overview - family research councilmifepristone + misoprostol: ru-486 • 8% or 1 in 12 women will...

Overview

Misoprostol, Mifepristone, & Ulipristal • Mechanism of Action

• Efficacy

• Adverse Effects

• Additional Information

Misoprostol (Cytotec®)

Image downloaded from drsfostersmith.com

Mechanism of Action How Does It Work

Misoprostol: Analog of Prostaglandin E1 • Analog: Related structurally

• Prostaglandin: Hormone-like substance that effects numerous body functions

• E1: Causes cervix to soften & uterus contractions resulting in vaginal expulsion of the uterus (womb) contents

References1, 2

EfficacyHow Well Does It Work

Misoprostol: Standard optimal regimen yet to be universally accepted

• 65% to 93% ‘general’ complete abortion rate, but efficacy is widely variable by regimen & gestational age.

• Oral (taken by mouth) misoprostol alone is considered not effective.

• Mifepristone plus misoprostol combination is “significantly more effective”

References1, 3, 4, 10

AE associated with misoprostol-only abortions are “generally more severe than those associated with the combined regimens”

Most common AE:

• Abdominal cramping

• Vaginal bleeding (mean duration of 2 wks)

• Abdominal pain (25% “much stronger” than menstrual pain)

• Passing blood clots and/or gray/tan tissue 1-2 inches in length

• Additional potential AE: nausea, vomiting, diarrhea, dizziness, headache, fever, chills, rashes, & pelvic pain.

References1, 5, 6

Adverse Effects

Current U.S. Medication Guide

SPECIAL NOTE FOR WOMEN: Cytotec may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women.

Teratogenic effects: Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient but the drug’s teratogenic mechanism has not been demonstrated. Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.

Reference 7

Mifepristone(Mifegyne©, Mifeprex™)

Image downloaded from http://img.timeinc.net/time/daily/2007/0708/ru_486_0815.jpg

Mechanism of Action How Does It Work

Mifepristone: Synthetic Progesterone Receptor Antagonist

• Synthetic: Designed or Man Made

• Progesterone Receptor: Needs to be activated for pregnancy to begin & continue

• Antagonist: Blocks receptor activation as a result the placenta detaches from the uterus (womb) which then ends fetal food & oxygen supply

References 1, 5, 8

Progesterone

Mifepristone & Ulipristal

The Lock = Progesterone Receptor(must be open to begin & continue pregnancy)

Efficacy Need to Combine with Misoprostol

“The efficacy of RU 486 in terminating early pregnancies was investigated in 18 healthy volunteers who requested legal abortion at a French family planning center. Subjects received 200 mg/day of the drug for 4 days. All were within 5-9 weeks since their last menstrual period. Spontaneous, complete evacuation of the uterus occurred in 7 cases. In another 2 cases, spontaneous abortion occurred but the uterus did not empty, necessitating vacuum aspiration. The remaining 9 women had no indication of pregnancy interruption during RU 486 treatment.“ Published 1985

11% partial abortion & 50% continued pregnancies - thus -

Mifepristone + Misoprostol = RU-486

Reference 9


Mifepristone + Misoprostol: RU-486 • 8% or 1 in 12 women will require surgery to

end pregnancy or control bleeding − Based on 1 uncontrolled U.S. trial

− After “early pregnancy” or 49 days of gestation the efficacy decreases (clinically useful window of 3 weeks)

Reference 10

• Pregnancy was terminated in: – 92% (1 out of 12 failed) 49 days or less gestation– 83% (1 out of 6 failed) 50-56 days gestation – 77% (1 out of 4 failed) 57-63 days gestation

• Complication rate doubled when gestational age was greater than 49 days.

