Mifepristone 181415 225842540 2008-07-15T17:32:31Z Rjwilmsi 203434 gen fixes + link/fix date fields in cite templates (explanation [[User:Rjwilmsi#My_correction_of_citation_templates|here]]) using [[Project:AutoWikiBrowser|AWB]] {{drugbox | |IUPAC_name = 11β-[p-(Dimethylamino)phenyl]-<BR>17β-hydroxy-17-(1-propynyl)estra-<BR>4,9-dien-3-one |CAS_number = 84371-65-3 | image = Mifepristone corrected.png |ATC_prefix = G03 |ATC_suffix = XB01 |PubChem = 55245 |DrugBank = APRD00432 |width = 240 |C=29 | H=35 | N=1| O=2 |molecular_weight = 429.60&nbsp;[[Gram|g]]/[[mole (unit)|mol]] |bioavailability = 69% |metabolism = [[Liver|hepatic]] |elimination_half-life = 18 hours |excretion = [[Feces|Fecal]]: 83%; [[Kidney|Renal]]: 9% |pregnancy_category = Used for terminating pregnancy |pregnancy_US = X |legal_status = |legal_US = Rx-only |routes_of_administration = [[Wiktionary:oral|Oral]] }} '''Mifepristone''' is a synthetic [[steroid]] compound used as a [[Medication|pharmaceutical]]. It is used as an [[abortifacient]] in the first two months of pregnancy, and in smaller doses as an [[emergency contraception|emergency contraceptive]]. It can also be used as a treatment for [[Obstetrical hemorrhage|obstetric bleeding]].[http://sfgate.com/cgi-bin/article.cgi?file=/c/a/2006/06/04/CMGPOIP80O1.DTL] During early trials, it was known as '''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. In France and countries other than the [[United States]] it is marketed and distributed by Exelgyn Laboratories under the tradename '''Mifegyne'''. In the United States it is sold by [[Danco Laboratories]] under the tradename '''Mifeprex'''. (The drug is still commonly referred to as "RU-486".) ==Pharmacology== Mifepristone is a 19-[[nor-|nor]] [[steroid]] with a bulky ''[[para|p]]''-(dimethylamino)[[phenyl group|phenyl]] [[substituent]] above the plane of the molecule at the 11β-position responsible for inducing or stabilizing an inactive [[steroid hormone receptor|receptor]] [[conformation]] and a [[hydrophobic]] 1-[[propynyl]] substituent below the plane of the molecule at the 17α-position that increases its [[progesterone receptor]] [[ligand (biochemistry)|binding affinity]]. In the presence of [[progesterone]], mifepristone acts as a [[competitive antagonist|competitive]] [[receptor antagonist]] at the progesterone receptor (in the absence of progesterone, mifepristone acts as a [[partial agonist]]).<!-- --><ref name="loose">{{cite book |author=Loose, Davis S.; Stancel, George M. |year=2006 |chapter=Estrogens and Progestins |editor=in Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.) |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=11th ed. |pages=pp. 1541-1571 |location=New York |publisher=McGraw-Hill |id=ISBN 0-07-142280-3}}</ref><!-- --><ref name="schimmer">{{cite book |author=Schimmer, Bernard P.; Parker, Keith L. |year=2006 |chapter=Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones |editor=in Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.) |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=11th ed. |pages=pp. 1587-1612 |location=New York |publisher=McGraw-Hill |id=ISBN 0-07-142280-3}}</ref><!-- --><ref name="fiala">{{cite journal |author=Fiala C, Gemzel-Danielsson K |year=2006 |title=Review of medical abortion using mifepristone in combination with a prostaglandin analogue |journal=Contraception |volume=74 |issue=1 |pages=66–86 |pmid=16781264 |doi=10.1016/j.contraception.2006.03.018}}</ref> In addition to being an antiprogestogen, mifepristone is also an antiglucocorticoid and a weak [[antiandrogen]]. Mifepristone's relative binding affinity at the progesterone receptor is more than twice that of progesterone, its relative binding affinity at the [[glucocorticoid receptor]] is more than three times that of [[dexamethasone]] and more than ten times that of [[cortisol]], its relative binding affinity at the [[androgen receptor]] is less than one third that of [[testosterone]]. It does not bind to the [[estrogen receptor]] or the [[mineralocorticoid receptor]].<!-- --><ref name="heikinheimo">{{cite journal |author=Heikinheimo O, Kekkonen R, Lahteenmaki P |year=2003 |title=The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action |journal=Contraception |volume=68 |issue=6 |pages=421–6 |pmid=14698071 |doi=10.1016/S0010-7824(03)00077-5}}</ref> Mifepristone as a regular [[contraceptive]] at 2 mg daily prevents [[ovulation]] (1 mg daily does not). A single [[follicular phase|preovulatory]] 10 mg dose of mifepristone delays ovulation by 3 to 4 days and is as effective an [[emergency contraception|emergency contraceptive]] as a single 1.5 mg dose of the [[progestin]] [[levonorgestrel]].<!-- --><ref name="chabbert-buffet">{{cite journal |author=Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM |year=2005 |title=Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications |journal=Hum Reprod Update |volume=11 |issue=3 |pages=293–307 |pmid=15790602 |doi=10.1093/humupd/dmi002}}</ref> In women, mifepristone at doses greater or equal to 1 mg/kg antagonizes the [[endometrium|endometrial]] and [[myometrium|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.<!