Mifepristone
Encyclopedia
Mifepristone is a synthetic steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...

 compound used as a pharmaceutical
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

. It is a progesterone receptor antagonist used as an abortifacient
Abortifacient
An abortifacient is a substance that induces abortion. Abortifacients for animals that have mated undesirably are known as mismating shots....

 in the first months of pregnancy, and in smaller doses as an emergency contraceptive
Emergency contraception
Emergency contraception , or emergency postcoital contraception, refers to birth control measures that, if taken after sexual intercourse, may prevent pregnancy.Forms of EC include:...

. During early trials, it was known as RU-38486 or simply RU-486, its designation at the Roussel Uclaf
Roussel Uclaf
Roussel Uclaf S.A. was the second largest French pharmaceutical company before it was acquired by Hoechst AG of Frankfurt, Germany in 1997, with pharmaceutical operations combined into the Hoechst Marion Roussel division...

 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 Mifegyne and Mifeprex.

History

In April 1980, as part of a formal research project at Roussel-Uclaf for the development of glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....

 antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

s, 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 receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...

 antagonist.

In October 1981, endocrinologist Étienne-Émile Baulieu
Étienne-Émile Baulieu
Étienne-Émile Baulieu is a French biochemist and endocrinologist who is best known for his research in the field of steroid hormones and their role in reproduction and aging.-Biography:...

, a consultant to Roussel-Uclaf, arranged tests of its use for medical abortion
Medical abortion
A medical abortion is a type of non-surgical abortion in which abortifacient pharmaceutical drugs are used to induce abortion. An oral preparation for medical abortion is commonly referred to as an abortion pill....

 in eleven women in Switzerland
Switzerland
Switzerland name of one of the Swiss cantons. ; ; ; or ), in its full name the Swiss Confederation , is a federal republic consisting of 26 cantons, with Bern as the seat of the federal authorities. The country is situated in Western Europe,Or Central Europe depending on the definition....

 by gynecologist Walter Herrmann at the University of Geneva
University of Geneva
The University of Geneva is a public research university located in Geneva, Switzerland.It was founded in 1559 by John Calvin, as a theological seminary and law school. It remained focused on theology until the 17th century, when it became a center for Enlightenment scholarship. In 1873, it...

'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
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

 analogue (initially sulprostone
Sulprostone
Sulprostone is an oxytocic.It is an analogue of prostaglandin E2....

 or gemeprost
Gemeprost
Gemeprost is an analogue of prostaglandin E1.-Clinical use:It is used as a treatment for obstetric bleeding.It is used with RU486 to terminate pregnancy up to 24 weeks gestation...

, later misoprostol
Misoprostol
Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...

) 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
Claude Évin
Claude Evin is a French politician and lawyer.He was first elected in 1978. Prior to becoming a Member of Parliament, Claude Evin was the deputy mayor of Saint-Nazaire, a post he held until 1989...

 explained that: "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
Great Britain
Great Britain or Britain is an island situated to the northwest of Continental Europe. It is the ninth largest island in the world, and the largest European island, as well as the largest of the British Isles...

 on July 1, 1991, and in Sweden
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....

 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 that it was donating without remuneration all rights for medical uses of mifepristone in the U.S. to the Population Council
Population Council
The Population Council is an international, nonprofit, non-governmental organization. The Council conducts biomedical, social science, and public health research and helps build research capacities in developing countries. One-third of its research relates to HIV and AIDS; its other major program...

, which subsequently licensed mifepristone to Danco Laboratories
Danco Laboratories
Danco Laboratories is an LLC which was incorporated in 1995. Danco has a license from the Population Council to distribute the drug mifepristone, under the brand name Mifeprex. Mifeprex is the only drug distributed by Danco. The offices of Danco are in New York City, and are under an unlisted phone...

, 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 U.S. 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.

Indications

Mifepristone is sold outside the U.S. by Exelgyn Laboratories as Mifegyne, made in France, and is approved for:
  1. Medical termination of intrauterine pregnancies of up to 49 days gestation
    Gestational age
    Gestational age relates to the age of an embryo or fetus . There is some ambiguity in how it is defined:*In embryology, gestational age is the time elapsed since conception. This interval is also termed fertilisation age....

