Enliven ® capsules contain Imatinib Mesylate equivalent to 100 mg of Imatinib free base.
INN
Anticancer
Enliven ® (Imatinib Mesylate) is indicated for the treatment of patients with:
1. Philadelphia chromosome positive chronic myeloid leukemia (CML) in blast crisis, (accelerated phase, or in chronic phase after failure of interieron-alpha therapy).
2. Enliven is also indicated for the treatment of patients with kit (CDI17) positive unresectable and/ or metastatic malignant gastrointestinal stromal tumors (GIST).
Use of Imatinib Mesylate is contraindicated in patients with hypersensitivity of Imatinib.
Therapy should be initiated by a physician experienced in the treatment of patients with chronic myeloid leukemia or gastrointestinal stromal tumors. 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. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. The recommended dosage of Imatinib is 400 mg/day for patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis. The recommended dosage of Imatinib is 400 mg/day or 600 mg/day for patients with unresectable and/ or metastatic, malignant GIST. In CML, dose increase from 400 mg to 600 mg in patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily)
The most frequently reported adverse reactions (greater than or equal to 30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain.
• Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus.
• Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics .
• Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction or dose interruption and in rare cases discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter .
• Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Patients with cardiac disease or risk factors for cardiac failure should be monitored and treated.
• Severe hepatotoxicity 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 .
• 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
• Gastrointestinal perforations, some fatal, have been reported.
• Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of Imatinib.in patients with conditions associated with high eosinophil levels .
• Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of Imatinib.
• Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients .
• Consider potential toxicities, specifically, liver, kidney, and cardiac toxicity, and immunosuppression from long-term use .
CYP3A4 inducers may decrease Imatinib C and AUC .
CYP3A4 inhibitors may increase Imatinib Cmax and AUC.
Imatinib is an inhibitor of CYP3A4 and may increase the Cmax and AUC of other drugs Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin.
Systemic exposure to acetaminophen is expected to increase when co-administered with Imatinib .
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).
The safety and effectiveness of Imatinib in paediatric patients have not been established.
Pregnancy Category D. Nursing Mothers: It is not known that whether Imatinib Mesylate or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while taking Imatinib.
Experience with doses greater than 800 mg is limited. In the event of over dosage, the patient should be observed and appropriate supportive treatment given.
Store below 25 °C & in a dry place. Keep away from light. Keep all medicines out of the reach of children.
Each box contains 7 blister strips of 4 capsules.
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