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Mifepristone

Clinical data
Pregnancy category	?
Routes of administration	Oral
ATC code	G03XB01 (WHO)
Legal status
Legal status	US: WARNING ?
Pharmacokinetic data
Bioavailability	69%
Metabolism	hepatic
Elimination half-life	18 hours
Excretion	Fecal: 83%; Renal: 9%
Identifiers
IUPAC name 11β-- 17β-hydroxy-17-(1-propynyl)estra- 4,9-dien-3-one
CAS Number	84371-65-3
PubChem CID	55245
DrugBank	APRD00432
CompTox Dashboard (EPA)	DTXSID5023322
ECHA InfoCard	100.127.911
Chemical and physical data
Formula	C29H35NO2
Molar mass	429.60 g/mol

Mifepristone is a synthetic steroid compound used as a pharmaceutical. It is used as an abortifacient in the first two months of pregnancy, and in smaller doses as an emergency contraceptive. During early trials, it was known as RU-486 after its designation at the Roussel Uclaf company, which designed the drug. The drug was initially made available in France, but other countries then followed suit, often amid controversy. In the United States it is sold by Danco Laboratories under the tradename Mifeprex. (In some countries including the United States and Australia, the drug is still commonly referred to as "RU-486".)

Pharmacology

The drug is composed of a 19-nortestosterone steroid compound, which has anti-progestagenic and anti-glucocorticoid effects, meaning it counters the effects of progesterone and glucocorticoid on the body. This synthetic compound is related to the naturally occurring anabolic steroid, nandrolone.

During early pregnancy, the endometrium is dependent upon progestagenic support from the corpus luteum. Mifepristone acts as a competitive inhibitor at progesterone receptors, by decreasing progesterone and increasing estrogen. Because progesterone receptors are found primarily in reproductive organs, mifepristone exerts its principal effect on the uterus: the endometrium and decidua. This leads to degeneration and shedding of the endometrial lining. In addition, mifepristone sensitises the myometrium to the contraction-inducing activity of prostaglandins. It is also an inhibitor of glucocorticoid action and has weak effects at the androgen receptor.

Chemical description

Mifepristone is a light yellow powder, highly soluble in methanol and only poorly soluble in water. Its structural name is 11β--17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one and has empirical formula of C₂₉H₃₅NO₂.

Gynaecological Uses

Mifeprex is sold by Danco Laboratories, made in China, and is FDA-approved to terminate pregnancy up to 49 days after the beginning of the latest menstrual cycle. Under the approved regimen, a 600 mg dose is administered by a clinician proceeding a counseling session about the pocedure. Two days later a clinician administers 400 mg of another medicine, Misoprostol, to induce contractions, and pregnancy is terminated in about 92% of cases. 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. There is no required observation period in the US, 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. As of 2000 the smallest dose available in the US was 200 mg. 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 mifepristone changes the steroid receptor expression in the fallopian tube, inhibits endometrial development, and effectively prevents implantation.

Other possible uses

Preliminary research has indicated that mifepristone may have value for a number of medical uses, including the treatment of androgen-independent prostate cancer, one cell line of gastric cancer, one cell line of ovarian cancer, and the psychotic aspect of psychotic major depression by bonding to glutocorticoid receptors in the brain. (but not the depression aspect. It may also have some use as a treatment for refractory Cushing's syndrome, or temporary treatment prior to surgery for Cushing's syndrome, but it is not considered promising as first-line treatment. Phase II clinical trials have begun to evaluate mifepristone as a treatment for steroid-associated intraocular pressure (IOP). Mifepristone has not completed clinical trials for any of these uses, or been approved by the FDA. Corlux--the brand name of mifepristone used by the company Corcept--recently performed the same as placebo in a phase III clinical trial for the psychotic aspect of psychotic major depression.

Side effects and contraindications

In clinical trials, all women using mifepristone experienced abdominal pain/uterine cramping, and vaginal bleeding or spotting for an average of nine to 16 days. Up to 8% of all subjects experienced some type of bleeding for 30 days or more. Some women experienced nausea, vomiting, diarrhea, dizziness, fatigue, and fever. Pelvic inflammatory disease (PID) is a very rare but serious complication. Excessive bleeding and incomplete termination of a pregnancy require further intervention by a doctor (such as vacuum aspiration). Between 4.5 and 7.9% of women required surgical intervention in clinical trials. All abortion carries the rare risk of sepsis, septic shock or death.

