Imatinib 100 & 400 Zydus 100 mg, 400 mg Tablet

IMATINIB ZYDUS is indicated for:

• treatment of adult and paediatric patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (CML) (for paediatric use, see section 4.2);
• treatment of adult and paediatric patients with CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy (for paediatric use, see section 4.2);
• treatment of adult patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy;
• treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy;
• treatment of adult patients with myelodysplastic / myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements;
• treatment of adult patients with systemic mastocytosis (SM) without the D816V c-Kit mutation and eosinophilia;
• treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1- PDGFRu03b1 rearrangement;
• treatment of adult patients with unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST);
• adjuvant treatment of adult patients following resection of Kit-positive GIST;
• treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).

The effectiveness of IMATINIB ZYDUS 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 SM, HES/CEL, on objective response rates and progression-free survival in unresectable and/or metastatic GIST, on recurrence free survival in adjuvant GIST, and on objective response rates in DFSP (see section 5). Increased survival in controlled trials has been demonstrated only in newly diagnosed chronic phase CML.

Therapy should be initiated by a medical practitioner experienced in the treatment of patients with malignancies.

Posology

Dosage in CML

The recommended dosage of IMATINIB ZYDUS is 400 mg/day for patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis. Treatment should be continued as long as the patient continues to benefit. Dose increase from 400 mg to 600 mg, or to 800 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg daily in patients in accelerated phase or blast crisis may be considered in the absence of severe adverse reactions 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 cytogenic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenic response.

Dosing in 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 and advanced phase CML (not to exceed the total dose of 600 mg daily). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations u2013 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 use of IMATINIB ZYDUS in children below 2 years of age.

Dosage in Ph+ ALL

The recommended dose of IMATINIB ZYDUS is 600 mg/day for patients with Ph+ ALL.

Dosage in MDS/MPD

The recommended dose of IMATINIB ZYDUS is 400 mg/day for patients with MDS/MPD.

Dosage in SM

For patients with SM associated with eosinophilia, a clonal haematological disease related to the fusion kinase FIP1L1- PDGFRu03b1, 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 reactions if assessments demonstrate an insufficient response to therapy.

Dosage in HES/GEL

For HES/CEL patients with demonstrated FIP1L1- PDGFRu03b1 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 reactions if assessments demonstrate an insufficient response to therapy.

Dosage in GIST

The recommended dose of IMATINIB ZYDUS is 400 mg/day for patients with unresectable and/or metastatic, malignant GIST. A dose increase from 400 mg to 600 mg or to 800 mg for patients may be considered in the absence of adverse reactions if assessments demonstrate an insufficient response to therapy. Treatment with IMATINIB ZYDUS in GIST patients should be continued until disease progression. The recommended dose of IMATINIB ZYDUS is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. In the adjuvant setting the optimal treatment duration with IMATINIB ZYDUS is not known. Efficacy has been demonstrated for a mean duration of one year.

Dosage in DFSP

The recommended dose of IMATINIB ZYDUS is 800 mg/day for patients with DFSP.

Method of 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 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).

• hypersensitivity to imatinib or to any of the excipients listed in section 6.1;
• safety during pregnancy and lactation has not been established (see section 4.6).

IMATINIB ZYDUS should be taken with food and a large glass of water to minimise the risk of gastrointestinal disturbances. When IMATINIB ZYDUS is co-administered with other medicines, there is a potential for medicine interactions. Caution should be used when taking IMATINIB ZYDUS with protease inhibitors, azole antifungals, certain macrolides (see section 4.5), CYP3A4 substrates with a narrow therapeutic window (e.g. ciclosporin, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives (see section 4.5).

Concomitant use of IMATINIB ZYDUS and medicines 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 IMATINIB ZYDUS, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and IMATINIB ZYDUS should be avoided (see section 4.5).

Hypothyroidism

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with IMATINIB ZYDUS (see section 4.5). Thyroid-stimulating hormone (TSH) levels should be closely monitored in such patients.

Hepatotoxicity

Metabolism of IMATINIB ZYDUS 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 (see sections 4.2, 4.8 and 5.2). 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 ZYDUS is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see section 4.5 and 4.8).

Fluid retention

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 IMATINIB ZYDUS. 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 older people and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction.

