Ulipristal Acetate Extends the Emergency Contraception Window

Abstract & Commentary

By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff Professor of Obstetrics and Gynecology, Vice Chair for Research, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: Ulipristal acetate is an effective and well-tolerated agent for emergency contraception given up to 120 hours after unprotected intercourse.

Source: Fine P, et al. Ulipristal acetate taken 48-120 hours after intercourse for emergency contraception. Obstet Gynecol 2010;115:257-263.

In this open-label study, women ages 18 years or older with regular cycles who presented for emergency contraception 48-120 hours after unprotected intercourse at 45 Planned Parenthood clinics throughout the United States were treated with a single oral dose of 30 mg ulipristal acetate. Pregnancy status was determined by high-sensitivity urinary human chorionic gonadotropin testing and return of menses. Of the 1241 women evaluated for efficacy, 26 were found to be pregnant at follow-up, yielding a pregnancy rate of 2.1% (95% confidence interval [CI], 1.4%-3.1%). Significantly, the efficacy did not decrease when dosing occurred after 72 hours: Pregnancy rates were 2.3% (95% CI, 1.4%-3.8%) when given between 48-72 hours, 2.1% (95% CI, 1.0%-4.1%) between 73-96 hours, and 1.3% (95% CI, 0.1%-4.8%) for more than 96-120 hours. The treatment was well tolerated, but did increase cycle length by an average of 2.8 days. The duration of menstrual bleeding did not change.

Synopsis: Ulipristal acetate is at least as effective as levonorgestrel for emergency contraception up to 72 hours after unprotected intercourse and, unlike levonorgestrel, continues to be highly effective up to at least 120 hours.

Source: Glasier AF, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: A randomised non-inferiority trial and meta-analysis. Lancet 2010;375:555-562.

In this randomized, single-blind multicenter, non-inferiority trial, more than 2200 women with regular menstrual cycles who presented to one of 35 family planning clinics located in the United Kingdom, Ireland, and the United States requesting emergency contraception within 5 days of unprotected sexual intercourse received a single supervised oral dose of either 30 mg ulipristal acetate or 1.5 mg levonorgestrel. Follow-up was done 5-7 days after expected onset of next menses. The primary endpoint was pregnancy rate in women who received emergency contraception within 72 hours of unprotected intercourse using a non-inferiority design. Overall, there were 15 pregnancies in the ulipristal acetate group (1.8%; 95% CI, 1.0%-3.0%) and 22 in the levonorgestrel group (2.6%; 95% CI, 1.7%-3.9%), with an odds ratio (OR) of 0.68 (95% CI, 0.35-1.31). In 203 women who received emergency contraception between 72 and 120 hours after sexual intercourse, there were 3 pregnancies, all of which were in the levonorgestrel group.


These two papers report the results with ulipristal acetate 30 mg as a single-dose agent for emergency contraception. This dose was recently approved (May 2009) by European regulatory authorities as an emergency contraceptive pill, and is marketed under the brand name EllaOne ™ (HRA Pharma). Ulipristal acetate, also known as CDB-2914, is a progesterone receptor antagonist that is derived from 19-norproge-sterone. It was developed for use in a variety of gynecologic applications including treatment of uterine fibroids, endometriosis, heavy or prolonged uterine bleeding, and cancer. It has also been tested as a daily contraceptive. Much of the early development and testing was done through the National Institutes of Health. In vitro and in vivo comparisons indicate that the progesterone antagonist activity of CDB-2914 is similar to that of mifepristone, but CDB-2914 exhibits lower antiglucocorticoid activity.1 It is important to point out that ulipristal has never been tested as an abortifacient.

