Drug Class Description
Protein-tyrosine Kinase Inhibitor

Generic Name
Imatinib (as Mesilate)

Drug Description
Glivec 100 mg film-coated tablets: Each film-coated tablet contains 100 mg imatinib (as mesilate).Glivec 400 mg film-coated tablets: Each film-coated tablet contains 400 mg imatinib (as mesilate).

Presentation
Glivec 100 mg film-coated tablets: Very dark yellow to brownish-orange film-coated tablet, round with “NVR” on one side and “SA” and score on the other side.Glivec 400 mg film-coated tablets: Very dark yellow to brownish-orange, ovaloid

Indications
Glivec is indicated for the treatment of• adult and paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment.• adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis.• adult patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.• adult patients with relapsed or refractory Ph+ ALL as monotherapy.• adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.• adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFR rearrangement. The effect of Glivec on the outcome of bone marrow transplantation has not been determined. Glivec is also indicated for the treatment of• adult patients with Kit (CD 117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).• adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. In adult and paediatric patients, the effectiveness of Glivec is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with GIST and DFSP. The experience with Glivec in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited. Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Adult Dosage
Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate.For doses of 400 mg and above (see dosage recommendation below) a 400 mg tablet (not divisible) is available.For doses other than 400 mg and 800 mg (see dosage recommendation below) a 100 mg divisible tablet is available.The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of gastrointestinal irritations. 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 mineral 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).Posology for CML in adult patientsThe recommended dosage of Glivec is 400 mg/day for 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 Glivec is 600 mg/day for 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 Glivec is 600 mg/day for 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 Glivec was continued until disease progression. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.Dose increases 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 400 mg twice daily) in patients with accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological 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 haematological 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 childrenDosing for children should be on the basis of body surface area (mg/m2). The doses of 340 mg/m2 daily is recommended for children with chronic phase CML and advanced phase CML (not to exceed the total dose of 800 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.Dose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological 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 haematological 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 Ph ± ALLThe recommended dose of Glivec is 600 mg/day for 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, Glivec 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 Glivec therapy can vary with the treatment programme selected, but generally longer exposures to Glivec have yielded better results.For adult patients with relapsed or refractory Ph+ALL Glivec monotherapy at 600 mg/day is safe, effective and can be given until disease progression occurs.Posology for MDS/MPD The recommended dose of Glivec is 400 mg/day for patients with MDS/MPD.Treatment duration: In the only clinical trial performed up to now, treatment with Glivec 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 HES/CELThe recommended dose of Glivec is 100 mg/day for patients with HES/CEL.Dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.Posology for GISTThe recommended dose of Glivec is 400 mg/day for patients with unresectable and/or metastatic malignant GIST.Limited data exist on the effect of dose increases from 400 mg to 600 mg or 800 mg in patients progressing at the lower doseThere are currently no data available to support specific dosing recommendations for GIST patients based on prior gastrointestinal resection. The majority (98%) of patients in the clinical trial had had prior resection. For all patients on the study, there was at least a two-week interval between resection and the first dose of Glivec administered; however, no additional recommendations can be made based on this study.Treatment duration: In clinical trials in GIST patients, treatment with Glivec 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.Posology for DFSPThe recommended dose of Glivec is 800 mg/day for patients with DFSP.Dose adjustment for adverse reactionsNon-haematological adverse reactionsIf a severe non-haematological adverse reaction develops with Glivec use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Glivec should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with Glivec may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 800 mg to 600 mg, and in children from 340 to 260 mg/m2/day.Haematological adverse reactionsDose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below.Dose adjustments for neutropenia and thrombocytopenia:HES/CEL (starting dose 100 mg)ANC < 1.0 x 109 /l and/or platelets < 50 x 109 /l1. Stop Glivec until ANC 1.5 x 109 /l and platelets 75 x 109 /l. 2. Resume treatment with Glivec at previous dose (i.e. before severe adverse reaction).Chronic phase CML, MDS/MPD and GIST (starting dose 400 mg) HES/CEL (at dose 400 mg)ANC < 1.0 x 109 /l and/or platelets < 50 x 109 /l1. Stop Glivec until ANC 1.5 x 109 /l and platelets 75 x 109 /l. 2. Resume treatment with Glivec at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x 109 /l and/or platelets < 50 x 109 /l, repeat step 1 and resume Glivec at reduced dose of 300 mg.Paediatric chronic phase CML at dose 340 mg/m2 )ANC < 1.0 x 109 /l and/or platelets < 50 x 109 /l1. Stop Glivec until ANC 1.5 x 109 /l and platelets 75 x 109 /l. 2. Resume treatment with Glivec at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x109 /l and/or platelets < 50 x109 /l, repeat step 1 and resume Glivec at reduced dose of 260 mg/m2 .Accelerated phase CML and blast crisis and Ph+ ALL (starting dose 600 mg) /td>a ANC < 0.5 x 109 /l and/or platelets < 10 x 109 /l1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of Glivec to 400 mg. 3. If cytopenia persists for 2 weeks, reduce further to 300 mg. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop Glivec until ANC 1 x 109 /l and platelets 20 x 109 /l, then resume treatment at 300 mg.Paediatric accelerated phase CML and blast crisis (starting dose 340 mg/m2 )a ANC < 0.5 x 109 /l and/or platelets < 10 x 109 /l1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of Glivec to 260 mg/m2 . 3. If cytopenia persists for 2 weeks, reduce further to 200 mg/m2 . 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop Glivec until ANC 1 x 109 /l and platelets 20 x 109 /l, then resume treatment at 200 mg/m2 .DFSP (at dose 800 mg)ANC < 1.0 x 109 /l and/orplatelets < 50 x 109 /l1. Stop Glivec until ANC 1.5 x 109 /l and platelets 75 x 109 /l. 2. Resume treatment with Glivec at 600 mg. 3. In the event of recurrence of ANC < 1.0 x 109 /l and/or platelets < 50 x 109 /l, repeat step 1 and resume Glivec at reduced dose of 400 mg.ANC = absolute neutrophil counta occurring after at least 1 month of treatmentPaediatric use: There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph+ ALL and very limited experience in children with MDS/MPD and DFSP. There is no experience in children or adolescents with GIST and HES/CEL. Hepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated. Liver dysfunction classification:Liver dysfunctionLiver function testsMildTotal bilirubin: = 1.5 ULN AST: >ULN (can be normal or ULN)ModerateTotal bilirubin: >1.5–3.0 ULN AST: anySevereTotal bilirubin: >3–10 ULN< AST: anyULN = upper limit of normal for the institutionAST = aspartate aminotransferaseRenal insufficiency: Since the renal clearance of imatinib is negligible, a decrease in free imatinib clearance is not expected in patients with renal insufficiency. Patients with mild or moderate renal dysfunction (creatinine clearance = 20–59 ml/min) should be given the minimum recommended dose of 400 mg daily as starting dose. Although very limited information is available, patients with severe renal dysfunction (creatinine clearance = < 20 ml/min) or on dialysis could also start at the same dose of 400 mg. However, in these patients caution is recommended. The dose can be reduced if not tolerated, or increased for lack of efficacy.Elderly patients: Imatinib pharmacokinetics have not been specifically studied in the elderly. No significant age-related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20% of patients age 65 and older. No specific dose recommendation is necessary in the elderly.