     (up to 63 days gestation in Britain and Sweden)
  2. Softening and dilatation of the cervix prior to mechanical cervical dilatation for pregnancy termination
  3. Use in combination with gemeprost
    Gemeprost
    Gemeprost is an analogue of prostaglandin E1.-Clinical use:It is used as a treatment for obstetric bleeding.It is used with RU486 to terminate pregnancy up to 24 weeks gestation...

     for termination of pregnancies between 13 and 24 weeks gestation
  4. Labor induction in fetal death in utero.

Mifepristone is sold in the U.S. by Danco Laboratories as Mifeprex, made in China, and is U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

-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
Misoprostol
Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...

, 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
Multicenter trial
A multicenter research trial is a clinical trial conducted at more than one medical center or clinic. Most large clinical trials, particularly Phase III trials, are conducted at several clinical research centers...

 in the U.S. 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 U.S. 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. There is no required observation period in the U.S., but it is strongly recommended.

According to the current RCOG
Royal College of Obstetricians and Gynaecologists
The Royal College of Obstetricians and Gynaecologists is a professional association based in the UK. Its members, including people with and without medical degrees, work in the field of obstetrics and gynaecology, that is, pregnancy, childbirth, and female sexual and reproductive health...

 abortion evidence-based
Evidence-based medicine
Evidence-based medicine or evidence-based practice aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments and diagnostic tests...

 clinical guideline:
  • All methods of first-trimester abortion carry a small risk of failure to terminate the pregnancy, thus necessitating a further procedure. The risk for surgical abortion is around 0.23% and for medical abortion 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 aspiration should be avoided at gestations below 7 weeks.
  • Early vacuum aspiration using a rigorous protocol (which includes magnification of aspirated material and indications for serum βhCG
    Human chorionic gonadotropin
    Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...

     follow-up) may be used at gestations below 7 weeks, although data suggest that 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 can also be used in smaller doses as an emergency contraceptive
Emergency contraception
Emergency contraception , or emergency postcoital contraception, refers to birth control measures that, if taken after sexual intercourse, may prevent pregnancy.Forms of EC include:...

; if taken after sex but before ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...

, 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
Fallopian tube
The Fallopian tubes, also known as oviducts, uterine tubes, and salpinges are two very fine tubes lined with ciliated epithelia, leading from the ovaries of female mammals into the uterus, via the utero-tubal junction...

, inhibits endometrial development, and effectively prevents implantation.

Other uses

Other medical applications of mifepristone that have been studied in Phase II clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s include regular long-term use as an oral contraceptive
Oral contraceptive
The combined oral contraceptive pill , often referred to as the birth-control pill or colloquially as "the Pill", is a birth control method that includes a combination of an estrogen and a progestin . When taken by mouth every day, these pills inhibit female fertility...

, and treatment of: uterine fibroids
Uterine fibroids
A uterine fibroid is a benign tumor that originates from the smooth muscle layer and the accompanying connective tissue of the uterus.Fibroids are the most common benign tumors in...

, endometriosis
Endometriosis
Endometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...

, major depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...

 with psychotic features
Psychotic depression
Psychotic major depression is a type of depression that can include symptoms and treatments that are different from those of non-psychotic major depressive disorder . PMD is estimated to affect about 0.4% of the population .PMD is sometimes "mistaken" for NPMD, schizoaffective disorder,...

, glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...

, meningioma
Meningioma
The word meningioma was first used by Harvey Cushing in 1922 to describe a tumor originating from the meninges, the membranous layers surrounding the CNS ....

s, breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

, ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....

, and prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...

. Mifepristone has been used to treat Cushing's syndrome
Cushing's syndrome
Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...

 with treatment durations being as long as 10 years without noticeable adverse effect.
Mifepristone has been studied as an antiretroviral for its in vivo interference with the HIV regulatory protein vpr. It showed no detectable anti-HIV activity in clinical trials.

It is currently being studied as a treatment for chronic multisymptom illness
Gulf War syndrome
Gulf War syndrome or Gulf War illness describes a medical condition that affected veterans and civilians who were near conflicts during or downwind of chemical weapons depot demolition, after the 1991 Gulf War. A wide range of acute and chronic symptoms have included fatigue, musculoskeletal...

. Mifepristone has not been approved by the FDA for any of these uses.

Mifepristone has shown significant effectiveness in psychotic major depression, a form of depression resistant to normal treatment. The effect was rapid and the study was double-blinded, but it was limited by small study group and limited treatment duration.

Use as a cervical ripening agent has also been described.

