Progress in Reproductive Health Research |
Comparing the Effectiveness of Different Doses of Mifepristone
Depending on the phase of the cycle when they are administered, antiprogestogens such as mifepristone either block or delay ovulation, or retard endometrial development. The potential of mifepristone for emergency contraception was tested in two randomized clinical trials supported by the Programme. In these studies, a single dose of 600 mg of mifepristone was more effective and induced significantly less nausea and vomiting than the Yuzpe method (Glasier A et al. Mifepristone compared with high-dose estrogen and progestogen for emergency postcoital contraception. New England Journal of Medicine, 1992, 327:1041–1044; Webb AMC et al. Comparison of Yuzpe regimen, danazol, and mifepristone RU 486 in oral postcoital contraception. British Medical Journal, 1992, 305:927–931).
Research on the effects of mifepristone on ovarian and endometrial functions suggested that lower doses than 600 mg also could confer protection against pregnancy when used for emergency contraception. Thus, the Programme supported a randomized, multinational trial to compare the efficacy and side-effects of single doses of 600 mg, 50 mg and 10 mg of mifepristone in emergency contraception when given within 120 hours (5 days) of unprotected sexual intercourse. The results of this study were published recently in The Lancet (1999, 353:697–702).
A total of 11 family planning clinics in six countries (Australia, China, Finland, Georgia, the United Kingdom and the USA) took part in the study and enrolled 1717 women. The subjects were healthy and had regular menstrual cycles. They were randomly assigned to three different treatment groups and advised to abstain from further acts of sexual intercourse until the onset of the next menses.
A total of 21 women were found to be pregnant after treatment, including one woman who on a retrospective pregnancy test was discovered to have been pregnant at the time of treatment. It appeared that six women may have conceived two weeks or more after the act of intercourse that prompted treatment. There were two tubal pregnancies, both in the 50 mg group. The proportions of pregnancies were similar in all three treatment groups. Thus, seven (1.3%) of the 559 women in the 600 mg group became pregnant, as did six (1.1%) of the 560 women in the 50 mg group, and seven (1.2%) of the 565 women in the 10 mg group. When the number of pregnancies that occurred (20) was compared to the number that would normally be expected without emergency contraception (136) the treatment can be seen to have prevented 85% of expected pregnancies. The authors note that "lowering the dose of mifepristone from 600 mg to 10 mg did not significantly impair its effectiveness as an emergency contraceptive under normal conditions or with typical use".
In all, 943 women had no further acts of sexual intercourse after treatment. These women had lower pregnancy rates: one (0.3%) of 328 in the 600 mg group became pregnant; three (1.0%) of 308 in the 50 mg group became pregnant; and one (0.3%) of 307 in the 10 mg group also became pregnant.
Delayed menstruation was the most important side-effect. The delay in onset of next menses was significantly (p<0.01) related to the dose of mifepristone and was more likely to occur in the 600 mg group. When women who became pregnant were excluded, 36% of women (196 out of 547) who received treatment with 600 mg of mifepristone experienced a delay of menses of more than seven days. Among those who received treatment with 50 mg of mifepristone, 23% (128 out of 550) experienced delayed menses, as did 18% of women (97 out of 553) who received treatment with 10 mg.
Bleeding within five days of treatment with mifepristone was significantly related to the dose. In all, 15% of women who received 10 mg, 31% of those who received 50 mg, and 35% of those who received 600 mg (p<0·01) had such bleeding. No other differences in side-effects were noted, although the proportion of women with fatigue and weakness increased with the dose (20% with 10 mg, 21% with 50 mg, and 24% with 600 mg). Overall, 17% of women had nausea, 13% experienced headache, 13% had dizziness, and 2% had vomiting.
Two tubal pregnancies occurred in this study, both in the 50 mg group. No information is available about the possible influence of antiprogestogens on tubal transport of fertilized eggs in women though if a woman already has a tubal pregnancy, mifepristone does not disturb it. The two women in the study with tubal pregnancies did not have any known risk factors for tubal pregnancy. The authors point out that the proportion of extrauterine pregnancies observed in the study—two (1·5%) out of 136 expected pregnancies—is in accordance with the incidence reported in a recent review of ectopic pregnancy.
The results of this study have several practical implications. A lower dose of mifepristone would be substantially cheaper than the 600 mg dose used in the two initial single-centre studies. Although it would be effective and better tolerated than the Yuzpe regimen, a dose of 600 mg of mifepristone would be too expensive as an emergency contraceptive. After lower doses, women are less likely to have a delay in the onset of the next menses, as shown in this study. A delay of this kind adds to worry about unintended pregnancy. Because mifepristone blocks or delays ovulation when administered during the preovulatory phase of the cycle, ovulation occurs later than anticipated and women who have further acts of unprotected intercourse are at risk of getting pregnant. Delayed ovulation probably occurred most often in the 600 mg group as the delay of menses was most common in this group.
The results also imply indirectly that the 10 mg dose of mifepristone may have advantages over the Yuzpe regimen, although no studies have directly compared these two methods. The Programme had planned to carry out such a study but, because the Programme's multicentre study comparing the Yuzpe regimen with the levonorgestrel-only method (see above) showed the major advantages of levonorgestrel in emergency contraception, the Scientific Review Committee recommended in November 1997 that future comparative studies should be carried out with levonorgestrel rather than with the Yuzpe regimen.
The authors comment: "Since mifepristone seems to be an effective emergency contraceptive at doses much lower than those required to induce abortion, it may prove valuable in preventing unwanted pregnancies and recourse to abortion. Whether mifepristone is a better choice than levonorgestrel awaits the results of a randomized comparison of these two regimens."
The Programme is participating in a technical capacity in a collaborative initiative in China, aimed at developing mifepristone for indications to reduce unwanted pregnancies and recourse to abortion. This work will, among otherthings, develop China-produced mifepristone for emergency contraception. Under this initiative, a large randomized double-blind study involving 10 centres is under way in China to compare the efficacy and side-effects of the 10 mg and 25 mg doses of Chinese mifepristone. The study protocol and the forms for data collection have been developed by the Programme in collaboration with the National Research Institute for Family Planning, Beijing. A total of 3000 women will be recruited for this study.
Levonorgestrel or mifepristone: which is best?
Which is the best choice for emergency contraception: levonorgestrel or mifepristone? The treatment regimen of levonorgestrel that has been used so far has one disadvantage—the drug needs to be taken in two doses 12 hours apart. Obviously it would be more practical if these two doses could be administered at the same time. The Programme is currently carrying out a large multinational randomized double-blind study to compare the efficacy and side-effects of 10 mg of mifepristone and two treatments of levonorgestrel (i.e. two doses of 0.75 mg administered with a 12-hour interval, or one single dose of 1.5 mg) in emergency contraception up to 120 hours after unprotected intercourse. The study began in mid-1998 and is being carried out in 15 centres. The target is to recruit a total of 4200 women. The clinical phase is expected to be completed by early 2000.