-- --><ref name="mifegyne UK SPC">{{cite web |author=Exelgyn Laboratories | month=February |year=2006 |title=Mifegyne UK Summary of Product Characteristics (SPC) |url=http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=617 |accessdate=2007-03-09}}</ref><!-- --><ref name="mifeprex US PI">{{cite web |author=Danco Laboratories | month=July 19, |year=2005 | title=Mifeprex US prescribing information |url=http://www.earlyoptionpill.com/pdfs/prescribing071905.pdf |accessdate=2007-03-09}}</ref> In medical abortion regimens, mifepristone blockade of progesterone receptors directly causes endometrial [[decidua]]l degeneration, [[cervix|cervical]] softening and dilatation, release of [[endogenous]] [[prostaglandin]]s 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 [[human chorionic gonadotropin|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 [[gestational age|gestation]]--until [[placenta]]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.<!-- --><ref name="loose"/><!-- --><ref name="fiala"/> ==Approved uses== {{Infobox abortion method | | name = Mifepristone | AKA/Abbreviation= "RU-486" | Abortion_type = [[Medical abortion|Medical]] | Date_first_use = [[1988]] approval ([[People's Republic of China|CN]] & [[France|FR]]) | Date_last_use = | Gestational_age = Up to 7 weeks<br>Up to 9 weeks ([[Great Britain|GB]] & [[Sweden|SE]]) | Usage_notes = Figures are total number of medical abortions. | Use_AU% = <!-- Australia --> | Use_AU_date = | Use_CA% = <!-- Canada--> | Use_CA_date = | Use_EW% = 30 | Use_EW_date = 2006 | Use_FR% = 42 | Use_FR_date = 2004 | Use_NZ% = | Use_NZ_date = | Use_AB% = 59.1 | Use_AB_date = 2006 | Use_SE% = 56.3 | Use_SE_date = 2006 | Use_US% = 9.3 | Use_US_date = 2004 | Use_ZA% = <!-- South Africa --> | Use_ZA_date = | Medical_notes = }} Mifegyne is sold outside the U.S. by Exelgyn Laboratories, made in France, and is approved for: #Medical termination of intrauterine pregnancies of up to 49 days [[gestational age|gestation]] (up to 63 days gestation in [[Great Britain|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 #Labor induction in fetal death in utero.<ref name="mifegyne UK SPC"/> Mifeprex is sold in the U.S. by Danco Laboratories, made in China,<ref>{{cite web|title=Chinese to Make RU-486 for U.S.|work=Washingtonpost.com|year=2000|url=http://www.washingtonpost.com/ac2/wp-dyn?pagename=article&node=&contentId=A53938-2000Oct11|accessdate=2006-08-22}}</ref> and is [[FDA]]-approved in the U.S. 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 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.<!-- --><ref name="spitz 1998">{{cite journal |author=Spitz IM, Bardin CW, Benton L, Robbins A |year=1998 |title=Early pregnancy termination with mifepristone and misoprostol in the United States |journal=[[New England Journal of Medicine|N Engl J Med]] |volume=338 |issue=18 |pages=1241–7 |pmid=9562577 |doi=10.1056/NEJM199804303381801}}</ref> 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.<ref>{{cite web|author=Suzanne Daley|title=Europe Finds Abortion Pill is No Magic Cure-All|publisher=''The New York Times''|year=October 5, 2000|accessdate=2006-09-16|url=http://query.nytimes.com/gst/fullpage.html?sec=health&res=9F03E3D61F3DF936A35753C1A9669C8B63}}</ref> According to the current [[Royal College of Obstetricians and Gynaecologists|RCOG]] abortion [[evidence-based medicine|evidence-based]] [[medical guideline|clinical guideline]]:<!-- --><ref name="rcog guideline">{{cite book |author=[[Royal College of Obstetricians and Gynaecologists|RCOG]] |year=2004 |title=The Care of Women Requesting Induced Abortion : Evidence-based clinical guideline number 7 |location=London |publisher=RCOG Press |url=http://www.rcog.org.uk/resources/Public/pdf/induced_abortionfull.pdf |id=ISBN 1-904752-06-3|format=PDF}}</ref> * 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 [[human chorionic gonadotropin|βhCG]] 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 contraception|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.<ref>{{cite journal|author=Piaggio G et al|title=Meta-analysis of randomized trials comparing different doses of mifepristone in emergency contraception|journal=Contraception|year=2003|volume=68|issue=6|pmid=14698075|pages=447|doi=10.1016/S0010-7824(03)00142-2}}</ref> Mifeprex and Mifegyne are only available in 200 mg tablets.<ref>{{cite journal | last = Wertheimer | first = Randy E. | title = Emergency Postcoital Contraception | journal = American Family Physician | date = [[2000-11-15]] | publisher = American Academy of Family Physicians | url = http://www.aafp.org/afp/20001115/2287.html | format = [[HTML]] | accessdate = 2006-07-23 }}</ref> 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.<ref>{{cite journal | last = Gemzell-Danielsson | first = K. | coauthors = Marions, L. | title = Mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception | journal = Human Reproduction Update | volume = 10 | issue = 4 | pages = 341–348 | date = [[2004-06-10]] | publisher = Oxford University Press | doi = 10.1093/humupd/dmh027 | format = [[HTML]] | accessdate = 2006-07-23 | pmid = 15192056 }}</ref> ===Other uses=== Other medical applications of mifepristone that have been studied in Phase II [[clinical trial]]s include regular long-term use as an [[oral contraceptive]], and treatment of: [[uterine fibroids]], [[endometriosis]], [[clinical depression|major depression]] [[psychotic depression|with psychotic features]], [[glaucoma]], [[meningioma]]s, [[breast cancer]], [[ovarian cancer]], [[prostate cancer]], and some types of [[Cushing's syndrome]]. 