Contraindications

In clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s, nearly all women using mifepristone experienced abdominal pain, uterine cramping, and vaginal bleeding or spotting for an average of 9–16 days. Up to 8% of women experienced some type of bleeding for 30 days or more. Other less common side effects included nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, vomiting, diarrhea, dizziness, fatigue, and fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

. Pelvic inflammatory disease
Pelvic inflammatory disease
Pelvic inflammatory disease is a generic term for inflammation of the uterus, fallopian tubes, and/or ovaries as it progresses to scar formation with adhesions to nearby tissues and organs. This may lead to infections. PID is a vague term and can refer to viral, fungal, parasitic, though most...

 (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
Suction-aspiration abortion
Vacuum or suction aspiration uses aspiration to remove uterine contents through the cervix. It may be used as a method of induced abortion, a therapeutic procedure used after miscarriage, or a procedure to obtain a sample for endometrial biopsy. The rate of infection is lower than any other...

). Between 4.5 and 7.9% of women required surgical intervention in clinical trials.
Mifepristone is contraindicated
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...

 in the presence of an intrauterine device
Intrauterine device
A copper IUD is a type of intrauterine device. Most IUDs have a plastic T- or U-shaped frame which is wrapped in copper wire, with the exception of Gynefix, which is a plastic string with several copper beads, affixed to the fundus of the uterus...

 (IUD), as well as with ectopic pregnancy
Ectopic pregnancy
An ectopic pregnancy, or eccysis , is a complication of pregnancy in which the embryo implants outside the uterine cavity. With rare exceptions, ectopic pregnancies are not viable. Furthermore, they are dangerous for the parent, since internal haemorrhage is a life threatening complication...

, adrenal
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...

 failure, hemorrhagic
Bleeding
Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...

 disorders, inherited porphyria
Porphyria
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...

, and anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

 or long-term corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...

 therapy.

The FDA prescribing information states that there are no data on the safety and efficacy of mifepristone in women with chronic medical conditions, and that "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."

Adverse effects

No long-term studies to evaluate the carcinogenic potential of mifepristone have been performed. Results from studies conducted in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

 and in animals have revealed no genotoxic
Genotoxic
In genetics, genotoxicity describes a deleterious action on a cell's genetic material affecting its integrity. This includes both certain chemical compounds and certain types of radiation....

 potential for mifepristone.

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
Teratology
Teratology is the study of abnormalities of physiological development. It is often thought of as the study of human birth defects, but it is much broader than that, taking in other non-birth developmental stages, including puberty; and other non-human life forms, including plants.- Etymology :The...

 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
In utero
In utero is a Latin term literally meaning "in the womb". In biology, the phrase describes the state of an embryo or fetus. In legal contexts, the phrase is used to refer to unborn children. Under common law, unborn children are still considered to exist for property transfer purposes.-See also:*...

 to mifepristone and misoprostol is very low, and may be due to misoprostol alone.

A postmarketing summary found that, of about 1.52 million women who had received mifepristone until April 2011 in the US, fourteen were reported to have died after application. Eight of these cases were associated with sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...

; the other six had various causes like drug abuse and suspected murder. Other incidents reported to the FDA included 612 non-lethal hospitalizations, 339 blood transfusions, 48 severe infections, and 2,207 (0.15%) adverse events altogether.

Pharmacology

In the presence of progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...

, mifepristone acts as a competitive
Competitive antagonist
A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor...

 progesterone receptor antagonist (in the absence of progesterone, mifepristone acts as a partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...

). Mifepristone is a 19-nor
Nor-
In chemical nomenclature, nor is a prefix to name a structural analog that can be derived from a parent compound by the removal of one carbon atom along with the accompanying hydrogen. The nor-compound can be derived by demethylation or by removal of a methylenegroup, a CH group or a C atom...

 steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...

 with a bulky p
Para
Para may refer to:*Para Loga, one among the seven Logas in Ayyavazhi mythology*Para-quaternions, expression from algebra in mathematics*Paramedic is a first response ambulance crew member...

