Mifepristone (or RU-486) is a synthetic steroid compound with both antiprogesterone and antiglucocorticoid properties. The compound is a 19-nor steroid with substitutions at positions C11 and C17 (17 beta-hydroxy-11 beta-[4-dimethylamino phenyl] 17 alpha-[1-propynyl]estra-4,9-dien-3-one), which antagonizes cortisol action competitively at the receptor level.
Mifepristone is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency contraceptive. It is also a powerful glucocorticoid receptor antagonist, and has occasionally been used in refractory Cushing's syndrome (due to ectopic/neoplastic ACTH/cortisol secretion). During early trials, it was known as RU-38486 or simply RU-486, its designation at the Roussel Uclaf company, which designed the drug. The drug was initially made available in France, and other countries then followed—often amid controversy. It is marketed under tradenames Korlym and Mifeprex, according to FDA Orange Book.
Mifepristone was the first antiprogestin to be developed and it has been evaluated extensively for its use as an abortifacient. The original target for the research group was the discovery and development of compounds with antiglucocorticoid properties. These antiglucocorticoid properties are of great interest in the treatment of severe mood disorders and psychosis, although a review of published articles was inconclusive on their efficacy, and considered the use of these drugs in mood disorders at 'proof of concept' stage.  It is on the World Health Organization's List of Essential Medicines.
All methods of first-trimester abortion carry a small risk of failure to terminate the pregnancy. The risk for surgical abortion is around 0.23% and for medical abortion is between 0.1% and 1.4% (depending on the regimen used and the experience of the centre).
Medical abortion using mifepristone plus prostaglandin is the most effective method of abortion at gestations of less than 7 weeks.
Conventional vacuum aspirations below 7 weeks have a higher failure rate than at later gestations. Protocols should include examination of the aspirate for the presence of the gestational sac and/or follow-up serum human chorionic gonadotrophin estimation, to ensure abortion completion.
Early vacuum aspiration using a rigorous protocol (which includes magnification of aspirated material and indications for serum βhCG follow-up) may be used at gestations below 7 weeks, although data suggest the failure rate is higher than for medical abortion.
Medical abortion using mifepristone plus prostaglandin continues to be an appropriate method for women in the 7–9 week gestation band.
Mifepristone is sold outside the United States by Exelgyn Laboratories as Mifegyne, made in France, and is approved for:
Medical termination of intrauterine pregnancies of up to 49 days gestation (up to 63 days gestation in Britain and Sweden)
Softening and dilatation of the cervix prior to mechanical cervical dilatation for pregnancy termination
Use in combination with gemeprost for termination of pregnancies between 13 and 24 weeks gestation
Mifepristone is sold in the United States by Danco Laboratories as Mifeprex, made in China, and is U.S. Food and Drug Administration-approved to terminate intrauterine pregnancies of up to 49 days gestation. Under the FDA-approved regimen, a 600-mg dose is administered by a clinician following a counseling session. Two days later, a clinician administers 400 µg of another medicine, misoprostol, to induce contractions. In European studies, this method terminated 96 to 99% of pregnancies of up to 49 days gestation, but in one large multicenter trial in the United States conducted from September 1994 to September 1995, the efficacy was lower (92%), which the authors of the study suggested may have been due to lack of experience with this method in the United States and/or the design of their study. In Europe and China, an observation period of several hours is required after administration of misoprostol. If expulsion of fetal tissue does not occur during the observation period, surgical abortion is offered. No observation period is required in the United States, but it is strongly recommended.
Mifepristone can also be used in smaller doses as an emergency contraceptive; if taken after sex but before ovulation, it can prevent ovulation and so prevent pregnancy. In this role, a 10-mg dose is not as effective as the 600-mg dose, but has fewer side effects. Mifeprex and Mifegyne are only available in 200-mg tablets.
A review of studies in humans found that the contraceptive effects of the 10-mg dose were probably due mainly to its effects on ovulation, and not inhibition of implantation, but "the knowledge of the mechanism of action remains incomplete". Treatment with 200 mg of mifepristone changes steroid receptor expression in the Fallopian tube, inhibits endometrial development, and effectively prevents implantation.
Mifepristone is approved for use in the United States and the EU for the treatment of Cushing's syndrome via a patented preparation manufactured by Corcept Therapeutics.
The FDA prescribing information states no data are available on the safety and efficacy of mifepristone in women with chronic medical conditions, and "women who are more than 35 years of age and who also smoke 10 or more cigarettes per day should be treated with caution because such patients were generally excluded from clinical trials of mifepristone."
No long-term studies to evaluate the carcinogenic potential of mifepristone have been performed. This is in accord with ICH guidelines, which do not require carcinogencity testing in nongenotoxic drugs intended for administration for fewer than 6 months.
