing CYP3A Metabolism Concomitant administration of imatinib mesylate tablets and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents [see Clinical Pharmacology (12.3) ] . 7.2 Agents Inhibiting CYP3A Metabolism Concomitant administration of imatinib mesylate tablets 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 (12.3) ] . 7.3 Interactions With Drugs Metabolized by CYP3A4 Imatinib mesylate tablets will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolobenzodiazepines, dihydropyridine calcium channel blockers, certain HMGCoA reductase inhibitors, etc.). Use caution when administering imatinib mesylate tablets with CYP3A4 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 in patients who require anticoagulation [see Clinical Pharmacology (12.3) ] . 7.4 Interactions With Drugs Metabolized by CYP2D6 Use caution when administering imatinib mesylate tablets with CYP2D6 substrates that have a narrow therapeutic window. 7.5 Interactions With Methotrexate Imatinib mesylate tablets may delay the clearance of methotrexate and result in sustained methotrexate concentrations when methotrexate is used at high doses (> 500 mg/m 2 ). Refer to the prescribing information for methotrexate injection for recommendations on management of methotrexate concentrations. Drug Interactions Clinical Studies Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of imatinib mesylate tablets, increased imatinib mesylate tablets oral-dose clearance by 3.8-fold, which significantly (p less than 0.05) decreased mean C max and AUC. Similar findings were observed in patients receiving 400 to 1200 mg/day imatinib mesylate tablets 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 imatinib mesylate tablets 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. Imatinib mesylate tablets doses up to 1,200 mg/day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers [see Dosage and Administration (2.12) ] . 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 imatinib mesylate tablets were coadministered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering imatinib mesylate tablets 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 ima…

8.1 Pregnancy Risk Summary Imatinib mesylate tablets can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of imatinib mesylate tablets in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate tablets during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise women to avoid pregnancy when taking imatinib mesylate tablets. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis. In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications. In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes. In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses. The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Fluid Retention and Edema [see Warnings and Precautions (5.1) ] • Hematologic Toxicity [see Warnings and Precautions (5.2) ] • Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions (5.3) ] • Hepatotoxicity [see Warnings and Precautions (5.4) ] • Hemorrhage [see Warnings and Precautions (5.5) ] • Gastrointestinal Disorders [see Warnings and Precautions (5.6) ] • Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions (5.7) ] • Dermatologic Toxicities [see Warnings and Precautions (5.8) ] • Hypothyroidism [see Warnings and Precautions (5.9) ] • Growth Retardation in Children and Adolescents [see Warnings and Precautions (5.11) ] • Tumor Lysis Syndrome [see Warnings and Precautions (5.12) ] • Impairments Related to Driving and Using Machinery [see Warnings and Precautions (5.13) ] • Renal Toxicity [see Warnings and Precautions (5.14) ] The most frequently reported adverse reactions (greater than or equal to 30%) are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic Myeloid Leukemia The majority of imatinib mesylate-treated patients experienced adverse reactions at some time. Imatinib mesylate was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate versus IFN+Ara-C, and in 12.5% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib. Imatinib mesylate 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 imatinib mesylate [see Dosage and Administration (2.13) ] . 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 imatinib mesylate 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 imatinib mesylate-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 Imatinib Mesylate Versus IFN+Ara-C Study (Greater Than or Equal to 10% of Imatinib Mesylate-Treated Patients)( All adverse reactions occurring in greater than or equal to 10% of imatinib mesylate-treated patients are listed regardless of suspected relationship…