Child Dosage
Dosing for children should be on the basis of body surface area (mg/m2). Doses of 260 mg/m2 and 340 mg/m2 daily are recommended for children with chronic phase CML and advanced phases CML, respectively. However, the total daily dose in children should not exceed adult equivalent doses of 400 and 600 mg, respectively. 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 3 years of age. 1 or 260 mg/m2 in children 2 or 200 mg/m2 in children 3 or 340 mg/m2 in children 4 occurring after at least 1 month of treatment Paediatric use: There is no experience with the use of Glivec in children below 3 years of age. The experience with Glivec in paediatric population with CML is limited to 14 patients with CML in chronic phase and 4 patients with CML in blast crisis. There is no experience in children or adolescents with GIST.

Elderly Dosage
Imatinib pharmacokinetics have not been specifically studied in the elderly. No significant age related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20% of patients age 65 and older.No specific dose recommendation is necessary in the elderly.

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

Special Precautions
When Glivec is co-administered with other medicinal products, there is a potential for drug interactions.Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John's Wort) may significantly reduce exposure to Glivec, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided.Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Glivec. TSH levels should be closely monitored in such patients.Metabolism of Glivec 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.Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients taking Glivec. Therefore, it is highly 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 elderly patients and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction.Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be eva luated and treated.In patients with hypereosinophilic syndrome (HES) and cardiac involvement, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, a careful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL population before treatment initiation. Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated with high eosinophil levels. eva luation by a cardiology specialist, performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids (1–2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of therapy.In the GIST clinical trial, both gastrointestinal and intra-tumoural haemorrhages were reported. Based on the available data, no predisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identified that place patients with GIST at a higher risk of either type of haemorrhage. Since increased vascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard practices and procedures for the monitoring and management of haemorrhage in all patients should be applied.Laboratory testsComplete blood counts must be performed regularly during therapy with Glivec. Treatment of CML patients with Glivec has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is likely to be related to the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with Glivec may be interrupted or the dose may be reduced.Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving Glivec.In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment should be given the minimum starting dose. Patients with severe renal impairment should be treated with caution. The dose can be reduced if not tolerated.

