Estradiol-containing (0.01% w/w) medicinal products for topical use

• High-strength estradiol creams (100 micrograms/gram) applied inside the vagina should only be used for a single treatment period of a maximum of 4 weeks. This is because the hormone estradiol in these creams can be absorbed into the bloodstream and may increase the risk of side effects.
• Do not use high-strength estradiol cream if you are already taking another HRT (hormone replacement therapy) medicine.
• If you have any questions about your treatment, talk to your doctor or pharmacist.

• High-strength estradiol creams (100 micrograms/gram) should not be prescribed for longer than a single treatment period of 4 weeks due to the risks associated with systemic exposure to estradiol.
• Pharmacokinetic data on high-strength estradiol creams for intravaginal use show systemic exposure to estradiol, with levels higher than the normal postmenopausal range (up to five times above the upper limit of the reference postmenopausal estradiol serum levels of 10–20 pg/ml).
• Systemic exposure to estradiol could be associated with side effects similar to those of oral and transdermal HRT products such as endometrial hyperplasia/carcinoma, breast and ovarian cancer and thromboembolic events.
• High-strength estradiol creams should not be prescribed with other HRT medicines.

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.