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

Current status

CMDh final position

Overview

Four-week limit for use of high-strength estradiol creams confirmed

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.

Information for patients

• 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.

Information for healthcare professionals

• 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.

More about the 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.

More about the procedure

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.

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - Four-week limit for use of high-strength estradiol creams confirmed

Reference Number: EMA/48567/2020

Key facts

About this medicine

• Approved name:
  Estradiol-containing (0.01% w/w) medicinal products for topical use
• International non-proprietary name (INN) or common name:
  estradiol
• Associated names:
  • Linoladiol
  • Linoladiol N
  • Linoladiol Estradiol
  • Estradiol Wolff
  • Montadiol
• Class:
  Hormonal

About this procedure

• Current status:
  CMDh final position
• Reference number:
  EMEA/H/A-31/1482
• Type:
  Article 31 referrals

  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.

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  PRAC-CMDh

Key dates and outcomes

• Procedure start date:
  11/04/2019
• PRAC recommendation date:
  16/01/2020
• CMDh position date:
  30/01/2020
• Outcome:
  Risk minimisation measures

All documents

Procedure started

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - Timetable (start of re-examination procedure)

Reference Number: EMA/PRAC/214200/2019 Rev. 2

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - Notification

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - Annex I

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - PRAC list of questions

Reference Number: EMA/PRAC/214199/2019

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - New review of risks with high-strength estradiol-containing creams

Reference Number: EMA/215459/2019

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - PRAC confirms four-week limit for use of high-strength estradiol creams

Reference Number: EMA/20248/2020

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - Four-week limit for use of high-strength estradiol creams

Reference Number: EMA/531250/2019

Position provided by CMDh

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - Annex II

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - PRAC assessment report

AdoptedReference Number: EMA/62697/2020

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - Timetable for the implementation of the CMDh position

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - Annex III

Estradiol-containing (0.01% w/w) medicinal products for topical use Article 31 referral - Four-week limit for use of high-strength estradiol creams confirmed

Reference Number: EMA/48567/2020

Description of documents published

Please note that some of the listed documents apply only to certain procedures.

• Overview - lay-language summary of the stage of the procedure
• Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
• Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
• List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
• Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
• List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
• List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
• Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
• Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
• Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
• Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
• Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
• Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
• Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
• Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

Note that older documents may have different titles.