Neonatal exposure to a single large dose of mifepristone in rats was not associated with any reproductive problems, although chronic low-dose exposure of newborn rats to mifepristone was associated with structural and functional reproductive abnormalities.
Teratology studies in mice, rats, and rabbits revealed teratogenicity for rabbits, but not rats or mice. The rate of birth defects in human infants exposed in utero to mifepristone and misoprostol is very low, and may be due to misoprostol alone.
A postmarketing summary found, of about 1.52 million women who had received mifepristone until April 2011 in the United States, 14 were reported to have died after application. Eight of these cases were associated with sepsis; the other six had various causes such as drug abuse and suspected murder. Other incidents reported to the FDA included 612 nonlethal hospitalizations, 339 blood transfusions, 48 severe infections, and 2,207 (0.15%) adverse events altogether.
In women, mifepristone at doses greater or equal to 1 mg/kg antagonizes the endometrial and myometrial effects of progesterone. In humans, an antiglucocorticoid effect of mifepristone is manifested at doses greater or equal to 4.5 mg/kg by a compensatory increase in ACTH and cortisol. In animals, a weak antiandrogenic effect is seen with prolonged administration of very high doses of 10 to 100 mg/kg.
In medical abortion regimens, mifepristone blockade of progesterone receptors directly causes endometrial decidual degeneration, cervical softening and dilatation, release of endogenousprostaglandins, and an increase in the sensitivity of the myometrium to the contractile effects of prostaglandins. Mifepristone-induced decidual breakdown indirectly leads to trophoblast detachment, resulting in decreased syncytiotrophoblast production of hCG, which in turn causes decreased production of progesterone by the corpus luteum (pregnancy is dependent on progesterone production by the corpus luteum through the first 9 weeks of gestation—until placental progesterone production has increased enough to take the place of corpus luteum progesterone production). When followed sequentially by a prostaglandin, mifepristone 200 mg is (100 mg may be, but 50 mg is not) as effective as 600 mg in producing a medical abortion.
'Contragestion' is a term promoted by Étienne-Émile Baulieu in the context of his advocacy of mifepristone, defining it as inclusive of some hypothesized mechanisms of action of some contraceptives and those of mifepristone to induce abortion. Baulieu's definition of a 'contragestive' included any birth control method that could possibly act after fertilization and before nine-weeks gestational age.
Preclinical studies point to the potential neuroprotective actions of mifepristone. It was found to protect rat primary hippocampal neurons, clonal mouse hippocampal cells, and organotypic hippocampal slice cultures against oxidative stress-induced neuronal cell death induced by amyloid beta protein, hydrogen peroxide, and glutamate. This effect was interestingly independent of the presence of glucocorticoid or progesterone receptors. Other studies have also subsequently demonstrated neuroprotective effects of mifepristone. Glucocorticoid receptor antagonists may have useful cognitive-enhancing and possibly antidepressant properties in bipolar disorder.
Mifepristone treatment was associated with a time-limited increase in cortisol awakening response and with a sustained improvement in spatial working memory performance in patients with bipolar depression compared with well-matched healthy controls.[unreliable medical source]
In April 1980, as part of a formal research project at Roussel-Uclaf for the development of glucocorticoid receptor antagonists, chemist Georges Teutsch synthesized mifepristone (RU-38486, the 38,486th compound synthesized by Roussel-Uclaf from 1949 to 1980; shortened to RU-486); which was discovered to also be a progesterone recepto] antagonist. In October 1981, endocrinologist Étienne-Émile Baulieu, a consultant to Roussel-Uclaf, arranged tests of its use for medical abortion in 11 women in Switzerland by gynecologist Walter Herrmann at the University of Geneva's Cantonal Hospital, with successful results announced on April 19, 1982. On October 9, 1987, following worldwide clinical trials in 20,000 women of mifepristone with a prostaglandin analogue (initially sulprostone or gemeprost, later misoprostol) for medical abortion, Roussel-Uclaf sought approval in France for their use for medical abortion, with approval announced on September 23, 1988.
On October 21, 1988, in response to antiabortion protests and concerns of majority (54.5%) owner Hoechst AG of Germany, Roussel-Uclaf’s executives and board of directors voted 16 to 4 to stop distribution of mifepristone, which they announced on October 26, 1988. Two days later, the French government ordered Roussel-Uclaf to distribute mifepristone in the interests of public health. French Health Minister Claude Évin explained: "I could not permit the abortion debate to deprive women of a product that represents medical progress. From the moment Government approval for the drug was granted, RU-486 became the moral property of women, not just the property of a drug company." Following use by 34,000 women in France from April 1988 to February 1990 of mifepristone distributed free of charge, Roussel-Uclaf began selling Mifegyne (mifepristone) to hospitals in France in February 1990 at a price (negotiated with the French government) of $48 per 600-mg dose.