In a 2006 study, Creinin and the other investigators in the NICHD-funded Contraceptive Clinical Trials Network reported the first results comparing the efficacy and adverse effects of CDB-2914 to levonorgestrel for emergency contraception. In this randomized, double-blind non-inferiority trial, women seeking emergency contraception within 72 hours of unprotected intercourse received either a single 50 mg dose of CDB-2914 plus a placebo 12 hours later or two doses of 0.75 mg of levonorgestrel taken 12 hours apart (the standard dosing regimen for Plan B at that time). Although fewer pregnancies occurred in the CDB-2914 group (0.9%; 95% CI, 0.2%-1.6%) this was statistically equivalent to the results obtained using levonorgestrel (1.7%; 95% CI, 0.8%-2.6%).2

Now we have two new well-designed studies that provide additional evidence to support the efficacy of ulipristal acetate. There are a few things to point out. First, although the design of the two randomized trials was a non-inferiority analysis, the direction of the effect in both studies suggests that ulipristal may be more effective than levonorgestrel. In fact, the Glasier paper included a secondary meta-analysis that combined the results with the randomized trial by Creinin. The combined analysis provided a sample with sufficient size to show that, compared to levonorgestrel, ulipristal acetate reduced the risk of pregnancy by almost half (OR 0.55; 95% CI, 0.32-0.93) if used within 120 hours of unprotected intercourse, and by almost two-thirds (OR 0.35; 95% CI, 0.11-0.93) if used within 24 hours.

Second, while the effectiveness of levonorgestrel becomes lower when taken more than 72 hours after unprotected intercourse, ulipristal provides protection when taken up to 120 hours after sex. A broader time window should allow for greater use.

The new studies also demonstrated that efficacy was maintained even with a dose reduction from 50 mg to 30 mg. Although side effects are typically mild, significantly more women treated with ulipristal (29%) than levonorgestrel (24%) reported nausea in the Creinin study. In contrast, with a 30 mg dose, the incidence of nausea was 13% in the randomized study by Glasier, and only 9% in the Planned Parenthood study by Fine et al (similar patient population to the Creinin study). While the reported pregnancy rates with the 30 mg dose were slightly higher, they were statistically equivalent to that seen with 50 mg. The lower pregnancy rate with the 50 mg dose is probably an artifact reflective of an overall low pregnancy rate for both treatments in the Creinin study.

The increase in cycle length (about 2-3 days longer) appears to be the same with either dose of ulipristal, and occurs in most users regardless of whether the drug is taken in the follicular or luteal phase. In contrast, women using levonorgestrel emergency contraception typically experience an earlier onset of bleeding if they use the product in the follicular phase of the cycle, and only have a delay in menses if they take levonorgestrel in the luteal phase. Since almost all women who use ulipristal for emergency contraception will experience an increase in cycle length regardless of the timing in the cycle, this is a key counseling point. Any delay in the onset of menstruation in a sexually active woman who does not wish to become pregnant is likely to provoke anxiety. Reassuring your patient that she will be late by 2-3 days after using ulipristal may reduce stress during the wait.

The biggest advantage of ulipristal will be the longer window for treatment. Both drugs work by inhibiting ovulation. Although levonorgestrel inhibits ovulation in 83% of menstrual cycles when the follicle measures up to 12-14 mm, it blocks ovulation in only 12% of cycles (placebo 13%) when the follicle reaches 18-20 mm, a size that typically occurs within 48 hours of ovulation.3,4 By contrast, ulipristal acetate prevents ovulation in 60% of cycles when the follicle measures 18-20 mm. Thus, ulipristal can block follicle rupture even when given after the LH surge shortly before an expected ovulation. This explains the greater efficacy and longer treatment window (up to 120 hours) after unprotected intercourse.

When will we see ulipristal acetate in the United States? Ulipristal will likely be a prescription medication, and therefore be more expensive than behind-the-counter levonorgestrel. The fact that women needing emergency contraception will have up to 5 days to obtain ulipristal is a plus, but taking the product as soon as possible after unprotected intercourse should always be advised. Remember, like levonorgestrel, this is still contraception and not an abortifacient. We have no evidence that the drug will prevent pregnancy if taken after ovulation, so the sooner the better. Same goes for FDA approval, the sooner the better please.


  1. Blithe DL, et al. Development of the selective progesterone receptor modulator CDB-2914 for clinical indications. Steroids 2003;68:1013-1017.
  2. Creinin MD, et al. Progesterone receptor modulator for emergency contraception: A randomized controlled trial. Obstet Gynecol 2006;108:1089-1097.
  3. Wilcox AJ, et al. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby. N Engl J Med1995;333:1517-1521.
  4. Croxatto HB, et al. The effects of immediate pre-ovulatory administration of 30 mg ulipristal acetate on follicular rupture. Rome, Italy: 8th Congress of the European Society of Gynecology; Sept. 10-13, 2009.