GLIVEC® (imatinib mesilate) Warnings/Precautions

Contraindications

Co-administration and interactions

Fluid retention

Hepatotoxicity

Hepatic impairment

Hepatitis B infections

Cardiac disease

Hypothyroidism

Gastrointestinal haemorrhage

Tumor lysis syndrome

Fertility, pregnancy, and lactation

Pediatric population

Driving and operating machinery

Contraindications

Glivec is contraindicated in patients who experience hypersensitivity to the active substance or to any of the excipients.

Co-administration and interactions

Caution should be used when taking other medicines. When Glivec is co-administered with other medicinal products, there is a potential for drug interactions. Caution should be used when taking Glivec with CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin); CYP3A4 inducers (e.g. dexamethasone, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort); and substrates of CYP3A4 (e.g. triazolobenzodiazepines, dihydropyridine calcium channel blockers, simvastatin, cyclosporine, pimozide), CYP2C9 (e.g. warfarin), or CYP2D6 (e.g. metoprolol).

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. Beware of severe fluid retention. It is recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and, if necessary, appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in older people and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction.

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. 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.

Hepatitis B infection/reactivation

Test for hepatitis B infection before initiating treatment with Glivec. In patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for hepatitis B infection during treatment, consult experts before initiating treatment. Reactivation of hepatitis B in patients who are chronic carriers of the 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. Closely monitor signs and symptoms of active hepatitis B infection in carriers of hepatitis B virus throughout therapy and for several months following termination of therapy.

Cardiac disease

Use with caution in patients with a history of cardiac disease or renal failure. 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. Cardiac screening should be considered in patients with HES/CEL and patients with MDS/MPD with a high level of eosinophils (echocardiogram, serum troponin level). If either is abnormal, prophylactic use of systemic steroids should be considered for 1 to 2 weeks concomitantly with imatinib at the initiation of therapy.

Hypothyroidism

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

Gastrointestinal haemorrhage

There have been reports of gastrointestinal haemorrhage and haemorrhages at the site of tumor deposits in GIST patients. There have been reports of gastric antral vascular ectasia (GAVE) in patients with CML, ALL, and other diseases. Patients should be monitored for gastrointestinal symptoms at the start of and during treatment. Discontinuation of Glivec may be considered.

Tumor lysis syndrome

There have been reports of tumor lysis syndrome (TLS). Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Glivec.

Fertility, pregnancy, and lactation

Women of childbearing potential must be advised to use effective contraception during treatment. Women of childbearing potential who open capsules should handle contents with caution, avoid skin-eye contact or inhalation, and wash hands immediately after handling open capsules. There have been reports of spontaneous abortions and infant congenital anomalies in women who have taken Glivec. Glivec should not be used during pregnancy unless clearly necessary. Women taking Glivec should not breastfeed.

Pediatric population

There have been reports of growth retardation in children and pre-adolescents taking imatinib. The growth of children and pre-adolescents taking Glivec should be closely monitored.

Driving and operating machinery

Caution is recommended when patients taking Glivec drive a car or operate machinery.