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Mifepristone
 

Mifepristone is a synthetic steroid with anti-progestagenic and anti-glucocorticoid effects. It is useful in humans as an abortifacient in the first two months of pregnancy, as well as medical treatment for certain endocrine conditions. 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 made by Danco Laboratories under the tradename Mifeprex. (In the United States, at least, the drug is still commonly referred to as "RU-486".)

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. Its empirical formula is C29H35NO2

Pharmacology

During early pregnancy, the endometrium is dependent upon progestagenic support from the corpus luteum. Mifepristone acts as a competitive inhibitor at the progesterone receptor and thus removes this basis for support. In addition, it 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.

Uses

Mifeprex is sold by Danco Laboratories and is approved to terminate pregnancy up to 49 days after the beginning of the latest menstrual cycle. It blocks a hormone required to sustain a pregnancy. When followed two days later by another medicine, Misoprostol, to induce contractions, the pregnancy is terminated.

Other uses include in cases of surgically intractable Cushing's disease or Cushing's syndrome, and other progestagen or glucocorticoid secreting tumours.

It is contraindicated in cases of ectopic pregnancy, adrenal failure, hemorrhagic disorders, anticoagulant or corticosteroid therapy. Side effects include an expected amount of abdominal pain and vaginal bleeding, with the possibility of nausea, vomiting and fever. Incomplete termination of a pregnancy would require further intervention by a doctor (such as vacuum aspiration).

Safety

Since its FDA approval in 2000, six women in the US and one in Canada have died following medical abortions, causing some medical abortion providers to stop using the method of intra-vaginal placement of the second drug, Misoprostol. Two Senators have introduced legislation calling for an immediate ban on the sale of Mifeprex, pending FDA review.

The number of patient fatalities in Mifepristone abortions is estimated at 1 in 200,000, about double the rate for suction-aspiration abortions of comparable terms, and about equal to the combined early and late term fatality rates for vacuum aspiration abortion. Deaths in childbirth are significantly more common in less developed parts of the world. In comparison, less controversial drugs such as Viagra and Claritin cause many more adverse reactions.

Opponents of the drug have claimed that its approval was "fast tracked" under sub-section H in the FDA approval process. However sub-section H actually 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 relevant part of sub-section H applies to drugs that must meet more rigorous standards and are subject to distribution restrictions. Mifepristone was approved under this second part of sub-section H. The result is that women must now receive the drug directly from their doctor; they may not pick it up at a pharmacy.

Recently, the FDA has released information about the deaths of five women who had previously taken Mifepristone. These deaths all occurred after the administration of the second medication, Misoprostol, while completing the off-label dosing regimen consisting of 200 mg of oral mifepristone followed by 800 mcg of intra-vaginally placed Misoprostol. This off-label method of administration of Mifepristone has been shown to be effective in clinical trials and has been shown to have a lower risk of side effects. One of the reported deaths occurred due to the rupturing of an ectopic pregnancy. Termination of ectopic pregnancies using Mifepristone is not recommended by Danco Laboratories, its U.S manufacturer, or by the FDA. The FDA has concluded that there is no established causal link between the deaths and Mifepristone.

On March 17, 2006, the FDA reported two additional deaths following medical abortions. However, on April 10, 2006, the FDA declared one of these deaths unrelated to Mifepristone use. The cause of other death has not yet been confirmed either way.

On May 11, 2006, experts from the FDA, the CDC, and the NIH gathered in Atlanta, Georgia for a meeting regarding Mifepristone's safety, in response to the four 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. There have been 11 other deaths associated with C. sordeillii, but unrelated to mifepristone.

Pro-life activists and physicians sometimes suggest that an abortion will increase the risk of breast cancer and depression in women. These statements have been widely refuted by the National Breast Cancer Coalition, the National Cancer Institute, and the American Psychological Association.