Patients with cardiac disease

Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.

In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of IMATINIB ZYDUS therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding IMATINIB ZYDUS. As cardiac adverse reactions have been reported uncommonly with imatinib, a careful assessment of the benefit/risk of IMATINIB ZYDUS 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. Evaluation 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 ZYDUS is administered. If either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids (1 u2013 2 mg/kg) for one to two weeks concomitantly with IMATINIB ZYDUS should be considered at the initiation of therapy.

Gastrointestinal haemorrhage

In a study in patients with unresectable and/or metastatic GIST, both gastrointestinal and intra-tumoral haemorrhages were reported (see section 4.8). 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.

In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has been reported in post-marketing experience in patients with CML, ALL and other diseases (see section 4.8). When needed, discontinuation of IMATINIB ZYDUS treatment may be considered.

Tumour lysis syndrome

Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of IMATINIB ZYDUS (see section 4.8).

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Patients should be tested for HBV infection before initiating treatment with IMATINIB ZYDUS.

Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with IMATINIB ZYDUS should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).

Phototoxicity

Exposure to direct sunlight should be avoided or minimised due to the risk of phototoxicity associated with imatinib treatment. Patients should be instructed to use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

Thrombotic microangiopathy

BCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy (TMA), including individual case reports for IMATINIB ZYDUS (see section 4.8). If laboratory or clinical findings associated with TMA occur in a patient receiving IMATINIB ZYDUS, treatment should be discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated in conjunction with low ADAMTS13 activity, treatment with IMATINIB ZYDUS should not be resumed.

Laboratory tests

Complete blood counts must be performed regularly during therapy with IMATINIB ZYDUS. Treatment of CML patients with IMATINIB ZYDUS 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 IMATINIB ZYDUS may be interrupted or the dose may be reduced, as recommended in section 4.2. Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving IMATINIB ZYDUS. 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 (see section 4.2 and 5.2). Long-term treatment with IMATINIB ZYDUS may be associated with a clinically significant decline in renal function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and closely monitored during therapy, with particular attention to those patients exhibiting risk factors for renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be prescribed in accordance with standard treatment guidelines.

Cerebrovascular events

Cerebrovascular adverse events identified as class related adverse events have occurred in patients treated with TKI (tyrosine kinase inhibitor) containing medicines. These class-related cerebrovascular adverse events, shared to a variable degree by all TKIs, are cerebrovascular accident (CA), transient ischaemic attack (TIA), ischaemic stroke (IS) and cerebral infarction (CI). These cerebrovascular events may occur in patients on treatment with TKIs with or without risk factors for these events and may occur at any time during treatment with TKIs.

Advise to the healthcare professionals

The above-mentioned cerebrovascular adverse events may occur in patients on treatment with TKI-containing medicines with or without risk factors for these events and may occur at any time during treatment with TKIs. Patients on treatment with TKI-containing medicines should be carefully monitored, and relevant risk factors managed to reduce the risk of these class-related cerebrovascular adverse events. Treatment with TKI-containing medicines should be discontinued, and alternative treatment options be considered in patients who develop these class-related cerebrovascular adverse events.

Paediatric population

There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib. In an observational study in the CML paediatric population, a statistically significant decrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and 24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. Close monitoring of growth in children under IMATINIB ZYDUS treatment is recommended (see section 4.8).

Active substances that may increase IMATINIB ZYDUS 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 ZYDUS 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 IMATINIB ZYDUS with inhibitors of the CYP3A4 family.

Active substances that may decrease IMATINIB ZYDUS 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 ZYDUS, potentially increasing the risk of therapeutic failure. Pre-treatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of imatinib resulted in decrease in Cmax and AUC(0-u221e) by at least 54 % and 74 %, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with imatinib while taking enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital and primidone. The plasma AUC for imatinib decreased by 73 % compared to patients not on EIAEDs. In two published studies, concomitant administration of imatinib and a product containing St Johnu2019s wort led to 30 u2013 32 % reduction in the AUC of imatinib. Concomitant use of rifampicin or other strong CYP3A4 inducers and IMATINIB ZYDUS should be avoided.