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.<ref>Flexner, Charles. “HIV drug development: the next 25 years”. Nat Rev Drug Discov. 2007 Dec;6(12):959-66.</ref> <!-- --><ref name="schimmer"/><!-- --><ref name="chabbert-buffet"/><!-- --><ref name="tang">{{cite journal |author=Tang OS, Ho PC |year=2006 |title=Clinical applications of mifepristone |journal=Gynecol Endocrinol |volume=22 |issue=12 |pages=655–9 |pmid=17162706 |doi=10.1080/09513590601005946}}</ref> Mifepristone has not been approved by the FDA for any of these uses. ==Side effects and contraindications== In [[clinical trial]]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]], [[vomit]]ing, diarrhea, dizziness, fatigue, and [[fever]].<ref name="miflabel">{{cite web | title=Mifeprex label | publisher=FDA | url=http://www.fda.gov/cder/foi/label/2005/020687s013lbl.pdf | format=PDF | date=2005-07-19 | accessdate=2006-08-22}}</ref> [[Pelvic inflammatory disease]] (PID) is a very rare but serious complication.<ref>{{cite journal|author=Lawton, BA et al|title=Atypical presentation of serious pelvic inflammatory disease following mifepristone-induced abortion|journal=Contraception|year=2006|volume=73|issue=4|page=431-2|pmid=16531180|pages=431|doi=10.1016/j.contraception.2005.09.003}}</ref> Excessive bleeding and incomplete termination of a pregnancy require further intervention by a doctor (such as [[Suction-aspiration abortion|vacuum aspiration]]). Between 4.5 and 7.9% of women required surgical intervention in clinical trials.<ref name="miflabel"/> Mifepristone is [[Contraindication|contraindicated]] in the presence of an [[intrauterine device]] (IUD), as well as with [[ectopic pregnancy]], [[Adrenal gland|adrenal]] failure, [[Bleeding|hemorrhagic]] disorders, inherited [[porphyria]], and [[anticoagulant]] or long-term [[corticosteroid]] therapy.<ref name="miflabel"/> 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."<ref name="miflabel"/> ==Carcinogenicity and teratogenicity== 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. A preliminary study in mice indicates that a single dose of mifepristone inhibited [[apoptosis]] of liver cells in the treated animals, which the authors hypothesized might increase susceptibility to [[hepatic cancer]].<ref name=youseff>{{cite web|author=Youssef, Jihan and Badr, Mostafa|title=Hepatocarcinogenic potential of the glucocorticoid antagonist RU486 in B6C351 mice|work=Molecular Cancer|year=2003|accessdate=2006-08-26|url=http://www.molecular-cancer.com/content/2/1/3}}</ref> [[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.<ref name="miflabel"/> [[Teratology]] studies in mice, rats and rabbits revealed teratogenicty for rabbits, but not rats or mice.<ref name="miflabel"/> The rate of birth defects in human infants exposed [[in utero]] to mifepristone and misoprostol is very low,<ref>{{cite web|author=Margaret M. Gary and Donna J. Harrison|title=Analysis of Severe Adverse Events Related to the Use of Mifepristone as an Abortifacient|publisher=The Annals of Pharmacology|year=December 2005|accessdate=2006-09-14|url=http://www.theannals.com/cgi/content/abstract/40/2/191?ck=nck}}</ref> and may be due to misoprostol alone.<ref>{{cite journal|author=Orioli, IM and Castilla, EE|title=Epidemiological assessment of misoprostol teratogenicity|journal=BJOG|volume=107|issue=4|year=2000|pmid=10759272|pages=519–23|doi=10.1111/j.1471-0528.2000.tb13272.x}}</ref> ==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 a prostaglandin, under the name Mifegyne. After license approval but before market release, Roussel Uclaf announced it would abandon distribution of the drug, bowing to pressure from pro-life groups and the threat of a boycott. However, two days later, the French government, part owner of Roussel Uclaf, intervened, leading to the resumption of production and distribution of RU-486. The French Health Minister, explaining the government's intervention, stated, "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."<ref name="leda">{{cite web|author=Julie A. Hogan|title=The Life of the Abortion Pill in the United States|publisher=Legal Electronic Document Archive, Harvard Law School|year=2000|accessdate=2006-09-14|url=http://leda.law.harvard.edu/leda/search/toc.php3?handle=HLS.Library.Leda/hoganja-life_abortion_pill}}</ref> 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){{Fact|date=February 2007}} Roussel Uclaf did not seek U.S. approval, so U.S. availability was not an initial possibility.<ref>{{cite journal|author=Klitsch M|title=Antiprogestins and the abortion controversy: a progress report|journal=Fam Plann Perspect|year=Nov-December 1991|volume=23|issue=6|pmid=1786809|pages=275–82|doi=10.2307/2135779}}</ref> The first [[George H. W. Bush|Bush]] administration 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.