Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
When Glivec is co-administered with other medicinal products, there is a potential for drug interactions.
Caution should be used when taking Glivec with protease inhibitors, azole antifungals, certain macrolides (see section 4.5), 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 (see section 4.5).
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 GLI FCT API May23 V17                                                                         EU SmPC March 2022

be avoided (see section 4.5).

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

Hepatotoxicity
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 (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 is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see sections 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 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 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 and systemic mastocytosis 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 or ASM 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.


GLI FCT API May23 V17                                                                     EU SmPC March 2022

Gastrointestinal haemorrhage
In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and intra- tumoural 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 Glivec 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 Glivec (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 Glivec. 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 Glivec 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 Glivec (see section 4.8). If laboratory or clinical findings associated with TMA occur in a patient receiving Glivec, 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 Glivec should not be resumed.


Laboratory tests
Complete 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 GLI FCT API May23 V17                                                                        EU SmPC March 2022

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, as recommended in section 4.2.
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 (see sections 4.2 and 5.2).
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.
Close monitoring of growth in children under imatinib treatment is recommended (see section 4.8).

Effects on Driving

4.7 Effects on ability to drive and use machines
Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with imatinib. Therefore, caution should be recommended when driving a car or operating machinery.