Mifegyne was subsequently approved in Great Britain on July 1, 1991, and in Sweden in September 1992, but until his retirement in late April 1994, Hoechst AG chairman Wolfgang Hilger, a devout Roman Catholic, blocked any further expansion in availability. On May 16, 1994, Roussel-Uclaf announced it was donating without remuneration all rights for medical uses of mifepristone in the United States to the Population Council, which subsequently licensed mifepristone to Danco Laboratories, a new single-product company immune to antiabortion boycotts, which won FDA approval as Mifeprex on September 28, 2000.
On April 8, 1997, after buying the remaining 43.5% of Roussel-Uclaf stock in early 1997, Hoechst AG ($30 billion annual revenue) announced the end of its manufacture and sale of Mifegyne ($3.44 million annual revenue) and the transfer of all rights for medical uses of mifepristone outside of the United States to Exelgyn S.A., a new single-product company immune to antiabortion boycotts, whose CEO was former Roussel-Uclaf CEO Édouard Sakiz. In 1999, Exelgyn won approval of Mifegyne in 11 additional countries, and in 28 more countries over the following decade.
Roussel Uclaf did not seek U.S. approval, so in the United States legal availability was not initially possible. The United States banned importation of mifepristone for personal use in 1989, a decision supported by Roussel Uclaf. In 1994, Roussel Uclaf gave the U.S. drug rights to the Population Council in exchange for immunity from any product liability claims. The Population Council sponsored clinical trials in the United States. The drug went on approvable status from 1996. Production was intended to begin through the Danco Group in 1996, but they withdrew briefly in 1997 due to a corrupt business partner, delaying availability again. Mifepristone was approved for abortion in the United States by the FDA, in September 2000. It is legal and available in all 50 states, Washington, D.C., Guam, and Puerto Rico. It is a prescription drug, but it is not available to the public through pharmacies; its distribution is restricted to specially qualified licensed physicians, sold by Danco Laboratories under the trade name Mifeprex.
Medical abortions voluntarily reported by 33 U.S. states to the CDC have increased as a percentage of total abortions every year since the approval of mifepristone: 1.0% in 2000, 2.9% in 2001, 5.2% in 2002, 7.9% in 2003, 9.3% in 2004, 9.9% in 2005, 10.6% in 2006, and 13.1% in 2007 (20.3% of those at less than 9 weeks gestation). A Guttmacher Institute survey of abortion providers estimated that medical abortions accounted for 17% of all abortions and slightly over 25% of abortions before 9 weeks gestation in the United States in 2008 (94% of nonhospital medical abortions used mifepristone and misoprostol, 6% used methotrexate and misoprostol). Medical abortions accounted for 32% of first trimester abortions at Planned Parenthood clinics in the United States in 2008.
Some drugs are approved by the FDA under subsection H, which has two subparts. The first sets forth ways to rush experimental drugs, such as aggressive HIV and cancer treatments, to market when speedy approval is deemed vital to the health of potential patients. The second part of subsection H applies to drugs that not only must meet restrictions for use due to safety requirements, but also are required to meet postmarketing surveillance to establish that the safety results shown in clinical trials are seconded by use in a much wider population. Mifepristone was approved under the second part of subsection H. The result is that women cannot pick the drug up at a pharmacy, but must now receive it directly from a doctor. Due to the possibility of adverse reactions such as excessive bleeding, which may require a blood transfusion and incomplete abortion, which may require surgical intervention, the drug is only considered safe if a physician who is capable of administering a blood transfusion or a surgical abortion is available to the patient in the event of such emergencies. The approval of mifepristone under subsection H included a black box warning.
Many pro-life groups in the United States actively campaigned against the approval of mifepristone, and continue to actively campaign for its withdrawal. They cite either ethical issues with abortion or safety concerns regarding the drug and the adverse reactions associated with it. Religious and antiabortion groups outside the United States have also protested mifepristone, especially in Germany and Australia.
