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Androcur: brain tumors and the scandal of off-label prescriptions

After the pills of 3e and 4e generation, it is the Androcur®'s turn to become the subject of a new crisis of the drug, or even a future health scandal.

Thanks to the relentless neurosurgeons who soon made the link between this drug and the increased risk of meningioma (at least 10 years ago), an investigation was conducted by the ANSM and this reveals that this anti-androgen is often prescribed as contraceptive or treatment for acne and endometriosis, multiplies by 7 the risk of meningiomas after 6 months and by 20 after 5 years of treatment.

A tumor that is more common in women

The meningioma is a so-called "benign" tumor, which develops at the level of the meninges and compresses the opposite part of the brain, because the skull is in the bone and is therefore non-stretchable. Meningiomas account for one third of all intracranial tumors and are more common in women because of their hormone dependence on progesterone: there are progesterone receptors on meningiomas and these would be stimulated with cyproterone acetate.

The development of meningiomas, usually slow, would be abnormal with this treatment, with faster development and multiple meningiomas. It is possible to see the meningioma decline when the Androcur stops. The severity of this tumor is due to the volume and the location, for example with a risk of blindness if a meningioma is located near the optical pathways.

A risk of meningiomas multiplied by 20

On its website, the National Agency for Drugs Safety (ANSM) acknowledges that since 2009 "cyproterone acetate has been under special supervision following the signal sent by France at European level on the risk of d The occurrence of meningiomas The evaluation of this signal by the European Medicines Agency (EMA) led to this risk being included in the drugs paper in 2011 ".

According to a pharmaco-epidemiological survey conducted by the health insurance company in collaboration with the department of neurosurgery of Lariboisière, the risk of meningiomas is multiplied by 7 for women treated with high doses over a long period (more than 6 months) and by 20 after 5 years of treatment. There is indeed a strong relationship between dose and effect, the risk is multiplied by more than 20 after a cumulative dose of 60 g, or about 5 years of treatment by 50 mg / day or 10 days. treatment duration of 25 mg / day (when the treatment is taken 20 days a month).

Figures that can be underestimated explain the Express Dr. Isabelle Yoldjian, head of the endocrinology medicine division at ANSM. "These figures are based on the analysis of the only operated cases, but physicians do not always remove tumors, because they may decrease after stopping treatment and some may also remain unnoticed for a long time." According to the study of health insurance, more than 500 women who took Androcur or one of its generic medicines had an intervention for their opinion between 2007 and 2015.

An anti-androgenally prescribed "off-AMM"

Placed on the market since the 1980s by Bayer laboratories, Androcur (and its generic medicines) has been prescribed an anti-androgen for years to thousands of women (57,000 in 2017, according to health insurance). In the steroid anti-androgens class, cyproterone acetate, the active ingredient of Androcur, is commonly used for the treatment of prostate cancer or hirsutism, an extreme development of hair, at a dose of 50 mg per day. In addition, cyproterone acetate is indicated at a dose of 100 mg per day for the treatment of paraphilies. But that is not his only use.

Because cyproterone acetate blocks the action of testosterone, Androcur and its generic drugs are routinely prescribed to women with rebellious acne, endometriosis or as contraception (especially in cases of hyperandrogenism). However, Androcur has never received the validation of these last three indications from the health authorities (marketing authorization or "SMP"): these are "off-label" regulations; ie not validated, although some scientific publications enable doctors to think that cyproterone acetate is effective there.

A growing scandal

The risks related to the drug have long been known (2008), the doctors already inform the patients, but they can always be blamed for not having done enough, and especially that most prescriptions of the AMM seem to be to be. There are already many voices coming up to ask why Androcur® and its generic drugs were prescribed to patients in the long term for acne "with more or less hair".

Androcur has undergone special monitoring by the EMA since 2009 and the notification of the risk of meningiomas is included on the package leaflet of the medicine, with a contraindication in case of antecedent or presence of a meningioma. In terms of patient information this is considered the minimum! In a study cited by the HAS in 2012 (IMS study), hirsutism and prostate cancer only represented 30% of the recipes when the reimbursement was extended! The numbers may have changed, but it would be nice to get them. Since Androcur® is largely generic, it is difficult for the Bayer laboratory to be considered responsible for the current off-label regulations. Who will that be?

A scandal that follows that of the Diane 35® pill

Finally, cyproterone acetate is the principle that also occurs in the pill Diane 35®, a pill that hit the headlines because of an increased risk of phlebitis and pulmonary embolism or even a stroke.

Studies have shown that the risk of venous thromboembolism is 1.5 to 2 times greater in users of Diane and third and fourth generation pills than in users of combined oral contraceptives (COCs) that contain levonorgestrel. From this point of view, the risk of thromboembolism with Androcur® is clearly indicated in the package leaflet, but some studies and assessments indicate that the thromboembolic risk is lower.

The ANSM established in June "a temporary specialized scientific committee (CSST) that wants to discuss the conditions of use and the prescription of these medicines to limit this risk." New recommendations developed with the relevant scientific societies should be published "at the end of the year" with indications indicating possible over-risk, dose and maximum duration as well as monitoring. In the meantime, "patients and health professionals can report any adverse drug-related adverse event directly on the Ministry's portal site responsible for health": signement-sante.gouv.fr

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