Gleevec

1 INDICATIONS AND USAGE Gleevec is 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 Gleevec 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. Gleevec 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 Gleevec 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 Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m 2 /day (not to exceed 600 mg). Gleevec 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 Gleevec treatment in children under 1 year of age. 2.4 Adult Patients With Ph+ ALL The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. 2.5 Pediatric Patients With Ph+ ALL The recommended dose of Gleevec 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). Gleevec 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 Gleevec is 400 mg/day for adult patients with MDS/MPD. 2.7 Adult Patients With ASM Determine D816V c-Kit mutation status prior to initiating treatment. The recommended dose of Gleevec is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If …

3 DOSAGE FORMS AND STRENGTHS 100 mg film coated tablets Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side 400 mg film coated tablets Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “gleevec” on one side and score on the other side. Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “400” on one side and score on the other side with “SL” on each side of the score. Tablets (scored): 100 mg and 400 mg

4 CONTRAINDICATIONS None. None. ( 4 )

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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 Gleevec-treated patients experienced adverse reactions at some time. Gleevec was discontinued due to drug-related adverse reactions in 2.4% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec versus IFN+Ara-C, and in 12.5% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec and nilotinib. Gleevec 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 Gleevec [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 Gleevec 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 Gleevec-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 Gleevec Versus IFN+Ara-C Study (Greater Than or Equal to 10% of Gleevec-Treated Patients) (1) Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha. * NCI Common Terminology Criteria for Adverse Events, version 3.0. (1) All adverse reactions occurring in greater than or equal to 10% of …

7 DRUG INTERACTIONS CYP3A4 inducers may decrease Gleevec C max and area under curve (AUC). ( 2.12 , 7.1 , 12.3 ) CYP3A4 inhibitors may increase Gleevec C max and AUC. ( 7.2 , 12.3 ) Gleevec is an inhibitor of CYP3A4 and CYP2D6 which may increase the C max 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 ) Gleevec 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 Gleevec 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 Gleevec 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 Gleevec will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Gleevec 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 Gleevec with CYP2D6 substrates that have a narrow therapeutic window. 7.5 Interactions With Methotrexate Gleevec 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Gleevec can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of Gleevec in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to Gleevec 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 Gleevec. 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. 8.2 Lactation Risk Summary Imatinib and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed infants from Gleevec, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose. Human Data Based on data from 3 breastfeeding women taking Gleevec, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight. 8.3 Females and Males of Reproductive Potential Human postmarketing reports and animal studies have sh …

12.1 Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation.

11 DESCRIPTION Imatinib is a small molecule kinase inhibitor. Gleevec film-coated tablets are supplied as 100 mg and 400 mg tablets for oral administration. Each 100 mg tablet contains 119.5 mg of imatinib mesylate equivalent to 100 mg of imatinib free base. Each 400 mg tablet contains 478 mg of imatinib mesylate equivalent to 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is: Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. Its molecular formula is C 29 H 31 N 7 O • CH 4 SO 3 and its molecular weight is 589.7 g/mol. Imatinib mesylate is soluble in aqueous buffers less than or equal to pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol, and ethanol, but is insoluble in n-octanol, acetone, and acetonitrile. Inactive Ingredients: colloidal silicon dioxide (NF); crospovidone (NF); hydroxypropyl methylcellulose (USP); magnesium stearate (NF); and microcrystalline cellulose (NF). Tablet coating: ferric oxide, red (NF); ferric oxide, yellow (NF); hydroxypropyl methylcellulose (USP); polyethylene glycol (NF), and talc (USP). Imatinib structural formula

10 OVERDOSAGE Experience with doses greater than 800 mg is limited. Isolated cases of Gleevec overdose have been reported. In the event of overdosage, observe the patient and give appropriate supportive treatment. Adult Overdose 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, GI pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases. 8 to 10 g (single dose): Vomiting and GI pain have been reported. A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Gleevec daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Gleevec daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Gleevec on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy. Pediatric Overdose One 3 year old male exposed to a single dose of 400 mg experienced vomiting, diarrhea, and anorexia; and another 3 year old male exposed to a single dose of 980 mg experienced decreased white blood cell (WBC) count and diarrhea.

16 HOW SUPPLIED/STORAGE AND HANDLING Gleevec film-coated tablets are supplied as 100 mg and 400 mg tablets for oral administration. Each 100 mg tablet contains 119.5 mg of imatinib mesylate equivalent to 100 mg of imatinib free base. Each 400 mg tablet contains 478 mg of imatinib mesylate equivalent to 400 mg of imatinib free base. 100-mg tablets Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side. Bottles of 90 tablets.......................................NDC 0078-0401-34 400-mg tablets Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “gleevec” on one side and score on the other side. Unit Dose (blister pack of 30) ...........................NDC 0078-0649-30 Unit Dose (carton box including 3 blister packs of 10)............NDC 0078-0649-13 Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “400” on one side and score on the other side with “SL” on each side of the score. Unit Dose (carton box including 3 blister packs of 10).............NDC 0078-1490-13 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container, USP. Do not crush Gleevec tablets. Avoid direct contact of crushed tablets with the skin or mucous membranes. If such contact occurs, wash thoroughly as outlined in the references. Avoid exposure to crushed tablets.