<ref>{{cite web|author=Katharine Q. Seelye|title=Accord Opens Way for Abortion Pill in US in 2 Years|date=1997-01-05-17|accessdate=2006-08-26|url=http://query.nytimes.com/gst/fullpage.html?sec=health&res=9D00E0DC1738F934A25756C0A962958260}}</ref><ref>{{cite web|author=Nancy Gibbs|title=The Pill Arrives|publisher=Cnn.com|year=October 2, 2000|accessdate=2006-09-20|url=http://www.cnn.com/ALLPOLITICS/time/2000/10/09/pill.html}}</ref> The Population Council sponsored US clinical trials<ref>{{cite web|author=Tamar Lewin|title=Clinical Trials Giving Glimpse of Abortion Pill|publisher=''The New York Times''|year=January 30, 1995|accessdate=2006-09-20|url=http://query.nytimes.com/gst/fullpage.html?res=990CE6D9173DF933A05752C0A963958260&sec=health&pagewanted=1}}</ref> 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.<ref>{{cite web|author=Tamar Lewin|title=Lawsuits' Settlement Brings New Hope for Abortion Pill|publisher=''The New York Times''|year=November 13, 1997|accessdate=2006-09-16|url=http://query.nytimes.com/gst/fullpage.html?sec=health&res=9906E7DB1638F930A25752C1A961958260}}</ref><ref>{{cite web|author=Sharon Lerner|title=RU Pissed Off Yet?|publisher=''Village Voice''|year=August 2000|accessdate=2006-09-16|url=http://www.villagevoice.com/news/0035,lerner,17757,1.html}}</ref> Mifepristone was approved for abortion in the U.S. by the FDA, in September 2000, during the final months of President [[Bill Clinton]]'s administration.<ref>{{cite web|title=FDA approval letter for Mifepristone|publisher=U.S. Gov|year=September 28, 2000|accessdate=2006-09-16|url=http://www.fda.gov/cder/foi/appletter/2000/20687appltr.htm}}</ref> It is legal and available in all 50 states, Washington D.C., [[Guam]] and [[Puerto Rico]].<ref>{{cite web|title=Medication Abortion in the United States: Mifepristone Fact Sheet|year=2005|publisher=Gynuity Health Projects|url=http://72.14.209.104/search?q=cache:ubJAF98bdMAJ:www.gynuity.org/documents/mife_fact_sheet.pdf+mifepristone+%2B+puerto+rico&hl=en&gl=us&ct=clnk&cd=3&ie=UTF-8}}</ref> Medical abortions as a percentage of total abortions in the United States have increased 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 (14.2% of those less than 9 weeks gestation); although data is limited by eleven states not reporting statistics to the [[Centers for Disease Control and Prevention]] (CDC) (including [[California]] where an estimated >23% of total U.S. abortions were performed in 1997).<ref>{{cite journal |author=Strauss LT, Gamble SB, Parker WY, Cook DA, Zane SB, Hamdan S; Centers for Disease Control and Prevention (CDC) |year=2007 |title=Abortion surveillance--United States, 2004 |journal=[[Morbidity and Mortality Weekly Report|MMWR Surveill Summ]] |volume=56 |issue=9 |pages=1–33 |pmid=18030283 |url=http://www.cdc.gov/mmwr/pdf/ss/ss5609.pdf}} Table 18 (39 states and NYC).</ref> ===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.<ref>{{cite web | last = Woodcock | first = Janet | title = Testimony on RU-486 | work = Committee on Government Reform, House of Representatives | publisher = FDA | date = 2006-05-12 | url = http://www.fda.gov/ola/2006/mifepristone0517.html | accessdate = 2006-08-19 }}</ref> The approval of mifepristone under Subsection H included a [[black box warning]]. ==Controversy== Many [[pro-life]] groups in the US actively campaigned against the approval of mifepristone,<ref>{{cite web|author=Paige Comstock Cunningham, Leanne McCoy, Clarke D. Ferguson|title=Citizen Petition to the U.S. Food and Drug Administration|publisher=Americans United for Life|year=February 28, 1995|accessdate=2006-09-20|url=http://www.fnsa.org/v1n3/americans1.html}}</ref><ref>{{cite web|author=Margaret Talbot|title=The Little White Bombshell|publisher=''The New York Times''|year=July 11, 1999|accessdate=2006-09-20|url=http://query.nytimes.com/gst/fullpage.html?res=9D00E5DC113DF932A25754C0A96F958260&sec=health&pagewanted=2}}</ref><ref>{{cite web|title=Abortion Foes To Boycott Drugs (Altace) Made By RU-486 Manufacturer|publisher=''The Virginia Pilot''|year=July 8, 1994|accessdate=2006-09-15|url=http://scholar.lib.vt.edu/VA-news/VA-Pilot/issues/1994/vp940708/07080818.htm}}</ref> and continue to actively campaign for its withdrawal.<ref>{{cite web|author=Stan Guthrie|title=Counteroffensive Launched on RU-486|publisher=''Christianity Today''|year=June 11, 2001|accessdate=2006-09-20|url=http://www.christianitytoday.com/ct/2001/008/13.58.html}}</ref> They cite either ethical issues with abortion or safety concerns regarding the drug and the adverse reactions associated with it, including death.<ref>{{cite web|author=Gina Kolata|title=Death at 18 Spurs Debate Over a Pill For Abortion|publisher=''The New York Times''|year=September 24, 2003|accessdate=2006-09-20|url=http://query.nytimes.com/gst/fullpage.html?res=9A03E7DD173DF937A1575AC0A9659C8B63&sec=health&pagewanted=1}}</ref> 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 namesake Holly Patterson's father,<ref>{{cite web|author=Karen Tumulty|title=Jesus and the FDA|publisher=''[[Time (magazine)|Time]]''|year=October 14, 2002|accessdate=2006-09-20|url=http://jcgi.pathfinder.com/time/magazine/article/0,9171,1003443,00.html}}</ref> 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?”