Mifepristone (Mifeprex)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
On September 28, 2000, the FDA approved the antiprogesterone agent mifepristone for the termination of early pregnancy. The drug, also known as RU 486, was granted "approvable" status by the FDA in 1996 based on French clinical trial results, but soon was embroiled in years of bitter debate at the agency. The approval is coupled with limitations and restrictions on the use of the drug, which are the culmination of years of negotiation. Since the drug was first introduced in France in 1988, more than 620,000 European women have used it to terminate pregnancy. The drug will be distributed by Danco Laboratories LLC, under the trade name Mifeprex. As required by the FDA, the drug will be supplied directly to qualified physicians and will not be available in pharmacies.
Indications
Mifepristone is indicated for the medical termination of intrauterine pregnancy through 49 days’ pregnancy.
Pregnancy is dated from the first day of the last menstrual period.1
Dosage
Three 200 mg tablets (600 mg) are taken in a single oral dose. On the third day, the patient is given two misoprostol tablets (400 m), unless abortion has occurred and been confirmed. Approximately 14 days after the administration of mifepristone, the patient is evaluated to confirm a complete termination of the pregnancy. Mifepristone may be administered in a clinic, medical office, hospital, or under the supervision of a physician able to assess the gestational age of an embryo and diagnose ectopic pregnancies. Physicians must also be able to provide surgical intervention in case of incomplete abortion or severe bleeding as well as access to blood transfusions and resuscitation, if necessary.1
Potential Advantages
Mifepristone/misoprostol is an effective form of medical abortion. For gestational age of 49 days or less, mean rate of complete abortion is between 92-96%.1,2,5 This method of abortion was found to be acceptable to American women. In a survey of women in a large U.S. study who used mifipristone/misoprostol (n = 2121), 95.7% of women would recommend this method to others and 91.2% would choose it again. Of women who had a previous surgical abortion (49.5%), 90% rated mifepristone/misoprostol as more satisfactory (77%) or just as satisfactory (13%).3
Potential Disadvantages
The efficacy of mifepristone decreased with increasing gestational age. In the large U.S. trial (n = 2121), efficacy was 92% in the 49 days or less with a lower 95% confidence interval of 90%. In the 50-56 days group 84% and 80%, and in the 57-63 days group, 77% and 74%, respectively.5 About one-half of the patients reported severe abdominal pain. The average duration of bleeding was 16 days (median 14 days). In 1% of the women, bleeding was heavy enough to require surgical intervention.1 There is a risk of fetal malformation if the treatment fails. In comparison to surgical abortion, failure rates are higher, there were more adverse events (cramping, nausea, vomiting), and higher levels of pain including post-abortion pain (77.1% vs 10.5%).7
Mifepristone is metabolized by cytochrome P450 isoenzyme 3A4. Drugs that inhibit this enzyme (e.g., ketoconazole, itraconazole, erythromycin, and grapefruit juice) may increase levels of mifepristone. On the other hand, drugs that induce metabolic enzymes (e.g., rifampin, phenobarbital, carbamazepine, phenytoin, and St John’s wort) may lower levels of mifepristone.1
Comments
Mifepristone (RU 486) is an antiprogestin derivative of norethindrone. In the presence of progesterone, mifepristone acts as an antagonist. In the absence of progesterone, mifepristone behaves as a partial agonist. The drug induces changes in the endometrium that lead to bleeding within 72 hours.4 These changes are consistent with the withdrawal of progesterone. Many studies have demonstrated the efficacy of mifepristone.1,2,5 In patients with gestation of 49 days or less, efficacy ranged from 92-96%.
These studies were done in healthy patients. Those with renal, respiratory, hepatic, cardiovascular, and thromboembolic diseases were generally excluded. In addition, women who smoked more than 10 cigarettes per day and those older than the age of 35 were also excluded. Mifepristone will not be available in pharmacies but will be distributed by Danco Laboratories LLC directly to physicians who meet the qualifications. These qualifications include having the ability to date pregnancies accurately and to diagnose tubal pregnancies. Surgery must be available should mifepristone fail and access to emergency care must be available. The patients must be given the medication guide that informs the patient about the mechanism of action of the drug, potential risks, and importance of follow-up visits. The patient must also sign an agreement that she has decided to end her pregnancy. The FDA rules are less restrictive than those in Britain and France, where the drug is available only in licensed facilities.6
Clinical Implications
It is estimated that each year in the United States about 700,000 women undergo a surgical abortion that may be early enough for medical abortion. Although the ethical issues surrounding abortion continue to be debated, mifepristone offers an option to a surgical abortion and may make abortion more accessible to some women.
References
1. Mifeprex Product Information. Danco Laboratories, LLC. September 2000.
2. Kahn JG, et al. Contraception 2000;61:29-40.
3. Winikoff B, et al. Arch Fam Med 1998;7(4):360-366.
4. Spitz IM, CW Bardin. N Engl J Med 1993;329(6):404-412.
5. Spitz IM, et al. N Engl J Med 1998;338(18):1241-1247.
6. Gibbs N, et al. Time October 9, 2000;40-49.
7. Mifepristone Medical Review. www.fda.gov/cder/approval/index.htm
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