Politics

Many pro-life groups in the US and elsewhere actively campaign for the withdrawal of Mifepristone, citing either ethical issues with abortion or the above-mentioned safety concerns over the drug itself and possible associated deaths. In the US, the proposed Holly's Law is the principle result of this effort. Critics of this law claim that a drug with an identical record for any other purpose would not prompt such action. The issue has now taken on political complexity with both pro-life and pro-choice campaigners involved.

History

The compound was discovered by researchers at Roussel Uclaf of France in 1980 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. Then on October 26 of that year, Roussel Uclaf stated that it would abandon distribution of the drug. It bowed to pressure from the government of France two days later to resume distribution. The use of Mifepristone has caused 500,000 abortions in France in the past two decades.

Mifepristone was approved in a number of other European countries as well. The United Kingdom and Sweden in 1991, followed by Germany in 1992, and most other European countries in 1999.

Early research was difficult, as Roussel Uclaf did not seek U.S. approval. It was further interrupted when the first Bush administration banned the importation of Mifepristone in 1989. This ban was not reversed until 1993. In 1994, Roussel Uclaf gifted the U.S. drug rights to the Population Council and 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, delaying availability again. It was approved by the U.S. Food and Drug Administration (FDA) in September 2000. Since then, it has been used 37,000 times, accounting for 6% of the total number of abortions in the U.S. This percent increased to 29% in 2002.

Usage in Australia and New Zealand

Mifepristone was effectively banned in Australia in 1996 in a compromise by the Howard Government with conservative Independent Senator for Tasmania Brian Harradine to amend the law to require ministerial approval of RU 486 in exchange for his support for the partial sale of the then fully state-owned telecom company Telstra.

In late 2005, a Private Member's Bill co-sponsored by Lyn Allison, Fiona Nash, Claire Moore and Judith Troeth was introduced to the Australian Senate to remove this statutory provision 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 attracted public support from the Democrats, Australian Greens and several individual members of the Labor, Liberal and National parties. Neither the Labor Opposition nor the Coalition parties took a party stand in favour or in opposition of the Bill and allowed for a conscience vote. The Family First Party and Coalition Senators Barnaby Joyce, Bill Heffernan and Ron Boswell signalled their strong opposition. The Health Minister Tony Abbott, a pro-lifer, was targeted by supporters of the Bill.

The Bill passed the Australian Senate on 10 February 2006, causing Minister Abbott to label it a no confidence vote in him and the Government. The Prime Minister disagreed, and indicated that the Senate vote was not a vote of no-confidence in Minister Abbott or government ministers. The Australian House of Representatives has considered the bill, and two amendments proposed during the debate, rejecting the both of them, and passing the bill unamended. The bill will award final-say on the drug's use to the TGA. If approved by the TGA, the availability of the drug may be assisted with listing on the Pharmaceutical Benefits Scheme.

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 the abortion drug was permitted.

Non-abortion usage

Mifepristone has been investigated in the treatment of Cushing's syndrome, endometriosis, and a number of cancers, as well as major depression with psychotic features.

Side effects

Usual: Nausea, vomiting, diarrhea, headache, dizziness, and fatigue may occur.

Rare: Bleeding and cramping are expected during this treatment. Usually, the symptoms mean the drugs are working. However, sometimes a woman can have cramps and bleeding and still be pregnant. Bleeding and spotting may last up to 30 days, and may be greater than a normal, heavy period. In a very few cases, this bleeding will need to be stopped by performing a surgical procedure.

Serious: fever, fainting, vaginal discomfort or itching, unusual vaginal discharge, fast heartbeat, stomach/abdominal pain or tenderness, any other sign of infection. A patient noticing other effects not listed above should contact their doctor or pharmacist.

Notes and references

External links

Abortifacients | Antiandrogens | Antiglucocorticoids

Mifepriston | Mifepriston | Mifépristone | Mifepristone | Mifepriston

 

This article is licensed under the GNU Free Documentation License. It uses material from the "Mifepristone".

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