<ref>{{cite web |url=http://reform.house.gov/CJDPHR/Hearings/EventSingle.aspx?EventI=1 | D=43922 |title=RU-486 - Demonstrating a Low Standard for Women’s Health? |date=2006-05-17 |accessdate=2006-08-25 |publisher=House Subcommittee on Criminal Justice, Drug Policy and Human Resources}}</ref>—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<ref>{{cite web|author=John L. Allen|title=Abortion debates rock Germany: introduction of abortion pill exacerbates controversy|publisher=''National Catholic Reporter''|date=[[February 12]], [[1999]]|accessdate=2006-09-14|url=http://www.findarticles.com/p/articles/mi_m1141/is_15_35/ai_53924378}}</ref> and Australia.<ref>{{cite web|title=Catholic and Evangelical students join Muslims in RU-486 fight|publisher=''Catholic News''|year=February 9, 2006|accessdate=2006-09-18|url=http://www.cathnews.com/news/602/54.php}}</ref><ref>{{cite web|title=Death Toll Rises to 11 Women|publisher=Australians Against RU-486|year=2006|accessdate=2006-09-20|url=http://www.aaru486.com.au/index.php?option=com_content&task=view&id=29&Itemid=26}}</ref> 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."<ref>{{cite web|author=Annette MacDonald|title=RU-486: A Dangerous Drug|work=[[The Vancouver Sun]]|year=1992|url=http://www.ru486.org/ru1.htm|accessdate=2006-08-22}}</ref> That mifepristone can be used as an abortifacient has also been a barrier to its adoption as a treatment for obstetric bleeding of particular value in the developing world (as it is low cost and heat stable).[http://sfgate.com/cgi-bin/article.cgi?file=/c/a/2006/06/04/CMGPOIP80O1.DTL] ===Fatalities=== Since [[Food and Drug Administration|FDA]] approval in 2000, eight women in the US, two women in the UK,<ref>{{cite web|author=Michael Day and Susan Bisset|title=Revealed: two British women die after taking controversial new abortion pill|publisher=Telegraph.co.uk|year=January 18, 2004|accessdate=2006-09-19|url=http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2004/01/18/nabort18.xml&sSheet=/news/2004/01/18/ixhome.html}}</ref> one woman in Sweden, and one in Canada have died following use of mifepristone. As a result of these deaths, two US Senators introduced legislation calling for an immediate ban on the sale of Mifeprex, pending FDA review.<ref>{{cite web | title=Mifeprex (mifepristone) Information | work=FDA.gov | url=http://www.fda.gov/cder/drug/infopage/mifepristone/ | accessmonthday=March 18 | accessyear=2006}}<br />{{cite web | title=Two more women die after taking 'abortion pill' | work=CNN.com | url=http://edition.cnn.com/2006/HEALTH/03/17/ru486.deaths.ap/index.html | accessmonthday=March 18 | accessyear=2006}}</ref> According to a [[United States House of Representatives|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 abortion]]s of comparable terms (8 weeks gestation).<ref name="SoCJDPaHR">{{cite web|title=FDA Questions for the Record Following the Subcommittee Hearing, “RU-486: Demonstrating a Low Standard for Women's Health?” | publisher=Subcommittee on Criminal Justice, Drug Policy and Human Resources | url=http://reform.house.gov/CJDPHR/News/DocumentSingle.aspx?DocumentI=1 | D=46016|accessdate=2006-08-24}}</ref> 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."<ref>{{cite web|author=Gardiner Harris|title=Some Doctors Voice Worry Over Abortion Pills' Safety|publisher=''The New York Times''|date=[[April 1]], [[2006]]|accessdate=2006-01-09|url=http://www.nytimes.com/2006/04/01/health/01abort.html?ex=1157256000&en=8ae3cdcbfc68ce7f&ei=5070}}</ref> 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.<ref>{{cite web|author=Gardiner Harris|title=After 2 More Deaths, Planned Parenthood Alters Method for Abortion Pill|publisher=''The New York Times''|year=March 18, 2006|accessdate=2006-09-20|url=http://www.nytimes.com/2006/03/18/national/18abort.html?ex=1300338000&en=2f5bb43bc205fb4d&ei=5088&partner=rssnyt&emc=rss}}</ref> [[Off-label use|Off-label]] intra-vaginal use of misoprostol has been shown to be effective in published studies, but not in [[clinical trial]]s. 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]].<ref>{{cite web|author=Timothy F. Kern|title=Three deaths prompt new warnings for mifepristone|publisher=''OB/GYN News''|year=December 15, 2004|accessdate=2006-09-20|url=http://findarticles.com/p/articles/mi_m0CYD/is_24_39/ai_n8697292}}</ref> There have been 27 reported cases of accidental use of mifepristone during ectopic pregnancy.<ref name="SoCJDPaHR" /> The FDA has concluded that there is no established [[Causal relationships|causal link]] between the deaths and mifepristone,<ref>{{cite web | title=Mifepristone Questions and Answers | work=FDA.gov | url=http://www.fda.gov/cder/drug/infopage/mifepristone/mifepristone-qa20041115.htm | accessdate=2006-08-24}}</ref> but also states that they "do not know whether using Mifeprex or misoprostol caused these deaths."<ref>{{cite web | title=Mifeprex (mifepristone) Information | work=FDA.gov | url=http://www.fda.gov/cder/drug/infopage/mifepristone/ | accessdate=2006-08-24}}</ref> 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.<ref>{{cite web| url = http://www.boston.com/business/globe/articles/2005/12/01/article_to_kindle_abortion_pill_fight/| title = Article to kindle abortion pill fight| accessdate = 2006-08-24| last = Henderson| first = Diedtra| date = 2006-12-01| work = [[The Boston Globe]]}}</ref> On [[May 11]], [[2006]], experts from the FDA, the [[Centers for Disease Control and Prevention|CDC]], and the [[National Institutes of Health|NIH]] gathered in [[Atlanta, Georgia]] for a meeting regarding cloistridal disease, partly in response to the five confirmed deaths resulting from [[infection|bacterial infection]].