Interactions
Active substances that may increase imatinib plasma concentrations:Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering Glivec with inhibitors of the CYP3A4 family.Active substances that may decrease imatinib plasma concentrations:Substances that are inducers of CYP3A4 activity could increase metabolism and decrease imatinib plasma concentrations. Co-medications which induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as St. John's Wort) may significantly reduce exposure to Glivec, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of Glivec resulted in decrease in Cmax and AUC(0-) by at least 54% and 74%, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with Glivec while taking enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbamazepine and phenytoin. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. Concomitant use of rifampicin or other strong CYP3A4 inducers and imatinib should be avoided.Active substances that may have their plasma concentration altered by GlivecImatinib 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 Glivec with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporin or pimozide). Glivec may increase plasma concentration of other CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.).Because warfarin is metabolised by CYP2C9, patients who require anticoagulation should receive low-molecular-weight or standard heparin.In vitro Glivec 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 patients treated with metoprolol clinical monitoring should be considered.In vitro, Glivec inhibits paracetamol O-glucuronidation (Ki value of 58.5 micromol/l at therapeutic levels).Caution should therefore be exercised when using Glivec and paracetamol concomitantly, especially with high doses of paracetamol.In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be decreased when Glivec is co-administered. Caution is therefore recommended. However, the mechanism of the observed interaction is presently unknown.In Ph+ ALL patients, there is clinical experience of co-administering Glivec with chemotherapy, but drug-drug interactions between imatinib and chemotherapy regimens are not well characterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increase and it has been reported that concomitant use with L-asparaginase could be associated with increased hepatotoxicity. Therefore, the use of Glivec in combination requires special precaution.

