Confusion as EU Advice on Vaginal Estradiol Differs from US

Miriam E. Tucker

November 15, 2019

A recent statement from an EU panel restricting use of "high-strength" estradiol vaginal creams to just 4 weeks has caused some confusion, but also illustrates actual differences between the European and US approaches to regulating the products.

The October 4 statement said that the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) "recommended limiting the use of high-strength creams containing 100 micrograms/gram (0.01%) of estradiol to a single treatment period of up to 4 weeks," as reported by Medscape Medical News.

The advice, which reconfirms a 2014 recommendation, "is intended to minimize the risk of side effects such as blood clots, strokes, and certain types of cancer caused by estradiol absorbed into the bloodstream from creams applied inside the vagina to treat symptoms of vaginal atrophy in women who have been through menopause."  

In response a week later, the North American Menopause Society (NAMS) posted a statement to its members saying that the EMA PRAC recommendation "is not evidence-based."

Moreover, the NAMS statement, authored by NAMS medical director Stephanie S. Faubion, MD, MBA, says the PRAC move "fails to recognize that genitourinary syndrome of menopause (GSM) is a chronic, progressive condition; symptoms do not resolve with time or short-term treatment."

"This warning from the European Medicines Agency is likely to result in women avoiding a safe, effective, and much-needed treatment for this common condition. Untreated GSM can have a devastating effect on vulvovaginal health and women's self-image, quality of life, and intimate relationships," the NAMS adds.

Both organizations acknowledged to Medscape Medical News that the product advice or labeling on vaginal estrogen creams in the respective markets could cause confusion among prescribers and inadvertently lead to less women receiving this medication for GSM.

In the US, all local vaginal estrogen creams have a Food and Drug Administration (FDA) label warning about side effects; Faubion said NAMS is working with the agency to get this removed because NAMS doesn't feel it is needed for locally applied vaginal creams.

Meanwhile, the EMA says it is making clear the distinction between low-dose and high-dose estradiol creams on respective product labels, so that doctors there can clearly distinguish between these two kinds of medications.

EMA Says Recommendation Only Applies to High-Strength Creams

Queried by Medscape Medical News, an EMA representative clarified that the PRAC recommendation applies solely to use of "high-strength creams containing 100 micrograms/gram (0.01% w/w) of estradiol only."

It does not apply to lower-strength products such as Vagifem (Novo Nordisk) tablets [estradiol 10 μg], Estring (Pfizer) [releasing estradiol 7.5 μg/d], Imvexxy (TherapeuticsMD) [estradiol 4 μg and 10 μg], or other comparable low-dose vaginal estrogen cream formulations.

Regarding the high-strength products, the EMA spokesperson said: "EMA's scientific recommendations are fully evidence-based; the evidence considered by EMA's scientific committees is described in the assessment report, which is transparently published on our website."

"NAMS' statement that EMA's 'advice is not evidence based' is therefore strongly refuted," the EMA spokesperson said. "This scientific recommendation is not new and all scientific evidence can be found in the initial review in 2014, where the whole issue was previously discussed."

The EMA representative continued: "Systemic absorption has been demonstrated with these medicinal products…The concentration of estradiol in blood after administration has been shown to be above the normal menopausal range for estradiol with these higher-strength topical products.

"Therefore, a restriction of the duration of use was necessary, to safeguard women's health against side effects due to systemic exposure with estradiol."

The PRAC did take into consideration the chronic nature of the disease, advising that if symptoms persist beyond 4 weeks then alternative therapies should be considered, such as a low-dose topical estradiol. 

"High" Dose vs "Low" Dose Is Artificial Concept With Estradiol Cream

But Faubion, who also directs the Mayo Clinic Center for Women's Health in Rochester, Minnesota, told Medscape Medical News that NAMS doesn't recognize the "high-dose" vs "low-dose" distinction "because it is artificial and driven by the amount one puts in the vagina. You can turn a cream into a 'low dose' by using a smaller amount, which is what the common practice in the US is."

Therefore, she said, "it doesn't make any sense to recommend against the use of a vaginal estrogen product simply because the dose used could be high enough to generate systemic levels.

"This is a matter of prescribing practices and educating patients and clinicians on the dose…needed to manage symptoms, which is often far less than was originally approved and is on the package label."

But even beyond that, Faubion asserts, "There are no data to support any adverse effects related to any vaginal estrogen product designed to treat [vulvovaginal atrophy]/GSM, including estradiol cream, and imposing such a restriction will no doubt lead to fewer women receiving therapy for this already under-recognized and undertreated common condition."

All Vaginal Estradiol Creams in US Carry Boxed Warning

In Europe, the PRAC-defined "high-strength" estradiol cream products are authorized only 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.

In the United States, the only such product on the market that meets the EMA PRAC definition of "high-strength" is Estrace (Allergan; estradiol vaginal cream, USP, 0.01%), for which each gram contains 0.1 mg (100 mcg) estradiol per gram of nonliquifying base, an FDA representative told Medscape Medical News

However, the FDA does not advise a 4-week restriction on use of Estrace or any vaginal cream.

Instead, all such products in the US carry similar warnings and precautions about estrogen use, including boxed warnings about endometrial cancer, cardiovascular disease, and other risks.

The labels state that "Estrogens with and without progestins should be prescribed at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman."

The FDA is currently reviewing the EMA PRAC recommendation, but "at this time, FDA's determination is that the benefits of these products outweigh the risks when used according to approved labeling, even if they increase estrogen levels compared to untreated women."

Difference in EU and US Directives: What Should the Labels Say?

Faubion said that NAMS has been working with FDA for several years to remove the boxed warning from all local vaginal estrogen therapies.

The organization has emphasized several points to support this stance, including the dramatically lower level of blood hormone levels achieved with low-dose vaginal estrogen products compared to standard systemic estrogen therapy; differences in metabolism of oral vs local vaginal products; and "the absence of randomized trial evidence or consistent observational evidence linking low-dose vaginal estrogen to cancer, cardiovascular disease, dementia, or other conditions highlighted in the boxed warning."

Moreover, NAMS contends that the boxed warnings discourage clinicians from prescribing the products, and cause confusion by suggesting that perhaps progestins should be prescribed, when actually, "one of the benefits of low‐dose vaginal products is the lack of a need for concomitant progestins."

The EMA spokesperson said that PRAC acknowledged that the new statement on the 4-week cap for "high-dose" estradiol products might also cause confusion among providers.

"Hence the Committee recommended that the strength of these topical products is marked clearly on the outer package as 100 microgram/g, so the comparison with alternative lower-dose products can be easily made by the prescribing physicians," the EMA representative said.

Faubion has disclosed no relevant financial relationships.

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