Mifepristone is contraindicated in ectopic pregnancy, adrenal failure, hemorrhagic disorders, anticoagulant or corticosteroid therapy.

The FDA-approved Mifeprex prescribing label states that "There are no data on the safety and efficacy of mifepristone in women with chronic medical conditions such as cardiovascular, hypertensive, hepatic, respiratory or renal disease; insulin-dependent diabetes mellitus; severe anemia or heavy smoking. 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."

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No long-term studies to evaluate the carcinogenic potential of mifepristone have been performed. Results from studies conducted in vitro and in animals have revealed no genotoxic potential for mifepristone. Genotoxicity is not the only initiator of carcinogenesis. A preliminary study in mice indicates that a single dose of mifepristone may increase the risk of hepatic cancer.

In rats, the lowest oral dose of mifespristone caused severe disruption of the estrus cycles for the three weeks of the treatment period, and the onset of puberty was observed to be slightly premature in female rats neonatally exposed to mifepristone. In a separate study in rats, oviduct and ovary malformations in female rats, delayed male puberty, deficient male sexual behavior, reduced testicular size, and lowered ejaculation frequency were noted after exposure to mifepristone.

Teratology studies in mice, rats and rabbits revealed teratogenicty for mice and rats, but not rabbits. 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.

History

The compound was discovered by researchers at Roussel Uclaf of France in 1980 (the "RU" in RU-486) while they were studying glucocorticoid receptor antagonists. Clinical testing began in 1982. The drug was first licensed in France in 1988, for use in combination with prostaglandin, under the name Mifegyne. After license approval but before market release, Roussel Uclaf announced it would abandon distribution of the drug, but bowed to pressure from the government of France (which owned one third of the patent rights) two days later to resume distribution. In early 1990, an international group of scientists and doctors based at the Necker Hospital in Paris reviewed the data of 30,000 women who had used RU 486 and issued a stern warning against it. They urged the Ministry of Health ‘to enforce what was inevitable: the immediate suppression of the distribution and use of RU 486.' The French government did not ban it, but did issue stricter guidelines for its use. (Klein et al)

Roussel Uclaf did not seek U.S. approval, so US availability was not an initial possibility. The first Bush administration banned importation of Mifepristone for personal use in 1989, a decision supported by Roussel Uclaf. This ban was not reversed until 1993, by President Clinton. 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 US clinical trials , but did not submit them to the FDA--they submitted the French clinical trial data instead. 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 by the FDA in September 2000. It is legal and available in all 50 states, Washington DC, Guam and Puerto Rico. In 2000 it accounted for %1 of all abortions, and this number increased to %5.2 in 2002, but data is limited.

Subsection H

Some drugs are approved by the FDA under sub-section H, which has two sub-parts. 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 sub-section 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 sub-section 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.

Comparison with surgical abortion

Surgical abortions can be completed in one visit to a clinic (approx 10 minutes); mifepristone abortions take between 3 and 30 days and involve between 2 and 4 visits to a clinician, though most of the abortion is completed at home. Surgical abortions are 99% effective, compared with the 92% efficacy of mifepristone abortions. The risk of death is higher with mifepristone than with surgical abortion.

Controversy

Many pro-life groups in the US 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, including death. The proposed "RU-486 Suspension and Review Act," also known as Holly's Law, was initiated by a citizen's petition to the FDA from Holly's father, and the May 17, 2006 House Subcommittee on Criminal Justice, Drug Policy and Human Resources hearing entitled "RU-486 - Demonstrating a Low Standard for Women’s Health?” - called by its pro-life chairman Rep. Mark Souder - are the principal results of this effort. Religious and pro-life groups outside the US have also protested mifepristone, especially in Germany and Australia.

A small but vocal group of female scientists from the Massachusetts Institute of Technology's Institute on Women and Technology issued a report under the name of "Feminist International Network of Resistance to Reproductive and Genetic Engineering" in the early 90s to express their opposition to mifepristone, because "We felt what was being lost in the political debate was how the drug affects women. In contrast with the groups who are anti-feminist and anti-abortion, the Institute on Women and Technology advocates women's rights to abortion and self determination," said Dr. Janice Raymond of FINRRAGE. Additional feminist critics exist, such as Pauline Connor (LI.B.) of Feminists Against Eugenics in England who stated, "What has been presented as a simple, pill-popping exercise is, in fact, an intensely medicalized and painful procedure which can involve up to four clinic visits and last 12 days."

