Cyproterone acetate and meningiomas

Cyproterone acetate (Androcur®, Bayer Schering Pharma and Procur®, Douglas Pharmaceuticals) is an antiandrogen that is indicated for the treatment of inoperable carcinoma of the prostate and the reduction of sexual drive in men. It is also indicated in women with severe signs of androgenization. Cyproterone acetate is available as 50mg and 100mg tablets. It is also found in smaller quantities, 2mg, in combined oral contraceptives Estelle-35®, Diane-35® and 1mg, Climen 28®.

Meningioma Cases

Since the launch of cyproterone acetate mono-preparations in 1972, Bayer Schering Pharma has received 24 reports (20 females, four males) of meningiomas suspected to be associated with Androcur® either used singly or in combination with estrogens. In nine of the 24 patients, multiple meningiomas were present at the time of the first meningioma diagnosis (seven females and two males). All the cases were associated with high doses of cyproterone acetate, ranging from 25mg to100mg daily and after long treatment periods of four to 24 years. Nineteen of these post-marketing cases originated from France.

Case Studies

A recently published literature abstract by Froelich et al¹reported nine case studies of female patients, aged between 33 to 62 years old, who presented with multiple meningiomas after receiving daily cyproterone acetate treatments for durations of between ten to 20 years. The nine case studies highlighted by Frolich were not included in Bayer Schering Pharma's existing database of cases.

All 9 female patients did not present with any clinical evidence of neurofibromatosis. Dose details were available for five of the nine female patients reported in the case studies. These five female patients were on high doses of cyproterone acetate, ranging from 25 to 100mg daily taken for 11 to 21 days of the menstrual cycle. The cyproterone acetate doses were given concomitantly with transdermal/transoral oestrogens for a prolonged time period, ranging from nine to 17 years.

Rapid onset of clinical symptoms was observed in six out of the nine patients, of which five of them experienced rapid decrease in visual acuity. Lesions were preferentially located at the base of the skull. Cyproterone acetate was stopped at the time of diagnosis in two of the nine patients.

Six of the nine patients were followed radiologically for a period between eight to 81 months before treatment withdrawal and significant increase in tumour size and/or the development of new lesions were observed in all the cases. A follow up of five to 32 months was initiated after treatment withdrawal and no clinical or radiological progression was observed.

Pharmacoepidemiological Study

A retrospective cohort study with nested case-control analysis will be performed by Bayer Schering Pharma® using data from The Health Improvement Network database (THIN) in the UK, to further investigate the association between cyproterone acetate and meningioma. Major study objectives will be to estimate the incidence of meningioma in the general population and among users of cyproterone acetate and to examine whether there is a dose-response relation and a duration-response relation between use of cyproterone acetate and meningioma. The study will start in 2009 and first results are expected in 2010.

Conclusion

To date, HSA has not received any local adverse drug reaction of meningiomas associated with the use of cyproterone acetate. However, healthcare professionals should take into consideration the above safety information when prescribing high dosages of cyproterone acetate to their patients. HSA will be working with the drug companies to update the prescribing information in the package inserts.

References

1. Endocrine Abstracts (2008) 16P158