EMA/609213/2014 Summary of the risk management plan (RMP) for Ketoconazole HRA (ketoconazole) This is a summary of the risk management plan (RMP) for Ketoconazole HRA, which details the measures to be taken in order to ensure that Ketoconazole HRA is used as safely as possible. For more information on RMP summaries, see here. This RMP summary should be read in conjunction with the EPAR summary and the product information for Ketoconazole HRA, which can be found on Ketoconazole HRA s EPAR page. Overview of disease epidemiology Ketoconazole HRA is a medicine used to treat adults and children above the age of 12 years with endogenous Cushing s syndrome, a rare hormonal disorder caused by long-term high levels of cortisol, a steroid hormone produced in the adrenal glands (two glands situated above the kidneys). Cushing s syndrome can either have an internal cause (endogenous Cushing s syndrome), or it may develop in response to some medications (exogenous Cushing s syndrome). Endogenous syndrome may be caused by a tumor of the adrenal gland(s) that makes too much cortisol or by a tumor in the pituitary gland (a small gland under the brain that produces large amounts of adrenocorticotropic hormone, ACTH), which in turn stimulates excessive production of cortisol from the adrenal glands (Cushings disease). Cushing s syndrome mostly affects women in their third and fourth decades of life. Cushing s syndrome is estimated to affect around 0.9 in 10,000 people in the European Union (EU). It is estimated that only 1 to 4 in every 1,000,000 persons in the EU will develop Cushing s syndrome each year. Summary of treatment benefits Ketoconazole HRA contains the active substance ketoconazole. Because ketoconazole is a well-known substance, and its use in Cushing s syndrome is well established, data on its benefits can be found in the scientific literature. The applicant presented data on more than 800 patients with Cushing s syndrome who were treated with ketoconazole either alone or in combination with other treatments. The average dose used was 600 to 800 mg daily. The main measure of effectiveness in these literature studies was the reduction in the level of cortisol in the urine, and ketoconazole treatment was shown to normalise urine cortisol levels in 43 to 80% of patients in the different studies. Unknowns relating to treatment benefits Data of ketoconazole use in elderly patients and patients with kidney problems are limited. There is insufficient experience with ketoconazole use in children aged less than 12 years. Page 1/6
Summary of safety concerns Important identified risks Risk What is known Preventability Liver toxicity (hepatotoxicity) Liver toxicity is the most significant side effect of Ketoconazole HRA. The active substance in Ketoconazole HRA, ketoconazole, affects the way certain medicines are broken down in the liver (by blocking certain liver P450 enzymes, especially of the CYP3A family). This means that blood levels of these medicines can increase, resulting in an increase and/or prolongation of their effects, which may lead to adverse effects on the liver. In order to minimise the well-recognised risk of liver toxicity, the patient s liver function should be checked with blood tests before treatment is started and weekly for one month after the start of treatment. It should then be checked monthly for 6 months. Treatment must not be started in patients suffering from acute or chronic liver disease and/or in patients with liver enzyme levels twice the upper limit of normal. If during treatment an increase in blood liver enzyme levels is detected (but below 3 times the upper limit of normal), the patient should be more closely monitored and the dose decreased (by at least 200 mg/day). Ketoconazole HRA should be discontinued if liver enzymes levels are equal to or above 3 times the upper limit of normal. In case the dose is increased after the first six months of treatment, monitoring of liver enzymes should be repeated on a weekly basis during one month. Before starting treatment, doctors should inform patients how to recognise signs suggestive of liver toxicity, such as loss of appetite (anorexia), feelings of sickness (nausea), vomiting, extreme tiredness, yellowing of the skin or whites of the eyes (jaundice), pain in the abdomen or dark urine. Patients should be informed that they should stop ketoconazole if any of these symptoms occur and should contact their doctor. Combining Ketoconazole HRA with other medicines known to cause liver damage is not recommended, since it may lead to enhanced liver toxicity. Page 2/6
Risk What is known Preventability Decreased production of hormones by the adrenal glands (adrenal insufficiency) Ketoconazole interaction with certain medicines that can alter heart rhythm (QT/QTc interval prolongation/ torsade de pointes) Ketoconazole is known to block the production of steroid hormones (cortisol, aldosterone, and male sex hormones or androgens) by the adrenal glands. Treating Cushing s syndrome with Ketoconazole HRA may therefore result in decreased blood levels of these hormones, a condition known as adrenal insufficiency. Ketoconazole is known to block the activity of certain liver enzymes called CYP3A4. This means that medicines which are broken down by these liver enyzmes can accumulate leading to increased and/or prolonged effects including side effects. Some of these medicines are known to alter the heart rhythm (prolong QT interval) and their prolonged effect can lead to clinically important irregular heartbeat. In order to prevent signs and symptoms associated with low levels of cortisol (hypocortisolism), cortisol levels in the blood (plasma/serum), saliva and/or urine should be regularly checked. Patients should be informed about the signs and symptoms of hypocortisolism such as weakness, extreme tiredness, feeling sick (nausea), vomiting, decreased blood pressure, low blood levels of a substance called sodium and blood sugar (glucose). If any of these occur, treatment with Ketoconazole HRA should be temporarily discontinued or the dose reduced. If needed, insuficient cortisol levels may be corrected by replacing the missing cortisol. Ketoconazole HRA must not be used together with medicines that are broken down by CYP3A4 enzymes and which are known to have serious side effects. These are listed in the product information. Important potential risks Risk Use in pregnant and breastfeeding women What is known In animal reproduction studies, ketoconazole impaired fertility in male and female animals. Very high doses of ketoconazole (80 mg/kg/day and higher) impaired fertility of female rats. Doses of 25 mg/kg and higher led to sperm abnormalities in male rats and dogs and reduced fertility in rats. In dogs, ketoconazole was toxic to the embryo and had harmful effects on development. In rabbits, ketoconazole was toxic to both the mother and the embryo and had harmful effects on the development of the embryo at high doses of 40 mg/kg in rabbits and 80 mg/kg in rats. Moreover, studies in pregnant animals (rats and guinea pigs) indicate that ketoconazole crosses the barrier from mother to embryo. There are no adequate data from the use of ketoconazole in pregnant women. Ketoconazole Page 3/6