Outside the United States, it is marketed and distributed by Exelgyn Laboratories under the tradename Mifegyne. Mifepristone was approved for use in France in 1988 (initial marketing in 1989), the United Kingdom in 1991, Sweden in 1992, then Austria, Belgium, Denmark, Finland, Germany, Greece, Luxembourg, the Netherlands, Spain, and Switzerland in 1999. In 2000, it was approved in Norway, Russia and Ukraine. Serbia and Montenegro approved it in 2001, Belarus and Latvia in 2002, Estonia in 2003, Moldova in 2004, Albania and Hungary in 2005, Portugal in 2007, and Romania in 2008. In Italy, clinical trials have been constrained by protocols requiring women be hospitalized for three days, but the drug was finally approved on the July 30, 2009 (officialized later in the year), despite strong opposition from the Vatican. In Italy, the pill must be prescribed and used in a clinical structure and is not sold at chemists. It was approved in Hungary in 2005, but as of 2005 had not been released on the market yet, and was the target of protests. Mifepristone is not approved in Ireland, where abortion is illegal, or Poland, where abortion is highly restricted.
In France, the percentage of medical abortions of all abortions continues to increase: 38% in 2003, 42% in 2004, 44% in 2005, 46% in 2006, 49% in 2007 (vs. 18% in 1996). In England and Wales, 52% of early abortions (less than 9 weeks gestation) in 2009 were medical; the percentage of all abortions that are medical has increased every year for the past 14 years (from 5% in 1995 to 40% in 2009) and has more than doubled in the last five years. In Scotland, 81.2% of early abortions in 2009 were medical (up from 55.8% in 1992 when medical abortion was introduced); the percentage of all abortions that are medical has increased every year for the past 17 years (from 16.4% in 1992 to 69.9% in 2009). In Sweden, 85.6% of early abortions and 73.2% of abortions before the end of the 12th week of gestation in 2009 were medical; 68.2% of all abortions in 2009 were medical. In Great Britain and Sweden, mifepristone is licensed for use with vaginal gemeprost or oral misoprostol. As of 2000, more than 620,000 women in Europe had had medical abortions using a mifepristone regimen. In Denmark, mifepristone was used in between 3,000 and 4,000 of just over 15,000 abortions in 2005.
Mifepristone was banned in Australia in 1996. In late 2005, a Private Member's bill was introduced to the Australian Senate to lift the ban and transfer the power of approval to the Therapeutic Goods Administration. The move caused much debate in the Australian media and amongst politicians. The bill passed the Senate on 10 February 2006, and mifepristone is now legal in Australia. It is provided regularly at several specialized abortion clinics per state.
In New Zealand, pro-choice doctors established an import company, Istar, and submitted a request for approval to MedSafe, the New Zealand pharmaceutical regulatory agency. After a court case brought by Right to Life New Zealand failed, use of mifepristone was permitted.
Clinical trials of mifepristone in China began in 1985. In October 1988, China became the first country in the world to approve mifepristone. Chinese organizations tried to purchase mifepristone from Roussel Uclaf, which refused to sell it to them, so in 1992 China began its own domestic production of mifepristone. In 2000, the cost of medical abortion with mifepristone was higher than surgical abortion and the percentage of medical abortions varied greatly, ranging from 30% to 70% in cities to being almost nonexistent in rural areas. A report from the United States Embassy in Beijing in 2000 said mifepristone had been widely used in Chinese cities for about two years, and that according to press reports, a black market had developed with many women starting to buy it illegally (without a prescription) from private clinics and drugstores for about $15, causing Chinese authorities to worry about medical complications from use without physician supervision.
In 2001, mifepristone was approved in Taiwan. Vietnam included mifepristone in the National Reproductive Health program in 2002.
It is approved in only one sub-Saharan African country—South Africa, where it was approved in 2001. It is also approved in one north African country—Tunisia, also in 2001.
Mifepristone was approved for use in India in 2002, where medical abortion is referred to as "medical termination of pregnancy". It is only available under medical supervision, not by prescription, due to adverse reactions such as excessive bleeding, and criminal penalties are given for buying or selling it on the black market or over-the-counter at pharmacies.
Medical abortion is available in Canada on a limited basis using[methotrexat] and misoprostol; mifepristone is not legally approved, and importation of that drug into Canada is currently illegal. Clinical trials were done in 2000 in various Canadian cities comparing methotrexate to mifepristone, after approbation by the federal government. While both drugs had overall similar results, mifepristone was found to act faster. As of January 2014, it is unclear whether or when RU-486 will be approved for use in Canada.
Mifepristone was registered for use in Azerbaijan, Georgia, and Uzbekistan in 2002, in Guyana and Moldova in 2004, in Mongolia in 2005, and in Armenia in 2007.
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Also contragestant, abortion pill. A substance called mifepristone, or RU-486, which was developed by Dr. Etienne Baulieu and the Roussel-Uclaf company. The contragestive blocks progesterone receptors in the endometrium (uterine lining), preventing its buildup by progesterone; hence the uterus cannot sustain a pregnancy. It does not prevent fertilization or implantation, so technically it is an ABORTIFACIENT rather than a contraceptive.
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