-(dimethylamino)phenyl
Phenyl group
In organic chemistry, the phenyl group or phenyl ring is a cyclic group of atoms with the formula C6H5. Phenyl groups are closely related to benzene. Phenyl groups have six carbon atoms bonded together in a hexagonal planar ring, five of which are bonded to individual hydrogen atoms, with the...

 substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...

 above the plane of the molecule at the 11β-position responsible for inducing or stabilizing an inactive receptor
Steroid hormone receptor
Steroid hormone receptors are found on the plasma membrane, in the cytosol and also in the nucleus of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days...

 conformation
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...

 and a hydrophobic 1-propynyl
Propynyl
In chemistry, propynyl is an propyl functional group bearing a triple bond. 2-Propynyl is known as propargyl group with the structure of HC≡C−CH2 and 1-propynyl group has the structure of CH3-C≡C-....

 substituent below the plane of the molecule at the 17α-position that increases its progesterone receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...

 binding affinity
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...

.

In addition to being an antiprogestogen, mifepristone is also an antiglucocorticoid and a weak antiandrogen
Antiandrogen
Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting...

. Mifepristone's relative binding affinity at the progesterone receptor is more than twice that of progesterone, its relative binding affinity at the glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....

 is more than three times that of dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...

 and more than ten times that of cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...

; its relative binding affinity at the androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...

 is less than one third that of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...

. It does not bind to the estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...

 or the mineralocorticoid receptor
Mineralocorticoid receptor
The mineralocorticoid receptor , also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.MR is a receptor with high affinity for mineralocorticoids...

.

Mifepristone as a regular contraceptive at 2 mg daily prevents ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...

 (1 mg daily does not). A single preovulatory
Follicular phase
The follicular phase is the phase of the estrous cycle, during which follicles in the ovary mature. It ends with ovulation. The main hormone controlling this stage is estradiol....

 10 mg dose of mifepristone delays ovulation by 3 to 4 days and is as effective an emergency contraceptive
Emergency contraception
Emergency contraception , or emergency postcoital contraception, refers to birth control measures that, if taken after sexual intercourse, may prevent pregnancy.Forms of EC include:...

 as a single 1.5 mg dose of the progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...

 levonorgestrel
Levonorgestrel
Levonorgestrel is a second generation synthetic progestogen used as an active ingredient in some hormonal contraceptives.-Chemistry:...

.

In women, mifepristone at doses greater or equal to 1 mg/kg antagonizes the endometrial
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...

 and myometrial
Myometrium
The myometrium is the middle layer of the uterine wall, consisting mainly of uterine smooth muscle cells , but also of supporting stromal and vascular tissue...

 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 decidua
Decidua
Decidua is the term for the uterine lining during a pregnancy, which forms the maternal part of the placenta. It is formed under the influence of progesterone and forms highly-characteristic cells.-Etymology:...

l degeneration, cervical
Cervix
The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...

 softening and dilatation, release of endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

 prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

s and an increase in the sensitivity of the myometrium to the contractile effects of prostaglandins. Mifepristone induced decidual breakdown indirectly leads to trophoblast
Trophoblast
Trophoblasts are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg...

 detachment, resulting in decreased syncytiotrophoblast
Syncytiotrophoblast
Syncytiotrophoblast is the epithelial covering of the placenta villous tree. It is a unique tissue in that it is a multi-nucleated, terminally differentiated syncytium, extending to 13m^2...

 production of hCG
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...

, which in turn causes decreased production of progesterone by the corpus luteum
Corpus luteum
The corpus luteum is a temporary endocrine structure in mammals, involved in production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A...

 (pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...

 is dependent on progesterone production by the corpus luteum through the first 9 weeks of gestation
Gestational age
Gestational age relates to the age of an embryo or fetus . There is some ambiguity in how it is defined:*In embryology, gestational age is the time elapsed since conception. This interval is also termed fertilisation age....

--until placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

l 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.

United States

Roussel Uclaf did not seek U.S. approval, so in the U.S.A. legal availability was not an initial possibility. 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
Population Council
The Population Council is an international, nonprofit, non-governmental organization. The Council conducts biomedical, social science, and public health research and helps build research capacities in developing countries. One-third of its research relates to HIV and AIDS; its other major program...

 in exchange for immunity from any product liability claims. The Population Council sponsored US clinical trials. 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 U.S. by the FDA, in September 2000. It is legal and available in all 50 states, Washington, D.C., Guam
Guam
Guam is an organized, unincorporated territory of the United States located in the western Pacific Ocean. It is one of five U.S. territories with an established civilian government. Guam is listed as one of 16 Non-Self-Governing Territories by the Special Committee on Decolonization of the United...

 and Puerto Rico
Puerto Rico
Puerto Rico , officially the Commonwealth of Puerto Rico , is an unincorporated territory of the United States, located in the northeastern Caribbean, east of the Dominican Republic and west of both the United States Virgin Islands and the British Virgin Islands.Puerto Rico comprises an...