Active substances that may have their plasma concentration altered by IMATINIB ZYDUS

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 ZYDUS with CYP3A4 substrates with a narrow therapeutic window (e.g. ciclosporin, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel and quinidine). IMATINIB ZYDUS may increase plasma concentration of other CYP3A4 metabolised medicines (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.).

IMATINIB ZYDUS also inhibits CYP2C9 and CYP2C19 activity in vitro. PT prolongation was observed following co-administration with warfarin. When giving warfarin, short-term PT monitoring is therefore necessary at the start and end of IMATINIB ZYDUS therapy and when altering the dosage. Alternatively, the use of low-molecular weight heparin should be considered. 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 warfarin.

In vitro IMATINIB ZYDUS inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. IMATINIB ZYDUS 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 u2013 1,30]). Dose adjustments do not seem to be necessary when IMATINIB ZYDUS is co-administered 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, IMATINIB ZYDUS inhibits paracetamol O-glucuronidation with Ki value of 58,5 u03bcmol/L. This inhibition has not been observed in vivo after the administration of IMATINIB ZYDUS 400 mg and paracetamol 1000 mg. Higher doses of IMATINIB ZYDUS and paracetamol have not been studied. Caution should therefore be exercised when using high doses of IMATINIB ZYDUS and paracetamol concomitantly.

In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be decreased when IMATINIB ZYDUS is co-administered (see section 4.4). 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 IMATINIB ZYDUS with chemotherapy (see section 5.1), but interactions between imatinib and chemotherapy regimens are not well characterised. IMATINIB ZYDUS 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 (see section 4.8). Therefore, the use of IMATINIB ZYDUS in combination requires special precaution.

Women of childbearing potential

Women of childbearing potential must be advised to use effective contraception during treatment.

Pregnancy

There are limited data on the use of IMATINIB ZYDUS in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken IMATINIB ZYDUS. Studies in animals have however shown reproductive toxicity (see section 5.3) and the potential risk for the foetus is unknown. IMATINIB ZYDUS should not be used during pregnancy unless clearly necessary (see section 4.3). If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breastfeeding

There is limited information on IMATINIB ZYDUS distribution on human milk. Studies in two breastfeeding women revealed that both IMATINIB ZYDUS and its active metabolite can be distributed into human milk. Therefore, women taking IMATINIB ZYDUS should not breastfeed (see section 4.3).

Fertility

In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies on patients receiving IMATINIB ZYDUS and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on IMATINIB ZYDUS treatment should consult with their doctor.

Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with IMATINIB ZYDUS. Therefore, caution should be recommended when driving a car or operating machinery.

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 medicines. In clinical trials in CML, medicine discontinuation for medicine-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 medicine was discontinued for medicine-related adverse reactions in 4 % of patients.

The most commonly reported (u2265 10 %) medicine-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 IMATINIB ZYDUS.

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 u201cfluid retentionu201d. These reactions can usually be managed by withholding IMATINIB ZYDUS temporarily and with diuretics and other appropriate supportive care measures. However, these events 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.

Adverse reactions

Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first.

Infections and infestations

Less frequent: herpes zoster, herpes simplex, nasopharyngitis, pneumonia, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis, fungal infection

Frequency unknown: hepatitis B reactivation*

Neoplasms benign and malignant (including cysts and polyps)

Less frequent: tumour lysis syndrome

Frequency unknown: tumour haemorrhage/tumour necrosis*

Blood and the lymphatic system disorders

Frequent: neutropenia, thrombocytopenia, anaemia, pancytopenia, febrile neutropenia

Less frequent: thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy, haemolytic anaemia, thrombotic microangiopathy

Immune system disorders

Frequency unknown: anaphylactic shock*, angioedema

Metabolism and nutrition disorders

Frequent: anorexia

Less frequent: hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemia, hyperkalaemia, hypomagnesaemia

Psychiatric disorders

Frequent: insomnia

Less frequent: depression, decreased libido, anxiety, confusional state

Nervous system disorders

Frequent: headache, dizziness, paraesthesia, taste disturbance, hypoaesthesia

Less frequent: migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage, increased intracranial pressure, convulsions, optic neuritis

Frequency unknown: cerebral oedema*

Eye disorders

Frequent: eyelid oedema, increased lacrimation, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision

