On 14 February 2020, the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has recommended that medicines with daily doses of 10 mg or more of cyproterone should only be used for androgen-dependent conditions such as hirsutism, alopecia, acne and seborrhoea once other treatment options, including treatment with lower doses, have failed. Once higher doses have started working, the dose should be gradually reduced to the lowest effective dose. The medicines should only be used for reduction of sex drive in sexual deviations in men when other treatment options are not suitable. There is no change in use of the medicines in men for prostate cancer. The recommendations follow a review of the risk of the rare tumour meningioma with cyproterone.
Overall, this side effect is rare: it may affect between 1 and 10 in 10 000 people, depending on the dose and duration of treatment.
As part of the ongoing surveillance of the safety of the medicines, companies marketing medicines containing 10 mg or more of cyproterone will be required to carry out a study to assess doctors’ awareness of the risk of meningioma and how to avoid it.
Meningioma is a rare, usually non-malignant tumour, but due to their location in and around the brain and spinal cord, meningiomas can cause serious problems.
Information for healthcare professionals:
- The occurrence of meningiomas (single and multiple) has been reported in association with the use of cyproterone acetate, primarily at doses of 25 mg/day and above.
- The risk increases with increasing cumulative doses of cyproterone acetate. Most cases have been reported after prolonged exposure (several years) to high doses of cyproterone (25 mg a day and above).
- Medicines containing 10 mg or more of cyproterone should only be used for hirsutism, androgenic alopecia, acne and seborrhoea once other treatment options, which could include low-dose cyproterone-containing medicines such as cyproterone acetate 2 mg/ethinylestradiol 35 micrograms, have not worked. After clinical improvement, the dose should be gradually reduced to the lowest effective dose.
- Cyproterone medicines should only be used in men for reduction of sex drive in sexual deviations when other treatments are not appropriate.
- Healthcare professionals should monitor patients for clinical signs and symptoms of meningioma in line with clinical practice. Symptoms may be unspecific and include changes in vision, hearing loss or ringing in the ears, loss of smell, headaches that worsen with time, memory loss, seizures or weakness in extremities.
- If a patient treated with cyproterone acetate is diagnosed with meningioma, treatment with all cyproterone-containing products must be permanently stopped.
- Cyproterone acetate (1 and 2 mg) in combination with ethinylestradiol or estradiol valerate will be contraindicated in patients with a meningioma or history of meningioma. Higher-dose cyproterone medicines already have this contraindication.
- There is no change in the use of cyproterone medicines for prostate cancer. These medicines are used as antiandrogen treatment in inoperable prostate cancer, including for prevention of the initial flare-up in treatment with luteinizing hormone-releasing hormone agonists.
- The association of cyproterone acetate with meningioma was first added to the product information for medicines with cyproterone daily doses of 10 mg or more in 2009, with a contraindication for people with a history of meningioma.
- This review included recent results from a French epidemiological study showing a cumulative dose-dependent association between cyproterone acetate and meningioma (Weill et al) and an analysis by the French medicines agency ANSM of cases of meningioma with cyproterone use in France. Recent published literature and analysis of the EU database of adverse events, EudraVigilance, were also included.
A direct healthcare professional communication (DHPC) will be sent to healthcare professionals prescribing, dispensing or administering the medicine in due course. The DHPC will also be published on a dedicated page on the EMA website.
Cyproterone is an antiandrogen medicine. Medicines containing cyproterone are available as tablets (10 mg, 50 mg, 100 mg) and solution for injection (300 mg/3 ml). Cyproterone medicines are used to treat various androgen-dependent conditions, such as hirsutism, alopecia, acne, prostate cancer and reduction of sex drive in sexual deviations in men. They are also used as contraception and in hormone replacement therapy. Cyproterone medicines contain either cyproterone alone or cyproterone at a lower dose in combination with an oestrogen.
Cyproterone has been authorised in the EU via national procedures since the 1970s and is available on prescription under various trade names. The review of cyproterone-containing medicines was initiated on 11 July 2019 at the request of France, under Article 31 of Directive 2001/83/EC. The review has been carried out by the PRAC, the EMA’s Committee responsible for the evaluation of safety issues for human medicines, which has made a set of recommendations.
The PRAC recommendations will now be sent to Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which will adopt a position. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures across the EU.