Enliven capsules contain Imatinib Mesylate equivalent to 100 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.

Enliven (Imatinib Mesylate) is indicated for the treatment of patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interieron-alpha therapy. Enliven is also indicated for the treatment of patients with kit (CDI17) positive unresectable and/ or metastatic malignant gastrointestinal stromal tumors (GIST). The effectiveness of Imatinib is based on overall hematologic and cytogenetic response rates in CML and objective response rate in GIST. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Chronic Myeloid Leukemia: The majority of Imatinib treated patients experienced adverse events at some time. Most events were of mild to moderate grade, but drug was discontinued for adverse events in 2% of patients in chronic phase, 3% in accelerated phase and 5% in blast crisis. The most frequently reported drug-related adverse events were nausea, vomiting, diarrhoea, edema and muscle cramps.

Hematologic Toxicity: Cytopenias and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses > 750 mg. The occurrence of cytopenias in CML patients was also dependent on the stage of the disease; with a frequency of grade 3 or 4 neutropenia and thrombocytopenia between 2 and 3 fold higher in blast crisis and accelerated phase compared to chronic phase.

Hepatotoxicity: Severe elevation of transaminases or bilirubin occurred in 1 -4% and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 0.5% of patients. However, one patient, who was taking Acetaminophen regularly for fever, died of acute liver failure.

Gastrointestinal Stromal Tumors: The majority of Imatinib treated patients experienced adverse events at some time. The most frequently reported adverse events were edema, nausea, diarrhoea, abdominal pain, muscle cramps, fatigue and rash. Most events were of mild to moderate severity.

General

Fluid Retention and Edema: Imatinib Mesylate is often associated with edema and occasionally serious fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Imatinib dose and age > 65 years in the CML studies. Severe fluid retention (e. g. pleural effusion, pulmonary edema, and ascites) was .reported in 2-8% of patients taking Imatinib for CML. In addition, severe superficial edema was reported in 2-5% of the patients with CML.

Severe superficial edema and severe fluid retention (pleural effusion, pulmonary edema and ascites) were reported in 1 -6% of patients taking Imatinib for GIST.

Gl Irritation: Imatinib is sometimes associated with Gl irritation. Imatinib should be taken with food and a large glass of water to minimize this problem.

Hemorrhage: In the GIST clinical trial seven patients (5%), four in the 600 mg dose group and three in the 400 mg dose group, had a total of eight events of CTC grade 3/4 gastrointestinal (Gl) bleeds (3 patients), intra-tumoral bleeds (3 patients) or both (1 patient). Gastrointestinal Tumor sites may have been the source of Gl bleeds. o

Hematologic Toxicity; Treatment with Imatinib is associated with neutropenia or thrombocytopenia. 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). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequently in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML.

Hepatotoxicity: Hepatotoxicity, occasionally severe, may occur with Imatinib. Liver function (transaminases, bilirubin and alkaline phosphatase) should be monitored before initiation of treatment and monthly or as clinically indicated. Laboratory abnormalities should be managed with interruption and/ or dose reduction of the treatment with Imatinib. Patients with hepatic impairment should be closely monitored because exposure to Imatinib may be increased. As there are no clinical studies of Imatinib in patients with impaired liver function, no specific advice concerning initial dosing adjustment can be given.

Toxicities from long-term Use: Because follow-up of most patients treated with Imatinib is relatively short there is no long-term safety data on Imatinib treatment. It is important to consider potential toxicities suggested by animal studies, specifically, liver and kidney toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic Imatinib treatment. In a 39- week monkey study, treatment with Imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in human ).



Drugs that may alter Imatinib plasma concentrations

Drugs that may increase Imatinib plasma concentrations Caution is recommended when administering Imatinib with inhibitors of the CYP3A4 family (e. g. ketoconazole, itrakonazole, erythromycin, clarithromycin). Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase Imatinib <- concentrations. There is a significant increase in exposure to Imatinib when Imatinib is co-administered with ketoconazole (CYP3A4 inhibitor).

Drugs that may decrease Imatinib plasma concentrations

Substances that are inducers of CYP3A4 activity may increase metabolism and decrease Imatinib plasma concentrations. Co-medications that induce CYP3A4 (e.g., Dexamethasone, Phenytoin, Carbamazepine, Rifampicin, and Phenobarbital) may reduce exposure to Imatinib.

Drugs that may have their plasma concentration altered by Imatinib

Imatinib increases the mean Cma* and AUC of Simvastatin (CYP3A4 substrate) 2- and 3.5 fold, respectively, suggesting an inhibition of the CYP3A4 by Imatinib. Particular caution is recommended when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window (e.g., Cyclosporine or Pimozide). Imatinib will increase plasma concentration of other CYP3A4 metabolized drugs (e. g., trizolo-benzodiazempines, Dihydropyridine calcium channel blockers, Certain HMG-CoA reductase inhibitors, etc.) Because Warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin.

Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with Imatinib Mesylate.Positive genotoxic effects were obtained for Imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the taking Imatinib.

Paediatric Use

The safety and effectiveness of Imatinib in paediatric patients have not been established.

Geriatric Use

In the CML clinical studies, approximately 40% of patients were older than 60 years and 10% were older than 70 years.No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Imatinib was similar in older and younger patients. In the GIST study, 29% of patients were older than 60 years and 10% of patients were older than 70 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

Drug Interactions

Drugs that may alter Imatinib plasma concentrations

Drugs that may increase Imatinib plasma concentrations Caution is recommended when administering Imatinib with inhibitors of the CYP3A4 family (e. g. ketoconazole, itrakonazole, erythromycin, clarithromycin). Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase Imatinib <- concentrations. There is a significant increase in exposure to Imatinib when Imatinib is co-administered with ketoconazole (CYP3A4 inhibitor).

Drugs that may decrease Imatinib plasma concentrations

Substances that are inducers of CYP3A4 activity may increase metabolism and decrease Imatinib plasma concentrations. Co-medications that induce CYP3A4 (e.g., Dexamethasone, Phenytoin, Carbamazepine, Rifampicin, and Phenobarbital) may reduce exposure to Imatinib.

Drugs that may have their plasma concentration altered by Imatinib

Imatinib increases the mean Cma* and AUC of Simvastatin (CYP3A4 substrate) 2- and 3.5 fold, respectively, suggesting an inhibition of the CYP3A4 by Imatinib. Particular caution is recommended when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window (e.g., Cyclosporine or Pimozide). Imatinib will increase plasma concentration of other CYP3A4 metabolized drugs (e. g., trizolo-benzodiazempines, Dihydropyridine calcium channel blockers, Certain HMG-CoA reductase inhibitors, etc.) Because Warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin.

Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with Imatinib Mesylate.Positive genotoxic effects were obtained for Imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test) an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay. In a study of fertility, in male rats dosed for 70 days prior to mating testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. This was not seen at dose < 20 mg/kg (one-fourth the maximum human dose of 800 mg). When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg /kg (approximately equal to the human dose of 800 mg), female rats had significant post implantation fetal loss and a reduced number of live fetuses. This was not seen at doses < 20 mg/kg (one fourth the maximum human dose of 800 mg).



Each box contains 7 X 4\'s capsules in blister pack