The European Medicines Agency’s (EMA’s) safety committee, the Pharmacovigilance Risk Assessment Committee (PRAC) at its last meeting held from 30 September to 3 October 2019 has recommended limiting the use of high-strength creams containing 100 micrograms/gram (0.01%) of oestradiol to a single treatment period of up to 4 weeks. This measure is intended to minimise the risk of side effects caused by oestradiol absorbed into the bloodstream from creams applied inside the vagina to treat symptoms of vaginal atrophy in women who have been through menopause.
The PRAC has reviewed available data on the safety and effectiveness of high-strength oestradiol-containing creams, including data on the amount of oestradiol in the blood. These data showed that in postmenopausal women who had used these creams, the levels of oestradiol in the blood were higher than normal postmenopausal levels. The PRAC concluded that absorption of oestradiol 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, stroke, endometrial cancer and breast cancer. In the absence of safety data for long-term use of high-strength oestradiol creams, the PRAC recommended that these creams should only be used for a single treatment period of a maximum of 4 weeks.
The prescribing information for these creams will 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.
Information for healthcare professionals state that:
- High-strength oestradiol creams should not be prescribed for longer than a single treatment period of 4 weeks due to the risks associated with systemic exposure to oestradiol.
- Pharmacokinetic data on high-strength oestradiol creams (100 micrograms/gram) for intravaginal use show substantial systemic exposure to oestradiol, with levels higher than the normal postmenopausal range (up to five times above the upper limit of the reference postmenopausal oestradiol serum levels of 10–20 pg/ml).
- Systemic exposure to oestradiol could be associated with side effects similar to those of oral and transdermal HRT products i.e. endometrial hyperplasia/carcinoma, breast and ovarian cancer and thromboembolic events.
- High-strength oestradiol creams should not be prescribed with other HRT medicines.
This review was initiated in April 2019 at the request of the European Commission, following a ruling by the EU Court of Justice that partially annulled the conclusions of a previous PRAC review of these medicines in 2014 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 PRAC recommendations will now be sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) to make a decision about their implementation. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway.