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    / Novartis


    Active Ingredient
    Imatinib 100 mg, 400 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Film Coated Tablets

    60 x 100 mg

    partial basket chart 62801 7708

    Film Coated Tablets

    30 x 400 mg

    partial basket chart 62802 7709

    Related information


    Dosage

    Therapy should be initiated by a physician experienced in the treatment of patients with hematological malignancies and malignant sarcomas, as appropriate. The prescribed dose should be administered orally with a meal and a large glass of water to minimize the risk of gastrointestinal disturbances. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening. 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). Treatment should be continued as long as the patient continues to benefit. Monitoring of response to Imatinib therapy in Ph+ CML patients should be performed routinely and when therapy is modified, to identify suboptimal response, loss of response to therapy, poor patient compliance, or possible drug-drug interaction. Results of monitoring should guide appropriate CML management. recommended dosage of Imatinib is 400 mg/day for adult patients in chronic phase CML. Chronic phase CML is defined when all of the following criteria are met: blasts < 15% in blood and bone marrow, peripheral blood basophils < 20%, platelets > 100 x 109/l. The recommended dosage of Imatinib is 600 mg/day for adult patients in accelerated phase. Accelerated phase is defined by the presence of any of the following: blasts ≥ 15% but < 30% in blood or bone marrow, blasts plus promyelocytes ≥30% in blood or bone marrow (providing < 30% blasts), peripheral blood basophils ≥20%, platelets < 100 x 109/l unrelated to therapy. The recommended dose of Imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts ≥30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Treatment duration: In clinical trials, treatment with Imatinib was continued until disease progression. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated. Dose increase from 400 mg to 600 mg or 800 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg (given as 400mg twice daily) in 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 hematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved hematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.
    Posology for CML in children: Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase CML and advanced phase CML (not to exceed the total dose of 600 mg). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening. The dose recommendation is currently based on a small number of paediatric patients. There is no experience with the treatment of children below 2 years of age.
    Posology for Ph+ ALL in adult patients: The recommended dose of Imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological experts in the management of this disease should supervise the therapy throughout all phases of care. Treatment schedule: On the basis of the existing data, Imatinib has been shown to be effective and safe when administered at 600 mg/day in combination with chemotherapy in the induction phase, the consolidation and maintenance phases of chemotherapy for adult patients with newly diagnosed Ph+ ALL. The duration of Imatinib therapy can vary with the treatment programme selected, but generally longer exposures to Imatinib have yielded better results. For adult patients with relapsed or refractory Ph+ALL Imatinib monotherapy at 600 mg/day is safe, effective and can be given until disease progression occurs.
    Posology for MDS/MPD: The recommended dose of Imatinib is 400 mg/day for adult patients with MDS/MPD. Treatment duration: In the only clinical trial performed up to now, treatment with Imatinib was continued until disease progression. At the time of analysis, the treatment duration was a median of 47 months (24 days – 60 months).
    Posology for SM: The recommended dose of Imatinib is 400 mg/day for adult patients with SM without the D816V KIT mutation or mutational status unknown or not responding satisfactorily to other therapies. For patients with SM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFR-alpha, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
    Posology for HES/CEL: The recommended dose of Imatinib is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFR-alpha fusion kinase, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
    Posology for GIST: The recommended dose of Imatinib is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. the lower dose. Treatment duration: In clinical trials in GIST patients, treatment with Imatinib was continued until disease progression. At the time of analysis, the treatment duration was a median of 7 months (7 days to 13 months). The effect of stopping treatment after achieving a response has not been investigated. The recommended dose of Imatinib is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. Optimal treatment duration is not yet established. Length of treatment in the clinical trial supporting this indication was 36 months.
    Posology for DFSP: The recommended dose of Imatinib is 800 mg/day for adult patients with DFSP.
    Dose adjustment for adverse drug reactions: See prescribing information for full details.


    Indications

    Treatment of adult patients and children 3 years of age and above with Ph+ chronic myeloid. leukaemia (Ph+ -CML) in chronic phase, accelerated phase or blast crisis. Treatment of adult patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST). Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. Treatment of adult patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) integrated with chemotherapy. Treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy. Treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. Treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements. Treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) who have the 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. Treatment of adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-kit mutation.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients.


    Special Precautions

    When Imatinib is co-administered with other medicinal products, there is a potential for drug interactions. Caution should be used when taking Imatinib with protease inhibitors, azole antifungals, certain macrolides, CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine,pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives. nib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, Concomitant use of imati, also known as St. John’s Wort) may Hypericum perforatumcarbamazepine, rifampicin, phenobarbital or herapeutic failure. Therefore, significantly reduce exposure to Imatinib, potentially increasing the risk of tconcomitant use of strong CYP3A4 inducers and imatinib should be avoided.
    Hypothyroidism: Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Imatinib. Thyroid Stimulating Hormone (TSH) levels should be closely monitored in such patients.
    Hepatotoxicity: Metabolism of Imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored. It should be noted that GIST patients may have hepatic metastases which could lead to hepatic impairment. Cases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. When imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic reactions has been detected. Hepatic function should be carefully monitored in circumstances where imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction.
    Fluid retention: Occurrences of severe fluid retention (pleural effusion, edema, pulmonary edema, ascites and superficial edema) have been reported in approximately 2.5% of newly diagnosed CML patients taking Imatinib. Therefore, it is recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in older people and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction.
    See prescribing information for full details.


    Side Effects

    Pancytopenia, febrile neutropenia, Anorexia, Dizziness, paresthesia, taste disturbance, hypoaesthesia, Eyelid edema, lacrimation increased, conjunctival hemorrhage, conjunctivitis, dry eye, blurred vision, Flushing, hemorrhage, Dyspnea, epistaxis, cough, Flatulence, abdominal distension, gastro-esophageal reflux, constipation, dry mouth, gastritis.
    See prescribing information for full details.


    Drug interactions

    Active substances that may increase imatinib plasma concentrations Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors such as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole antifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin) could decrease metabolism and increase imatinib concentrations.
    Active substances that may decrease imatinib plasma concentrations: Substances that are inducers of CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or hypericum perforatum, also known as St. John’s Wort) may significantly reduce exposure to Imatinib , potentially increasing the risk of therapeutic failure. Concomitant use of rifampicin or other strong CYP3A4 inducers and imatinib should be avoided. Active substances that may have their plasma concentration altered by Imatinib. Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering Imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of other CYP3A4 metabolized drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.). Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g. haemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard heparin, instead of coumarin derivatives such as warfarin. In vitro, Imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23% (90%CI [1.16-1.30]). Dose adjustments do not seem to be necessary when imatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6 substrates with a narrow therapeutic window such as metoprolol. In with metoprolol clinical monitoring should be considered.
    See prescribing information for full details.


    Pregnancy and Lactation

    Pregnancy: Women of childbearing potential must be advised to use effective contraception during treatment.
    Lactation: There is limited information on imatinib distribution on human milk. women taking imatinib should not breast feed.
    See prescribing information for full details.  


    Overdose

    Experience with doses higher than the recommended therapeutic doses is limited. Isolated cases of Imatinib overdose have been reported spontaneously and in the literature. In the event of overdose the patient should be observed and appropriate symptomatic treatment given. Generally the reported outcome in these cases was “improved” or “recovered”. Events that have been reported at different dose ranges are as follows:
    Adult population: 1200 to 1600 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. 1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointestinal pain. 6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.
    Pediatric population: 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 count and diarrhea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.


    Important notes

    Storage: Do not store above 30°C. Protect from moisture. Store in the original package.        


    Manufacturer
    Novartis Pharma Stein AG Switzerland
    Licence holder
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