<ref>{{cite web |url=http://www.fda.gov/cder/meeting/clostridia_disease.htm |title=Emerging Clostridial Disease Public Workshop |date=2006-05-11 |accessdate=2006-08-25 |publisher=FDA}}</ref> 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 [[Human flora|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.<ref>{{cite journal|author=Rorbye, C et al|title=Postpartum clostridium sordellii infection associated with fatal toxic shock syndrome|journal=Acta obstetrica et gynecologica Scandinavica|year=2000|volume=79|issue=12|pages=1134–5|pmid=1130102|doi=10.1034/j.1600-0412.2000.0790121134.x}}</ref> 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.<ref>{{cite journal |author=Miech RP |title =Pathophysiology of mifepristone-induced septic shock due to ''Clostridium sordellii'' |journal=Ann Pharmacother |volume=39 |issue=9 |pages=1483–8 | month=September |year = 2005 |pmid = 16046483 |url=http://www.theannals.com/cgi/reprint/aph.1G189v1 |doi =10.1345/aph.1G189}}</ref> 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."<ref>{{cite web |url=http://reform.house.gov/UploadedFiles/Rarick%20Testimony.pdf#search=%22rarick%20gynecology%22 |title=Written Testimony/Prepared Statement |work=RU-486 - Demonstrating a Low Standard for Women’s Health? |date=2006-05-17 |accessdate=2006-08-25 |publisher=House Subcommittee on Criminal Justice, Drug Policy and Human Resources}}</ref> 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 medical 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 transplant]]s. Until proven otherwise, women's exposure to synthetic PG during abortion procedures can be regarded as an immune insult."<ref name=klein>{{cite book |author=Klein, Renate; Raymond, Janice G.; Dumble, Lynette J. |title=RU 486 : misconceptions, myths, and morals |year=1991 |publisher=Spinifex |location=North Melbourne |id=ISBN 1-875559-01-9 |url=http://www.spinifexpress.com.au/non-fict/ru486.htm}}</ref> 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)<ref>{{cite book |author=Di Francesco P, Pica F, Tubaro E, Favalli C, Garaci E |editor=Samuelsson, Bengt (ed.) (1991) |title=7th International Conference on Prostaglandins and Related Compounds (Advances in Prostaglandin, Thromboxane, and Leukotriene Research). Florence, Italy. May 28-June 1, 1990 |year=1990 |publisher=Lippincott Williams & Wilkins |location=New York |id=ISBN 0-88167-742-6 |pages=p. 336 |chapter=Inhibitory effects of cocaine on the cellular immune response in normal mice (abstract)}}</ref> have reported that isolated immune insults are more harmful than those of a chronic nature (as practised in transplantation)."<ref name=klein /> 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]].<ref>{{cite journal|author=Sternberg, Esther|title=Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids, and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products|volume=181|issue=2|pages=207–21|years=2004}}</ref> In addition to the studies cited by Sternberg, a 1992 study of female rats treated with mifepristone found that some developed lethal bacterial infections.<ref>{{cite journal|author=van der Schoot, P|title=Treatment with mifepristone (RU-486) and oestradiol facilitates the development of genital septic disease after copulation in female rats|volume=7|issue=5|pages=601–5|year=1992|pmid=1639975}}</ref> 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 [[decidua]]l tissue."<ref>{{cite journal |author=Fischer M, Bhatnagar J, Guarner J, Reagan S, Hacker JK, Van Meter SH, Poukens V, Whiteman DB, Iton A, Cheung M, Dassey DE, Shieh WJ, Zaki SR |title =Fatal toxic shock syndrome associated with ''Clostridium sordellii'' after medical abortion |journal=N Engl J Med |volume=353 |issue=22 |pages=2352–60 |month=December 1, |year= 2005 |pmid=16319384 |doi= 10.1056/NEJMoa051620}}</ref> [[Misoprostol]] not only dilates the cervix, but also softens it. It can also cause uterine ruptures.<ref>{{cite journal|author=Kim, JO et al|title=Oral misoprostol and uterine rupture in the first trimester of pregnancy: a case report|volume=20|issue=4|pages=575–77|year=November–December 2005|pmid=15982851}}</ref><ref>{{cite journal|author=Lialos, G et al|title=Uterine perforation as a rare complication of attempted pregnancy termination with misoprostol: a case report|journal=The Journal of Reproductive Medicine|volume=51|issue=7|pages=599–600|year=2006|pmid=16913556}}</ref> 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.<ref>{{cite web|title=FDA Alert-Risks of Use in Labor and Delivery|work=Center for Drug Evaluation and Research|publisher=FDA|date=May, 2005|url=http://www.fda.gov/cder/drug/infopage/misoprostol/default.htm|accessdate=2006-08-21}}</ref> Drug combinations, in which one drug is approved and the other is not (such as mifespristone + misoprostol), are sometimes allowed by the FDA.<ref>{{cite web|title=Some Hospitals Shun Drug Used with RU-486, Obstetricians Say Move is Harmful to Women|publisher=National Public Radio|year=October 12, 2000|accessdate=2006-09-17|url=http://www.npr.org/about/press/001012.ru486.html}}</ref> 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.