Direct healthcare professional communication on the risk of hepatotoxicity related to use of Ketaconazole HRA (ketoconazole)
02.12.2015
Laboratoire HRA Pharma, in agreement with the Agency for Medicinal Products and Medical Devices (HALMED) and the European Medicines Agency (EMA), has informed healthcare professionals about important safety information in relation to Ketoconazole HRA, authorised for the treatment of endogenous Cushing’s syndrome in adults and adolescents above 12 years.
Summary
- Ketoconazole HRA treatment should be initiated and supervised by physicians experienced in the treatment of Cushing`s syndrome and having the appropriate facilities for monitoring of biochemical responses since the dosage must be adjusted to meet the patient’s therapeutic need, based on the normalisation of cortisol levels.
- Ketoconazole HRA is contraindicated in patients with acute or chronic liver disease and/or if pre-treatment liver enzymes levels are above 2 times the upper limit of normal (> 2x ULN).
- To minimise the risk of severe liver injury, monitoring of liver function tests is mandatory in all patients receiving Ketoconazole HRA before initiation and periodically thereafter as recommended in the Product Information.
- Before starting the treatment it is necessary to measure liver enzymes (AST, ALT, GGT and AP) and bilirubin as well as to inform the patients about the risk of hepatotoxicity, including to stop the treatment and to contact their doctor immediately if they feel unwell or in the event of symptoms such as anorexia, nausea, vomiting, fatigue, jaundice, abdominal pain or dark urine. If these occur, treatment should be stopped immediately and liver function tests should be performed.
- During the treatment, a close clinical follow-up should be undertaken and liver enzymes (AST, ALT, GGT and AP) and bilirubin should be measured at frequent intervals (weekly for one month after initiation of the treatment, then monthly for 6 months as well as weekly during one month whenever the dose was increased).
- In the case of an increase in liver enzymes of less than 3 times the upper limit of normal (< 3x ULN), more frequent monitoring of liver function tests should be performed and the daily dose should be decreased by at least 200 mg.
- In the case of an increase in liver enzymes equal to or greater than 3 times the upper limit of normal (> 3x ULN), Ketoconazole HRA should be stopped immediately and should not be reintroduced due to the risk of serious hepatic toxicity.
- Ketoconazole HRA should be discontinued without any delay if clinical symptoms of hepatitis develop.
- Although hepatotoxicity is usually observed at treatment initiation and within the first six months of treatment, in case of long term treatment (more than 6 months) monitoring of liver enzymes should be done under medical criteria. As a precautionary measure, in case of a dose increase after the first six months of treatment, monitoring of liver enzymes should be repeated on a weekly basis for one month.
Further information
The letter provides the healthcare professionals with further information on the risk of hepatotoxicity related to use of Ketoconazole HRA.
Here you may view the direct healthcare professional communication.
The healthcare professionals are being reminded that they should report any adverse reaction, as well as quality defect to HALMED. Patients who have developed any adverse reaction to medicinal product may report it directly to HALMED. HALMED recommends the patients to contact their doctor or pharmacist regarding any adverse reaction they may notice.