Fatalities

Since FDA approval in 2000, eight women in the US, two women in the UK, one woman in Sweden, and one in Canada have died following mifepristone abortions. As a result of these deaths, two US Senators introduced legislation calling for an immediate ban on the sale of Mifeprex, pending FDA review. According to a House Subcommittee on Criminal Justice, Drug Policy and Human Resources document, the number of patient fatalities in the US related to mifepristone abortions is estimated at 1.39 in 100,000, almost fourteen times the rate for suction-aspiration abortions of comparable terms (8 weeks gestation). According to the New York Times, the risk is "a bit more than 1 in 100,000," and "some deaths may have gone unreported, meaning the real risk may be even higher."

Recently, the FDA has released information about the deaths of five American women who had mifepristone abortions. The deaths all occurred after intravaginal administration of the second medication, misoprostol, which is only FDA approved for oral use. Some medical abortion providers in the US have since stopped prescribing intravaginal placement of misoprostol. Off-label intra-vaginal use of misoprostol has been shown to be effective in published studies, but not in clinical trials. The FDA has not reviewed the safety of off-label intravaginal misoprostol, and cannot do so unless the manufacturer submits data from clinical trials and requests a review. One of the reported deaths occurred due to the rupturing of an undiagnosed ectopic pregnancy. Termination of ectopic pregnancies using mifepristone is contraindicated but can sometimes be difficult to detect, even by ultrasound. There have been 27 reported cases of accidental use of mifepristone during ectopic pregnancy. The FDA has concluded that there is no established causal link between the deaths and mifepristone, but also states that they "do not know whether using Mifeprex or misoprostol caused these deaths." An American microbiologist who first linked tampons to fatal toxic shock syndrome said vaginal administration of misoprostol should be prohibited because it can increase infection risk. "That may, in and of itself, eliminate the problem," said Philip M. Tierno, director of clinical microbiology and immunology at New York University Medical Center.

On May 11, 2006, experts from the FDA, the CDC, and the NIH gathered in Atlanta, Georgia for a meeting regarding cloistridal disease, partly in response to the five confirmed deaths resulting from bacterial infection. While the five deaths were verified as being linked to Clostridium sordellii infection, the cause of the infection is still unknown. While clostridium is a normal flora inhabitant of the vagina in 5-10% of women (a percentage which increases with pregnancy) clostridium infections are extremely rare, and have occurred not just with Mifeprex, but also after normal postpartum delivery, although in a fewer relative number of cases.

Dr. Ralph Miech, associate professor emeritus of molecular pharmacology, physiology and biotechnology at Brown University, has asserted that mifepristone is immunosuppressive, and that impairment of the body's natural immunity allows the endometrial spread of C. sordellii infection. Dr. Lisa Rarick, obstetrician/gynecologist and former FDA official, testifying at the House subcommittee hearing, contradicted this theory by observing that "immune suppression-associated infection would not appear as reports of infections of only one organism." But Dr. Renate Klein, biologist, associate professor of women's studies at Deakin University, member of FINRRAGE, and author of several books on reproductive technology, and Dr. Lynette Dumble, a medical scientist who spent 27 years in the surgery department of Royal Melbourne Hospital, affirm the immunosuppressive capability of the chemical abortion regimen: "We are unaware of any studies which assure healthy women that RU 486 and PG, taken together, does not weaken immune defence against malignancy and infection. Synthetic PG (prostaglandin) analogues, in microgram amounts, induce sufficient immune suppression in animals to delay the rejection of experimental, heart and kidney transplants. Until proven otherwise, women's exposure to synthetic PG during abortion procedures can be regarded as an immune insult." They also note, "Proponents of PGs in pregnancy-related procedures claim that a single exposure to a 'small dose of prostaglandin' has no effect on the immune system, but Di Francesco et al, (1990) have reported that isolated immune insults are more harmful than those of a chronic nature (as practised in transplantation)." Dr. Miech has also stated, as a panel expert at the "Emerging Cloistridal Disease Workshop," that "the hypothesis that mifepristone could facilitate infection and lead to lethal septic shock is supported by animal experimentation," and Dr. Esther Sternberg of the NIH, fellow panel expert, has reported both that even endotoxin-nonresponsive mice can be made endotoxin sensitive by mifepristone, and that mifepristone enhances the severity and lethality of bacterial and viral infections, by suppressing the immune response of the hypothalamic-pituitary-adrenal axis. In addition to the studies cited by Sternberg, a 1992 study of female rats treated with mifepristone found that some developed lethal bacterial infections.

