For the third time, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has advised a 4-week single-treatment limitation on use of “high-strength” estradiol creams for treating vaginal atrophy in menopausal women.
As reported by Medscape Medical News in October 2019, the PRAC had then concluded that the use of creams containing 100 μg/g (0.01%) of estradiol should be limited to a single treatment period of up to 4 weeks and the size of the tube limited to 25 grams to prevent overuse.
That decision had confirmed PRAC’s initial 2014 review and recommendation for the 4-week limit, which was partially annulled in March 2019 by the EU Court of Justice on the basis of procedural grounds.
The current re-examination of the October 2019 recommendation had been requested by one of the manufacturers of the high-strength estradiol creams.
The specific products in question are marketed in Austria, Bulgaria, Croatia, Czech Republic, Estonia, Germany, Hungary, Latvia, Lithuania, and Slovakia under the trade names Linoladiol, Linoladiol N, Linoladiol Estradiol, Estradiol Wolff, and Montadiol.
Disconnect With US Recommendations
The October decision had caused confusion among some providers, as reported by Medical Medscape News in November 2019. At the time, an EMA representative clarified that the 4-week limitation does not apply to lower-strength products such as Vagifem tablets (estradiol 10 μg; Novo Nordisk), Estring (estradiol 7.5 μg/day; Pfizer), Imvexxy (estradiol 4 μg and 10 μg; TherapeuticsMD), or other comparable low-dose vaginal estrogen cream formulations.
Nonetheless, the North American Menopause Society (NAMS) has said in a statement that the PRAC recommendation “is not evidence-based” and “fails to recognize that genitourinary syndrome of menopause is a chronic, progressive condition; symptoms do not resolve with time or short-term treatment.”
In the United States, the Food and Drug Administration (FDA) does not impose a 4-week limit on the use of any estradiol cream, including the only PRAC-defined “high-strength” vaginal estradiol cream on the US market, Estrace (estradiol vaginal cream, USP, 0.01%; Allergan).
NAMS has been working with the FDA for several years to remove the boxed warning from all local vaginal estrogen therapies.
Since these products are all authorized at the national level in Europe, 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 responsible for ensuring harmonized safety standards for medicines authorized through national procedures across the European Union, Iceland, Lichtenstein, and Norway.