IMATINIB

2. Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving imatinib. 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. 2). Long-term treatment with imatinib 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.

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.

8). 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.

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 with inhibitors of the CYP3A4 family. 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.

Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of imatinib 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 imatinib while taking enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine 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. 5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib.

g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel and quinidine). g. 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. 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. 5 micromol/l. This inhibition has not been observed in vivo after the administration of imatinib 400 mg and paracetamol 1000 mg. Higher doses of imatinib and paracetamol have not been studied.

Caution should therefore be exercised when using high doses of imatinib and paracetamol concomitantly. 4). Caution is therefore recommended. However, the mechanism of the observed interaction is presently unknown. 1), but drug-drug interactions between imatinib and chemotherapy regimens are not well characterised.

e. hepatotoxicity, myelosuppression or others, may increase and it has been reported that […]

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.

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 study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced CTC grade 3/4 GI bleeds (3 patients), intra- tumoural bleeds (3 patients) or both (1 patient). 4). 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, diarrhea, 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. 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.

Considering the limited safety database, the adverse events thus far reported in children are consistent with the known safety profile in adult patients with Ph+ ALL. The safety database for children with Ph+ ALL is very limited though no new safety concerns have been identified.

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 imatinib 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 reactions Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency categories are defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), 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 are reported in Table 1. Table 1 Tabulated summary of adverse reactions Infections and infestations Uncommon: Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis Rare: Fungal infection Not known: Hepatitis B reactivation* Neoplasm benign, malignant and unspecified (including cysts and polyps) Rare: Tumour lysis syndrome Not known: Tumour haemorrhage/tumour necrosis* Immune system disorders Not known: Anaphylactic shock* Blood and lymphatic system disorders Very common: Neutropenia, thrombocytopenia, anaemia Common: Pancytopenia, febrile neutropenia Uncommon: Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy Rare: Haemolytic anaemia, thrombotic microangiopathy Metabolism and nutrition disorders Common: Anorexia Uncommon: Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemia Rare: Hyperkalaemia, hypomagnesaemia Psychiatric disorders Common: Insomnia Uncommon: Depression, libido decreased, anxiety Rare: Confusional state Nervous system disorders Very common: Headache2 Common: Dizziness, paraesthesia, taste disturbance, hypoaesthesia Uncommon: Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage Rare: Increased intracranial pressure, convulsions, optic neuritis Not known: Cerebral oedema* Eye disorders Common: Eyelid oedema, lacrimation increased, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision Uncommon: Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema Rare: Cataract, glaucoma, papilloedema Not known: Vitreous haemorrhage* Ear and labyrinth disorders Uncommon: Vertigo, tinnitus, hearing loss Cardiac disorders Uncommon: Palpitations, tachycardia, cardiac failure congestive3, pulmonary oedema Rare: Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion Not known: Pericarditis*, cardiac tamponade* Vascular disorders4 Common: Flushing, haemorrhage Uncommon: Hypertension, haematoma, subdural haematoma, peripheral coldness, hypotension, Raynaud’s phenomenon Not known: Thrombosis/embolism* Respiratory, thoracic and mediastinal disorders Common: Dyspnoea, epistaxis, cough Uncommon: Pleural effusion5, pharyngolaryngeal pain, pharyngitis Rare: Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage Not known: Acute respiratory failure11 *, interstitial […]

1. 4 Special warnings and precautions for use When Imatinib is co-administered with other medicinal products, there is a potential for drug interactions. g. 5). g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St.

John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. 5). 5). 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.

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.

8). 5% of newly diagnosed CML patients taking imatinib. 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 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. 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 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. 8). 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. 8). When needed, discontinuation of Imatinib treatment may be considered.

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. 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 […]