Less frequent: eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema, cataract, glaucoma, papilloedema

Frequency unknown: vitreous haemorrhage*

Ear and labyrinth disorders

Less frequent: vertigo, tinnitus, hearing loss

Cardiac disorders

Less frequent: palpitations, tachycardia, cardiac failure, congestive pulmonary oedema, dysrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion

Frequency unknown: pericarditis*, cardiac tamponade*

Vascular disorders

Frequent: flushing, haemorrhage

Less frequent: hypertension, haematoma, subdural haematoma, peripheral coldness, hypotension, Raynaud's phenomenon

Frequency unknown: thrombosis/embolism*

Respiratory, thoracic and mediastinal disorders

Frequent: dyspnoea, epistaxis, cough

Less frequent: pleural effusion, pharyngolaryngeal pain, pharyngitis, pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage

Frequency unknown: acute respiratory failure*, interstitial lung disease*

Gastrointestinal disorders

Frequent: nausea, diarrhoea, vomiting, dyspepsia, abdominal pain, flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis

Less frequent: stomatitis, mouth ulceration, gastrointestinal haemorrhage, eructation, melaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitis, colitis, ileus, inflammatory bowel disease

Frequency unknown: Ileus/intestinal obstruction*, tumor haemorrhage/tumor necrosis, gastrointestinal perforation*, diverticulitis*, gastric antral vascular ectasia (GAVE)

Hepato-biliary disorders

Frequent: increased hepatic enzymes

Less frequent: hyperbilirubinaemia, hepatitis, jaundice, hepatic failure, hepatic necrosis

Skin and subcutaneous tissue disorders

Frequent: periorbital oedema, dermatitis/eczema/rash, pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction

Less frequent: pustular rash, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, exfoliative dermatitis, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruptions, acute febrile neutrophilic dermatosis (Sweet's syndrome), nail discolouration, vesicular rash, erythema multiforme, leucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis (AGEP)

Frequency unknown: palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen planus*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS)*, pseudoporphyria*

Musculoskeletal and connective tissue disorders

Frequent: muscle spasm and cramps, musculoskeletal pain including myalgia, arthralgia, bone pain, joint swelling

Less frequent: joint and muscle stiffness, muscular weakness, arthritis, rhabdomyolysis/myopathy

Frequency unknown: avascular necrosis/hip necrosis*, growth retardation in children*

Renal and urinary disorders

Less frequent: renal pain, haematuria, acute renal failure, increased urinary frequency

Frequency unknown: chronic renal failure

Reproductive system and breast disorders

Less frequent: gynaecomastia, erectile dysfunction, menorrhagia, irregular menstruation, sexual dysfunction, nipple pain, breast enlargement, scrotal oedema, haemorrhagic corpus luteum/haemorrhagic ovarian cyst

General disorders and administration site conditions

Frequent: fluid retention and oedema, fatigue, weakness, pyrexia, anasarca, chills, rigors

Less frequent: chest pain, malaise

Investigations

Frequent: increased weight, decreased weight

Less frequent: increased blood creatinine, increased blood creatine phosphokinase, increased blood lactate dehydrogenase, increased blood alkaline phosphatase, increased blood amylase

*These types of reactions have been reported mainly from post-marketing experience. 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 Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST.

2 Headache was the most common in GIST patients.

3 Cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML.

4 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).

5 Reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML.

6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients.

8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported.

9 Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed in post-marketing.

10 Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients.

11 Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions.

Experience with doses greater than 800 mg is limited. Isolated cases of overdose have been reported. In the event of overdosage, the patient should be observed and appropriate supportive treatment given. A patient with myeloid blast crisis inadvertently took imatinib 1200 mg for 6 days and experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin. Treatment was temporarily interrupted and there was complete reversal of all abnormalities within one week. Treatment was resumed at a dose of 400 mg without recurrence of problems. Another patient developed severe muscle cramps after taking imatinib 1600 mg daily for six days. Following interruption of treatment, complete resolution of muscle cramps occurred and treatment was subsequently resumed. Another patient who was prescribed 400 mg daily took imatinib 800 mg on day 1 and 1200 mg on day 2. Treatment was interrupted, no adverse events occurred and the patient resumed treatment.