Dr. Marc Fischer, CDC medical epidemiologist, states that because vaginal flora constantly vary according to many factors, "the apparent association between C. sordellii toxic shock syndrome and gynecologic infections may be attributed to a rare confluence of events." They also note that pregnancy, childbirth, or abortion "may predispose a small number of women to acquire C. sordellii in the vaginal tract, with dilation of the cervix allowing for ascending infection of necrotic decidual tissue."

Misoprostol not only dilates the cervix, but also softens it. It can also cause uterine ruptures. It is not approved by the FDA for uses other than the prevention and treatment of ulcers, and the FDA has sent out a warning letter regarding the dangers of off-label use of misoprostol to induce labor. Drug combinations, in which one drug is approved and the other is not (such as mifespristone + misoprostol), are sometimes allowed by the FDA.

On July 20, 2005, the FDA updated the black box warning for Mifeprex, to inform patients of the sepsis cases, and to be alert to signs and symptoms, although the symptoms match those caused by mifepristone.

Politics and use outside the United States and France

Europe

Mifepristone was approved for use in the United Kingdom and Sweden in 1991, followed by Germany in 1992, Denmark in 1998, and in Austria, Switzerland, Belgium, Spain, Finland, Greece, Luxembourg, and the Netherlands in 1999. It is not a popular method in the Netherlands. In 2000, it was approved in Norway. Serbia and Montenegro approved it in 2001, Latvia in 2002, Estonia in 2003, Moldova in 2004, and Albania in 2005. In Sweden and the UK, mifepristone is used with gemeprost instead of misoprostol. More than 620,000 women in Europe have had medical abortions using a mifepristone regimen. European women prefer surgical abortion over chemical abortion. In two UK countries--England and Wales-- about 8% of all early abortions are chemical instead of surgical. In Scotland the percentage is higher--about 50%. Approximately one third of early abortions in Sweden use mifepristone. In Denmark, between 3,000 and 4,000 women per year use mifepristone, and no deaths have been reported. Mifepristone is not approved in Portugal, Ireland, or Poland. Clinical trials were stopped in Italy after a woman bled severely. It was approved in Hungary in 2005, but has not been released on the market yet, and is the target of protests.

Australia and New Zealand

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 available in Australia. 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.

Israel

Mifepristone was approved in Israel in 1999.

Asia

Mifepristone was approved in China in 1992, but was not widely used until 1998. It is legally available only with medical supervision--not by prescription. An over-the-counter black market exists, and dangerous health complications from medically unsupervised use are of concern to Chinese physicians. In 2001, mifepristone was approved in Taiwan. Vietnam included mifepristone in the National Reproductive Health program in 2002.

Africa

Mifepristone is approved in only one subsaharan African country--South Africa, where it was approved in 2001. It is also approved in one north African country--Tunisia, also in 2001.

India

Mifepristone was approved for use in India in 2002, where chemical abortion is referred to as "Medical Termination of Pregnancy" (MTP). It is only available under medical supervision, not by prescription, due to adverse reactions such as excessive bleeding, and there are criminal penalties for buying or selling it on the black market or over-the-counter at pharmacies.

Canada

Mifepristone is not available in Canada. Clinical trials were suspended in 2001 after the death of a woman from septic shock caused by clostridium sordelli.

The former Soviet Union

Mifepristone was registered for use in Russia and the Ukraine in 2000, and in Azerbaijan, Georgia, and Uzbekistan in 2002.

South America, Central America, and Mexico

Mifepristone is not approved in any South American or Central American countries, or in Mexico.

Cuba

Mifepristone is legal in Cuba.

Notes and references

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See also

External links

• US Food and Drug Administration Mifeprex (mifepristone) Information
• Commonly asked questions about RU-486 from the education arm of the National Coalition of Abortion Providers
• RU-486 Research - Current research on RU-486 from the primary literature.
• A comprehensive listing of offices offering The Abortion Pill - All members of NCAP or NAF, the two main organizations advocating for abortion providers
• Danco prescribing information
• Mifepristone
• Australians for RU-486 - established in Feb 2006 to lobby for passage of bill in Parliament to enable the availability of Mifepristone.
• RU-486 Files - articles and newsclippings on RU-486

• Sex hormones
• Abortifacients
• Antiandrogens
• Antiglucocorticoids