. 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
Danco Laboratories
Danco Laboratories is an LLC which was incorporated in 1995. Danco has a license from the Population Council to distribute the drug mifepristone, under the brand name Mifeprex. Mifeprex is the only drug distributed by Danco. The offices of Danco are in New York City, and are under an unlisted phone...

 under the tradename Mifeprex.

Medical abortions voluntarily reported by 33 U.S. states to the CDC
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

 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, 13.1% in 2007 (20.3% of those at less than 9 weeks gestation). A Guttmacher Institute
Guttmacher Institute
The Guttmacher Institute is a non-profit organization which works to advance sexual and reproductive health. The institute operates in the United States and globally "through an interrelated program of social science research, policy analysis and public education." According to their mission...

 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
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

 and misoprostol). Medical abortions accounted for 32% of first trimester abortions at Planned Parenthood
Planned Parenthood
Planned Parenthood Federation of America , commonly shortened to Planned Parenthood, is the U.S. affiliate of the International Planned Parenthood Federation and one of its larger members. PPFA is a non-profit organization providing reproductive health and maternal and child health services. The...

 clinics in the United States in 2008.

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
Postmarketing surveillance
Postmarketing surveillance is the practice of monitoring the safety of a pharmaceutical drug or device after it has been released on the market and is an important part of the science of pharmacovigilance...

 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
Pharmacy
Pharmacy is the health profession that links the health sciences with the chemical sciences and it is charged with ensuring the safe and effective use of pharmaceutical drugs...

 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
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...

 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
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...

.

FDA controversy

Many pro-life
Pro-life
Opposition to the legalization of abortion is centered around the pro-life, or anti-abortion, movement, a social and political movement opposing elective abortion on moral grounds and supporting its legal prohibition or restriction...

 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
Holly's Law
Holly's Law was a proposed law which would have banned mifepristone in the United States. The ostensible reason was concern over the drug's safety, though much of the support for the measure has come from pro-life groups that oppose the drug on principle....

, was initiated by a citizen's petition to the FDA from namesake Holly Patterson'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
Mark Souder
Mark Edward Souder is an American Republican politician who was a U.S. Representative from Indiana from 1995 to 2010.During the 1980s and early 1990s, he worked as a congressional aide to Dan Coats and committee staff director. He was elected to his congressional seat in 1994...

—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
Massachusetts Institute of Technology
The Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in...

'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
Women's rights
Women's rights are entitlements and freedoms claimed for women and girls of all ages in many societies.In some places these rights are institutionalized or supported by law, local custom, and behaviour, whereas in others they may be ignored or suppressed...

 to abortion and self determination", said Dr. Janice Raymond of FINRRAGE. Additional critics who call themselves feminists 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."

Europe

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 (less than 9 weeks gestation) 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 (before the end of the 9th week of gestation) 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
Gemeprost
Gemeprost is an analogue of prostaglandin E1.-Clinical use:It is used as a treatment for obstetric bleeding.It is used with RU486 to terminate pregnancy up to 24 weeks gestation...

 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.

Other countries

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
Therapeutic Goods Administration
The Therapeutic Goods Administration is the regulatory body for therapeutic goods in Australia . It is a Division of the Australian Department of Health and Ageing established under the Therapeutic Goods Act 1989 ...

 (TGA). 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 performed 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.

The drug was approved in Israel in 1999.

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
Roussel Uclaf
Roussel Uclaf S.A. was the second largest French pharmaceutical company before it was acquired by Hoechst AG of Frankfurt, Germany in 1997, with pharmaceutical operations combined into the Hoechst Marion Roussel division...

, who 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 cites 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 subsaharan 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" (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.

Medical abortion
Medical abortion
A medical abortion is a type of non-surgical abortion in which abortifacient pharmaceutical drugs are used to induce abortion. An oral preparation for medical abortion is commonly referred to as an abortion pill....

 is available in Canada on a limited basis using methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

 and misoprostol
Misoprostol
Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...

; mifepristone is not legally approved, and importation of that drug in 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 May 2005, 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, Guyana and Moldova in 2004, Mongolia in 2005, and Armenia in 2007.

External links

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