Risk What is known HRA must not be used during pregnancy. It is unknown whether ketoconazole is excreted in human milk. However, in animal studies ketoconazole was found in milk. Breastfeeding must therefore be discontinued during treatment with Ketoconazole HRA. The effect on the electrical activity of the heart (QT/QTc interval prolongation/torsade de Pointes) Allergic reactions (hypersensitivity reactions) Worsening or reappearance of immune disorders once Cushing s syndrome has been controlled (immune dysfunctions following Cushing s syndrome remission) Laboratory studies have shown that ketoconazole can alter the electrical activity of the heart and may prolong the QT interval. The risk of QT prolongation is increased when ketoconazole is given together with certain medicines known to have effects on the heart and that interact with ketoconazole. The medicines must not be given together with ketoconazole. An examination of the patient s heart electrical activity (electrocardiograph) should be performed before starting treatment and regularly during treatment. In general, allergic reactions to any medicine can be potentially lifethreatening in susceptible patients. Therefore Ketoconazole HRA must not be used in patients allergic to ketoconazole, and/or to other medicine of the same class (called imidazole antifungals) or other components of this medicinal product. Patients with Cushing s syndrome produce high levels of glucocorticoid hormones (cortisol hormone in particular) that suppress the body s immune system and may mask the effects of immune disorders the patient may have. After the normalisation of glucocorticoid levels following treatment of Cushing s syndrome, autoimmune or inflammatory disorders may reappear or get worse. This is a long-term consequence of successfully treating Cushing s syndrome that is not specific to ketoconazole and may be also observed following surgical cure of Cushing s syndrome. Patients with Cushing s syndrome and coexisting inflammatory/autoimmune disorders should therefore be closely monitored for worsening or reappearance of the associated immune disease after normalisation of cortisol production. Missing information Risk Use in children under the age of 12 years Safety in elderly patients Long-term use What is known There is insufficient experience with the use of ketoconazole in children under the age of 12 years, therefore Ketoconazole HRA is not recommended in this population. There is insufficient experience with the use of ketoconazole in patients older than 65 years. However, there is no evidence to suggest that dose adjustment is required in these patients. In some patients, ketoconazole was given for up to 10 years. However, most of the evidence about long-term efficacy and safety cover the period up to 3 years of treatment. Page 4/6
Summary of risk minimisation measures by safety concern All medicines have a summary of product characteristics (SmPC) which provides physicians, pharmacists and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimising them. Information for patients is available in lay language in the package leaflet. The measures listed in these documents are known as routine risk minimisation measures. The SmPC and the package leaflet are part of the medicine s product information. The product information for Ketoconazole HRA can be found on Ketoconazole HRA s EPAR page. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). Full details on these conditions and the key elements of any educational material can be found in Annex II of the product information which is published on Ketoconazole s EPAR page; how they are implemented in each country however will depend upon agreement between the marketing authorisation holder and the national authorities. These additional risk minimisation measures are for the following risks: Liver toxicity Risk minimisation measure: Direct healthcare professional communication (DHPC) Objective and rationale: to increase awareness about the potential risk of liver toxicity during treatment with Ketoconazole HRA in patients with Cushing s syndrome and providing guidance on how to manage that risk. Description: the aim of circulating the targeted DHPC is to raise the awareness among prescribers about the exact time intervals that liver function tests are to be performed according to the SmPC and to provide guidance on how to manage this risk Planned post-authorisation development plan List of studies in post-authorisation development plan Study/activity (including study number) European Registry on Cushing s syndrome (preferably considering the Objectives To assess drug utilisation patterns and to document the safety and effectiveness Safety concerns /efficacy issue addressed Hepatotoxicity QT/QTc interval prolongation/ Torsade de Pointes Status Planned Planned date for submission of (interim and) final results Feasibility assessment within 3 months after the EC Decision existing European profile of Registry on Cushing s ketoconazole in routine daily syndrome practice. (ERCUSYN) where feasible) Page 5/6
Studies which are a condition of the marketing authorisation Multi-country, observational registry to collect clinical information on patients with Cushing Syndrome patients exposed with Ketoconazole (preferably considering the existing European Registry on Cushing s syndrome (ERCUSYN) registry where feasible). Summary of changes to the risk management plan over time Not applicable. This summary was last updated in 11-2014. Page 6/6