Adverse Reactions
Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of adverse reactions difficult to assess due to the variety of symptoms related to the underlying disease, its progression, and the co-administration of numerous medicinal products.In clinical trials in CML, drug discontinuation for drug-related adverse reactions was observed in 2.4% of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse reactions in 4% of patients.The adverse reactions were similar in all indications, with two exceptions. There was more myelosuppression seen in CML patients than in GIST, which is probably due to the underlying disease. In the GIST clinical trial, 7 (5%) patients experienced CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour sites may have been the source of the GI bleeds. GI and tumoural bleeding may be serious and sometimes fatal. The most commonly reported ( 10%) drug-related adverse reactions in both settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and rash. Superficial oedemas were a common finding in all studies and were described primarily as periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of Glivec.When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed.Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight gain with or without superficial oedema may be collectively described as “fluid retention”. These reactions can usually be managed by withholding Glivec temporarily and with diuretics and other appropriate supportive care measures. However, some of these reactions may be serious or life-threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric clinical trials.Adverse reactionsAdverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequencies are defined as: very common (>1/10), common (>1/100, 1/10), uncommon (>1/1,000, 1/100), rare (1/1,000), not known (cannot be estimated from the available data).Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first.Adverse reactions and their frequencies reported in Table 1 are based on the main registration studies.Table 1 Adverse reactions in clinical studiesInvestigationsVery common:Weight increasedCommon :Weight decreasedUncommon :Blood creatinine increased, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increasedRare:Blood amylase increasedCardiac disordersUncommon:Palpitations, tachycardia, cardiac failure congestive1 , pulmonary oedemaRare:Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusionBlood and lymphatic system disordersVery common:Neutropenia, thrombocytopenia, anaemiaCommon:Pancytopenia, febrile neutropeniaUncommon:Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathyRare:Haemolytic anaemiaNervous system disordersVery common:Headache2Common:Dizziness, paraesthesia, taste disturbance, hypoaesthesiaUncommon:Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhageRare:Increased intracranial pressure, convulsions, optic neuritisEye disordersCommon:Eyelid oedema, lacrimation increased, conjunctival haemorrhage, conjunctivitis, dry eye, blurred visionUncommon:Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedemaRare:Cataract, glaucoma, papilloedemaEar and labyrinth disordersUncommon:Vertigo, tinnitus, hearing lossRespiratory, thoracic and mediastinal disordersCommon:Dyspnoea, epistaxis, coughUncommon:Pleural effusion3 , pharyngolaryngeal pain, pharyngitisRare:Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhageGastrointestinal disordersVery common:Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain4Common:Flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritisUncommon:Stomatitis, mouth ulceration, gastrointestinal haemorrhage5 , eructation, melaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitisRare:Colitis, ileus, inflammatory bowel diseaseRenal and urinary disordersUncommon:Renal pain, haematuria, renal failure acute, urinary frequency increasedSkin and subcutaneous tissue disordersVery common:Periorbital oedema, dermatitis/eczema/rashCommon:Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reactionUncommon:Rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis exfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruptionsRare:Acute febrile neutrophilic dermatosis (Sweet's syndrome), nail discolouration, angioneurotic oedema, rash vesicular, erythema multiforme, leucocytoclastic vasculitis, Stevens-Johnson syndromeMusculoskeletal and connective tissue disordersVery common:Muscle spasm and cramps, musculoskeletal pain including myalgia, arthralgia, bone pain6Common:Joint swellingUncommon:Joint and muscle stiffnessRare:Muscular weakness, arthritisMetabolism and nutrition disordersCommon:AnorexiaUncommon:Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemiaRare:Hyperkalaemia, hypomagnesaemiaInfections and infestationsUncommon:Herpes zoster, herpes simplex, nasopharyngitis, pneumonia7 , sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsisRare:Fungal infectionVascular disorders8Common:Flushing, haemorrhageUncommon:Hypertension, haematoma, peripheral coldness, hypotension, Raynaud's phenomenonGeneral disorders and administration site conditionsVery common:Fluid retention and oedema, fatigueCommon:Weakness, pyrexia, anasarca, chills, rigorsUncommon:Chest pain, malaiseHepatobiliary disordersCommon:Increased hepatic enzymesUncommon:Hyperbilirubinaemia, hepatitis, jaundiceRare:Hepatic failure9 , hepatic necrosisReproductive system and breast disordersUncommon:Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, sexual dysfunction, nipple pain, breast enlargement, scrotal oedemaPsychiatric disordersCommon:InsomniaUncommon:Depression, libido decreased, anxietyRare:Confusional state1 On a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML.2 Headache was the most common in GIST patients.3 Pleural effusion was reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML.4+5 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients.6 Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients.7 Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST.8 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC).9 Some fatal cases of hepatic failure and of hepatic necrosis have been reported.The following types of reactions have been reported mainly from post-marketing experience with Glivec. This includes spontaneous case reports as well as serious adverse events from ongoing studies, the expanded access programmes, clinical pharmacology studies and exploratory studies in unapproved indications. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib exposure.1 Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions.Laboratory test abnormalitiesHaematologyIn CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses 750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the frequency of grade 3 or 4 neutropenias (ANC < 1.0 x 109/l) and thrombocytopenias (platelet count < 50 x 109/l) being between 4 and 6 times higher in blast crisis and accelerated phase (59–64% and 44–63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed patients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed chronic phase CML grade 4 neutropenia (ANC < 0.5 x 109/l) and thrombocytopenia (platelet count < 10 x 109/l) were observed in 3.6% and < 1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with Glivec, but can in rare cases lead to permanent discontinuation of treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the first several months of therapy.In patients with GIST, grade 3 and 4 anaemia was reported in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-tumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts occurred mainly during the first six weeks of therapy, with values remaining relatively stable thereafter.BiochemistrySevere elevation of transaminases (< 5%) or bilirubin (< 1%) was seen in CML patients and was 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 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 ALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) elevations were observed. Bilirubin elevation was below 3%.There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome was fatal, including one patient on high dose paracetamol.Table 2 Adverse reactions from post-marketing reportsNeoplasm benign, malignant and unspecified (including cysts and polyps)Not known:Tumour haemorrhage/tumour necrosisImmune system disorders Not known:Anaphylactic shockCardiac disordersNot known:Pericarditis, cardiac tamponadeNervous system disordersNot known:Cerebral oedemaEye disordersNot known:Vitreous haemorrhageRespiratory, thoracic and mediastinal disordersNot known:Acute respiratory failure1 , interstitial lung diseaseGastrointestinal disordersNot known:Ileus/intestinal obstruction, gastrointestinal perforation, diverticulitisSkin and subcutaneous tissue disordersNot known:Lichenoid keratosis, lichen planusNot known:Toxic epidermal necrolysisMusculoskeletal and connective tissue disordersNot known:Avascular necrosis/hip necrosisVascular disordersNot known:Thrombosis/embolism

Manufacturer
Novartis Pharmaceuticals UK Ltd

Drug Availability
(POM)

Updated
11 August 2009