<ref>{{cite web | title = Patient Information Sheet: Mifepristone | work = Center for Drug Evaluation and Research | publisher = FDA | date = 2006-07 | url = http://www.fda.gov/cder/drug/InfoSheets/patient/mifepristonePIS.htm | accessdate = 2006-08-19 }}</ref> == Politics and use outside the United States == ===Europe=== 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.<!-- --><ref>{{cite journal |author=Christin-Maitre S, Bouchard P, Spitz IM |year=2000 |title=Medical termination of pregnancy |journal=N Engl J Med |volume=342 |number=13 |pages=946–56 |pmid=10738054 |doi=10.1056/NEJM200003303421307}}</ref> In 2000, it was approved in Norway. Serbia and Montenegro approved it in 2001,<ref>{{cite journal|author=Stojnic J et al|title=Medicamentous abortion with mifepristone and misoprostol in Serbia and Montenegro|year=2006|volume=63|issue=6|pmid=16796021|pages=558–63}}</ref> Latvia in 2002, Estonia in 2003, Albania and Hungary in 2005.<ref name="gynuity">{{cite web |title=Mifepristone approval |url=http://www.gynuity.org/documents/mife_approval_2007_list.pdf |year=2007 |work=Gynuity.org accessdate=2007-07-27|format=PDF}}</ref> In Sweden and the UK, mifepristone is licensed for use with vaginal [[gemeprost]] instead of oral misoprostol. As of seven years ago, more than 620,000 women in Europe had had medical abortions using a mifepristone regimen.<ref>{{cite web|title=FDA Approves Mifepristone for the Termination of Early Pregnancy|publisher=FDA press release/US Gov|year=2000|accessdate=2006-09-17|url=http://www.fda.gov/bbs/topics/news/NEW00737.html}}</ref> In France, the percentage of medical abortions continues to increase, from 38% of all abortions in 2003 to 42% of all abortions in 2004.<ref>{{cite web |author=Vilain, Annick |year=2006 |title=Voluntary terminations of pregnancies in 2004 |publisher=DREES, Ministry of Health |url=http://www.sante.gouv.fr/drees/etude-resultat/er522/er522.pdf |accessdate=2007-02-18|format=PDF}}</ref> In England and Wales, 42% of early abortions (less than 9 weeks gestation) in 2006 were medical; the percentage of all abortions that are medical has increased every year for the past 11 years (from 5% in 1995 to 30% in 2006).<ref>{{cite web |author=Department of Health |year=2007 |title=Abortion statistics, England and Wales: 2006 |url=http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsStatistics/DH_075697 |accessdate=2007-07-08}}</ref> In Scotland, 77.8% of early abortions (less than 10 weeks gestation) in 2006 were medical; the percentage of all abortions that are medical has increased every year for the past 14 years (from 16.4% in 1992 to 59.1% in 2006).<ref>{{cite web |author=ISD Scotland |year=2007 |title=Abortion Statistics 2006 |url=http://www.isdscotland.org/isd/info3.jsp?pContentID=1923&p_applic=CCC&p_service=Content.show& |accessdate=2007-07-08}}</ref> In Sweden, 60.6% of early abortions (before the end of the 12th week of gestation) in 2006 were medical; 56.3% of all abortions in 2006 were medical.<ref>{{cite web |author=National Board of Health and Welfare, Sweden |year=2007 |title=Induced Abortions 2006 |url=http://www.socialstyrelsen.se/NR/rdonlyres/8971390B-0F54-4BC0-9ED3-FB2D41C7AC5D/7633/2007427.pdf |accessdate=2007-07-08|format=PDF}}</ref> In Denmark, mifepristone was used in between 3,000 and 4,000 of just over 15,000 abortions in 2005.<ref>{{cite web|title=The abortion pill Mifegyne tested for adverse reactions|publisher=Danish Medicines Agency|year=July 27, 2005|accessdate=2006-09-20|url=http://www.dkma.dk/1024/visUKLSArtikel.asp?artikelI=1 | D=6496}}</ref> Mifepristone is not approved in Ireland, where abortion is illegal, or Poland, where abortion is highly restricted.<ref>{{cite web|author=Peter S. Green|title=A Rocky Landfall for a Dutch Abortion Boat|publisher=''The New York Times''|year=June 24, 2003|accessdate=2006-09-16|url=http://query.nytimes.com/gst/fullpage.html?sec=health&res=9F02E3D7153BF937A15755C0A9659C8B63}}</ref> Clinical trials in Italy have been constrained by protocols requiring women be hospitalized for three days.<ref>{{cite web |author=Rey, Anne-Marie Rey |month=October 17, |year=2006 |title=Abortion in Italy |url=http://64.233.179.104/translate_c?hl=en&u=http://www.svss-uspda.ch/fr/facts/italie.htm&prev=/search%3Fq%3D%2522Silvio%2BViale%2522%2Bsuspended%26hl%3Den%26rls%3Dcom.microsoft:en-US |publisher=SVSS-USPDA |accessdate=2007-03-01}}</ref> 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.<ref>{{cite web|title=Abortion pill sparks bitter protest|publisher=The Budapest Times|year=September 19, 2005|accessdate=2006-09-16|url=http://www.budapesttimes.hu/index.php?art=1077}}</ref> ===Australia=== 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]] (TGA). The move caused much debate in the Australian media and amongst politicians. The Bill passed the Senate on [[10 February]] [[2006]], and whilst mifepristone is now legal for use in Australia, as of yet, no drug company has applied to import and distribute it. Currently there are only a couple of known instances where a doctor has applied to the TGA for dispensing mifepristone in specific cases. ===New Zealand=== 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.