Estradiol-containing (0.01% w/w) medicinal products for topical use - referral
Current status
Referral
Human
On 16 January 2020, EMA’s safety committee (PRAC) confirmed its recommendation to limit the use of high-strength creams containing 100 micrograms/gram (0.01%) of estradiol to a single treatment period of up to 4‑weeks. This followed a re-examination of its recommendation of October 2019 which was requested by one of the companies that market high-strength estradiol cream.
The PRAC reviewed available data on the safety and effectiveness of high-strength estradiol-containing creams used to treat symptoms of vaginal atrophy in women who have been through menopause. Data on these creams show that in postmenopausal women who use them, the levels of estradiol in the blood were higher than normal postmenopausal levels. The PRAC concluded that absorption of estradiol into the bloodstream is of concern and could result in similar side effects to those seen with hormone replacement therapy (HRT). The side effects of HRT taken orally or used transdermally (as patches) include venous thromboembolism (formation of blood clots in the veins), stroke, endometrial cancer (cancer of the lining of the womb) and breast cancer. In addition, there are limited safety data on long term use of high-strength estradiol creams. For these reasons, the PRAC recommended that these creams should only be used for a single treatment period of a maximum of 4 weeks.
The PRAC recommended that the prescribing information for these creams be updated with the new recommendations. A warning that the medicine is to be used for a single treatment period of up to 4 weeks only will be placed on the outer and inner packaging and the size of the tube will be limited to 25 grams to prevent use for longer than recommended.
The PRAC recommendations were adopted by the CMDh by consensus and will be implemented directly at national level.
The estradiol-containing creams covered by this review contain 100 micrograms of estradiol per gram of cream.
They are a type of topical hormone replacement therapy: they contain the female hormone estradiol, used to replace natural estradiol, which declines in the body after menopause. These high-strength estradiol creams have been authorised in the EU for a number of years to treat symptoms of vaginal atrophy in postmenopausal women. They are marketed in Austria, Bulgaria, Croatia, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania and Slovakia under the following trade names: Linoladiol, Linoladiol N, Linoladiol Estradiol, Estradiol Wolff and Montadiol.
The review of high-strength estradiol-containing creams (0.01%) was initiated on 11 April 2019 at the request of the European Commission, under Article 31 of Directive 2001/83/EC.
In 2014, EMA had completed a review of the risk of systemic absorption with high-strength estradiol creams and recommended measures to minimise it, including limiting the use of the creams for up to 4 weeks. However, in March 2019 the Court of Justice of the European Union partially annulled the conclusions of the review on procedural grounds. Although the Court of Justice did not question the scientific conclusions, the partial annulment meant that some of the measures taken to minimise the risk were invalidated.
The review was first carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations. Following a re-examination requested by one of the marketing authorisation holders, the PRAC subsequently confirmed its conclusions.
The PRAC recommendations were sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted them by consensus on 30 January 2020. 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.
The PRAC recommendations will now be implemented by EU Member States, Iceland, Lichtenstein and Norway.
This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.
Description of documents published
Please note that some of the listed documents apply only to certain procedures.
Note that older documents may have different titles.