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New ulipristal treatment not the answer

By Julie Lynch McDonald, Pharm.D. • Craig, Alaska

Despite the abundant availability of sterilization procedures, male and female condoms, spermicides in the form of gels, creams, foams, and films, sponges, cervical caps,diaphragms, copper and hormonal IUDs, a plethora of hormonal contraceptive drug combinations available as tablets, patches, vaginal rings, implants, and injections, and three approved “emergency contraception” tablets, half of all pregnancies in the United States are still unplanned. 

What is the solution? According to the Population Council, it is another contraceptive drug regimen.

This commentary is written to briefly evaluate an article titled, “Vaginal ring delivery of selective progesterone receptor modulators for contraception,” written by Dr. Jeffery T. Jensen of Oregon Health and Science University and published in Contraception1. To provide some background, research is being conducted on the use of a drug called ulipristal—the active agent in ella®—through a ring inserted vaginally to prevent pregnancy by inhibiting ovulation.

This research is being conducted by the Population Council, which was founded in 1952 with the stated mission of helping “achieve a humane, equitable, sustainable balance between people and resources.”

Ulipristal belongs to a group of drugs called Selective Progesterone Receptor Modulators (SPRMs). The first SPRM approved for use in the United States was mifepristone, which is commonly known as “the abortion pill.” Mifepristone is effective at terminating implanted, growing pregnancies due to its ability to block progesterone, an essential hormone for pregnancy. Blocking of progesterone by mifepristone results in fetal detachment from the placenta, which is followed by vaginal expulsion of the fetus.

SPRMs such as ulipristal and mifepristone can both suppress ovulation as well as terminate implanted pregnancies. The manner in which they act depends primary on the timing of administration (when it is taken within a woman’s cycle), and potentially the serum concentration (amount of drug in the body).

Upon review of Dr. Jensen’s article, there are two primary concerns. First, women will be given a drug marketed to prevent contraception that also possesses an established capability to terminate implanted pregnancies. Second, SPRMs such as ulipristal have questionable safety for women, especially with long-term use. Both concerns will be briefly discussed in the following paragraphs under the topic headings, “Risk to Pregnancies,” and, “Risk to Women.”

Risk to Pregnancies

Dr. Jensen’s article stated that 32% of test patients (25 out of 78 women) still ovulated despite the use of ulipristal vaginal rings. There was no discussion on if pregnancies occurred in the 25 women who ovulated, nor was there a description of the outcomes for these pregnancies if any did occur. The future goal was identified to be a tripling of the dose of ulipristal given to women in order to decrease the percent of women who ovulate to 10%, but this is still a high percentage of women who may become pregnant, especially given the following: Ulipristal is proposed to be given on a daily basis via a vaginal ring inserted for three months. Women who do achieve pregnancy despite use of ulipristal, then, will expose their embryo/fetus for two months to a drug known to be “embryotoxic at low doses.”2

Furthermore, since the absence of menstruation is typical in women using ulipristal vaginal rings, women could be unaware of their pregnancy for months. Therefore, beyond the fetal risk from direct daily exposure to ulipristal, the fetus could also be exposed to risky behavior (including drug and alcohol use), and denied standard prenatal care simply because the mother is unaware of her pregnancy.

None of these concerns were addressed in the article.

Risk to Women

There are two key risks to women posed by use of SPRMs. The first risk is infection, which is increased due to a suppressed immune system and the potential for a deceased fetus, which would serve as a medium for bacterial growth prior to its vaginal expulsion. The second risk is related to changes in the lining of the endometrium, or wall of a woman’s womb.

SPRMs are well-documented to produce antiglucocorticoid effect, which means they suppress the immune system. The Department of Health and Human Services’ Emerging Clostridial Disease Workshop found that mifepristone’s effect on the immune system resulted in the “clinical findings of rapid fulminating lethal shock syndrome” that was neither preventable nor treatable.3 It is established that ulipristal has a “high affinity” for progesterone and glucocorticoid receptors. The concern for ulipristal to have antiglucocorticoid effects was mentioned in the article, but no evaluation of this concern was provided.

Dr. Jensen’s article stated SPRM-associated endometrial effects “were frequently observed,” and were reported in 41% of women using the ulipristal ring. Since the endometrial effects such as endometrial hyperplasia or cancer are dose-dependent, it is reasonable to assume higher concentrations of ulipristal will result in a higher incidence of this adverse effect. Therefore, in the future it can be expected to have a greater risk when the dose is tripled in an effort to increase the percentage of women who will not ovulate. According to the article, a six-month study is being conducted to evaluate the long-term safety of using ulipristal vaginal rings, but this timeframe is unrealistically short.

In conclusion, development of SPRMs has been highly controversial due to their innate ability to terminate implanted pregnancies and the risks they pose to women. Nonetheless, SPRMs have been rushed through the FDA approval process under the subpart H, which is a fast-track reserved for “new drugs to treat serious or life-threatening diseases.”4

The push to develop ulipristal as “contraception” is being completed without evident concern for fetal effects and in an apparent absence of appropriate communication to patients about ulipristal’s ability to terminate implanted pregnancies.

Concern for the risk to women due to ulipristal appears to be secondary to the priority placed on preventing unplanned pregnancies. While a goal of reducing unplanned pregnancies is commendable, realistically, unplanned pregnancies will never be completely eliminated—and maybe they shouldn’t be. When did unplanned pregnancies become equivalent to horrific diseases like cancer or the plague that would be worthy of risking women’s health and exposing fetuses to toxic agents?

As a pharmacist and a woman, I hope the scientific community can begin to take a more proactive approach to solving unplanned pregnancies, rather than continually pushing for chemical solutions that pose an often under-reported and under-studied risk to women and their fetuses.


Sources

1. Jeffrey T. Jensen , “Vaginal ring delivery of selective progesterone receptor modulators for contraception,” Contraception 86 (2012), http://www.contraceptionjournal.org/article/S0010-7824%2812%2900804-9/abstract (accessed March 11, 2013).

2. European Medicines Agency. CHMP Assessment Report for EllaOne. Document reference EMEA/261787/2009.

3. Department of Health and Human Services. Emerging Clostridial Disease Workshop. Summary of Proceedings. May 2006.

4. Code of Federal Regulations. Title 21, Chapter 1, Part 314, Subpart H, “Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses,” Sec. 314.500.