<ref>{{cite journal|author=Sparrow MJ|title=A woman's choice|journal=Aust NZ J Obstet Gynaecol|year=2004|volume=44|issue=2|page=88-92|pmid=15089829|pages=88|doi=10.1111/j.1479-828X.2004.00190.x}}</ref> ===Israel=== Mifepristone was approved in Israel in 1999.<ref>{{cite web|author=Etienne-Emile Baulieu, Daniel S. Seidman, Selma Hajri|title=Mifepristone(RU-486) and voluntary termination of prgnancy: enigmatic variations or anecdotal religion-based attitudes?|publisher=Human Reproduction|year=October 2001|accessdate=2006-09-16|url=http://humrep.oxfordjournals.org/cgi/content/full/16/10/2243}}</ref> ===Asia=== 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]], but they 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.<!-- --><ref name="ulmann">{{cite journal |author=Ulmann A |year=2000 |title=The development of mifepristone: a pharmaceutical drama in three acts |journal=J Am Med Women's Assoc |volume=55 |issue=3 Suppl |pages=117–20 |pmid=10846319}}</ref><!-- --><ref name="wu">{{cite journal |author=Wu S |year=2000 |title=Medical abortion in China |journal=J Am Med Women's Assoc |volume=55 |issue=3 Suppl |pages=197–9, 204 |pmid=10846339}}</ref> 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 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.<ref>{{cite web|title=Family planning in China: RU-486, abortion, and population trends|publisher=U.S. Embassy Beijing|year=2000|accessdate=2006-09-14|url=http://www.usembassy-china.org.cn/sandt/ru486.html}}</ref> In 2001, mifepristone was approved in Taiwan.<ref>{{cite journal|author=Tsai EM, Yang CH, Lee JN|title=Medical abortion with mifepristone and misoprostol: a clinical trial in Taiwanese women|journal=J Formos Med Assoc|year=2002|volume=101|issue=4|pmid=12101864|pages=277–82}}</ref> Vietnam included mifepristone in the National Reproductive Health program in 2002.<ref>{{cite journal|author=Ganatra B, Bygdeman M, Nguyen DV, Vu ML, Phan BT|title=From research to reality: the challenges of introducing medical abortion into service delivery in Vietnam|journal=Reprod Health Matters|year=2004|volume=12|issue=24|page=105-13|pmid=15938163|pages=105|doi=10.1016/S0968-8080(04)24022-8}}</ref> ===Africa=== Mifepristone is approved in only one subsaharan African country--South Africa, where it was approved in 2001.<ref>{{cite web|title=Medical Abortion-Implications for Africa|publisher=Ipas|year=2003|accessdate=2006-09-16|url=http://www.ipas.org/publications/en/Medical_Abortion/med_ab_africa_web_only_en.pdf.}}</ref> It is also approved in one north African country--Tunisia, also in 2001.<ref>{{cite journal|author=Hajri S|title=Medication abortion: the Tunisian experience|journal=Afr J Reprod Health|year=2004|volume=8|issue=1|pmid=15487615|pages=63–9|doi=10.2307/3583307}}</ref> ===India=== 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.<ref>{{cite web|title=Mifepristone can be sold only to approved MTP Centres: Rajasthan State HRC|publisher=Indian Express Health Care Management|year=2000|url=http://www.expresshealthcaremgmt.com/20040515/oped01.shtml}}</ref> ===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 sordellii]]''.<ref>{{cite web|author=Jennifer Laliberte|title=Still no mifepristone for Canada: is it safe?|publisher=National Review of Medicine|date=[[September 30]], [[2005]]|accessdate=2006-09-16|url=http://www.nationalreviewofmedicine.com/issue/2005/09_30/2_policy_politics02_16.html}}</ref> ===The former Soviet Union=== Mifepristone was registered for use in Russia and Ukraine in 2000, and in Azerbaijan, Belarus, Georgia, and Uzbekistan in 2002, Moldova in 2004, and Armenia in 2007.<ref>{{cite web|title=Medication Abortion|publisher=Ibis|year=2002|accessdate=2006-09-19|url=http://www.medicationabortion.com/mifepristone/index.html}}</ref><ref name="gynuity" /> ===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]]. {{Expand-section|date=June 2008}} ==Notes and references== <div class="reflist4" style="height: 220px; overflow: auto; padding: 3px" > {{reflist|2}} </div><!--<div class="references-small"><references/></div>--> ==See also== {|width=100% |-valign=top |width=50%| *[[Abortion]] *[[Medical abortion]] *[[Suction-aspiration abortion]] |width=50%| *[[Food and Drug Administration]] *[[Pharmacology]] *[[Emergency contraception]] |} ==External links== *[http://www.fda.gov/cder/drug/infopage/mifepristone/ US Food and Drug Administration] Mifeprex (mifepristone) Information *[http://www.ru486.com/topics/articles/article_73.asp Commonly asked questions about RU-486] from the education arm of the [[National Coalition of Abortion Providers]] *[http://www.Abortion.com A comprehensive listing of offices offering The Abortion Pill]; all members of NCAP or NAF, the two main organizations advocating for abortion providers *[http://www.earlyoptionpill.com/pdfs/prescribing071905.pdf Danco prescribing information] *[http://www.ru486.org.au Australians for RU-486] - established in February 2006 to lobby for passage of bill in Australia's Parliament to enable the availability of Mifepristone {{AbortionMethods-horizontal}} {{Sex hormones}} [[Category:Sex hormones]] [[Category:Abortifacients]] [[Category:Antiandrogens]] [[Category:Antiglucocorticoids]] [[Category:Methods of abortion]] [[cs:Mifepriston]] [[de:Mifepriston]] [[fr:Mifépristone]] [[it:Mifepristone]] [[hu:Mifepriston]] [[nl:Mifepriston]] [[ru:Мифепристон]] [[tr:Mifepristone]]