Reference 10

Efficacy & Gestational AgeDuring Mifepristone + Misoprostol U.S. Trial

Adverse EffectsDuring Mifepristone + Misoprostol U.S. Trial

99% experienced at least one of the following: – abdominal pain (97%) – nausea (67%) – headache (32%) – vomiting (34%) – diarrhea (23%) – dizziness (12%)– fatigue (9%) – back pain (9%)– uterine hemorrhage (7%) – fever (4%) – viral infections (4%) – vaginitis (4%) – rigors (3%)

23% of the AEs were judged to be severe

* = s/sx of C. Sordellii infection


*

*

**

**

Serious Events During Mifepristone + Misoprostol U.S. Trial

• 295 surgeries• 49 admin. IV fluids• 19 admitted in

emergency rooms• 27 hospitalizations


• 4 blood transfusions

• 146 given meds to stop bleeding

• 1 suicide attempt

• Adverse Events Reporting System (AERS)– “reporting of adverse events is a voluntary process

with inherent underreporting”– An average estimate is 1 out of 20 AE is reported– GAO commented on the underreporting, stating

the FDA is unable to use AERS data to “establish the true frequency of adverse events” therefore making “it hard to establish the magnitude of a safety problem”

References11, 14

Serious EventsMifepristone + Misoprostol AERS Data

Serious Events Mifepristone + Misoprostol AERS Data

References11, 15, 17

Through AERS the FDA acknowledges 950 AE cases were reported during the 1st 67 months & included:

• 6 deaths• 88 cases of infection• 116 blood transfusions• 232 hospitalizations• 237 cases of hemorrhage• 513 surgical interventions

Serious Events Mifepristone + Misoprostol AERS Data

References11, 15

950 AE cases reported through the AERS represent an ave. of 1 AE case reported every other day

• Underreporting (1 out of 20), provides a speculative ave. of 9.5 AE cases actually occurred every day.

• Increasing trend: according to available data− 9/00-9/04: FDA received ave. 1 AE report every 0.44 days.− 9/04-7/05: FDA received ave. 1 AE report every 0.75 days.− 7/05-4/06: FDA received ave. 1 AE report every 0.75 days.

Serious EventsDisplay Serious Threat in U.S.

Congressman Mark Souder, former Chairman of the House Subcommittee on Criminal Justice, Drug Policy & Human Resources, convened a hearing on the U.S. approval of RU-486 following 4 U.S. deaths.

The subcommittee's report concluded that “RU-486 is a hazardous drug for women, its unusual approval demonstrates a lower standard of care for women, and its withdrawal from the market is justified and necessary to protect the public’s health.”

Reference 11

Key ComplicationsMifepristone + Misoprostol

• Infection (Septic Shock)

• Excessive Severe Bleeding

• Cardiopulmonary

• Failure to Follow-Up

• Emotional/Psychological

Key Complications: Infections

• The risk of death from infection alone is at least 10 times greater with RU-486 abortions than all causes of early surgical abortion deaths.

• 5 known U.S. deaths associated specifically with Clostridium infections following RU-486 use. – After RU-486, C. Sordellii has been able to “flourish,

causing a widespread, multi-organ infection”.– Very difficult to detect, C. Sordellii infection is not

accompanied by fever & the s/sx overlap with the expected RU-486 adverse effects.



• FDA Emerging Clostridial Disease Workshop: Found Correlation w/ RU-486 Use– Aborting uterus acts as an “ideal bacterial culture”

– Mifepristone has an innate ability to suppress the body’s natural immune response (anti-glucocortocoid)

– These 2 factors “work together synergistically to produce the clinical findings of rapid fulminating lethal shock syndrome that were the hallmark of the four cases [of death] that occurred in California.”

Reference 16


• FDA Emerging Clostridial Disease Workshop:

– Currently there is no “window of opportunity” for treatment, even through major interventions such as surgery.

– Providing prophylactic antibiotics is unlikely to prevent this infection & may actually be harmful.

– There has been a 100% fatality rate for women infected with C. Sordellii following RU-486.

References16, 11

• In U.S. trial, due to excessive bleeding:– 32 surgical interventions– 4 transfusions – 146 (7%) women were given meds – 22 women administered IV fluids– 25 out of 27 hospitalizations and/or ER visits

• In U.S. trial, 9% of women reported some bleeding after 30 days & 1% after 60 days.

Key Complications:Excessive Severe Bleeding


• From AERS as of Sept 2005, 15 women hemorrhaged to the point of losing >1/2 their blood volume & “would have died without rapid access to emergency room services”.

• From AERS reports as of April 2006, there were 237 hemorrhages reported:– 1 fatal– 42 life threatening


References 11, 17

– 168 serious cases– 68 required transfusions

• A study in India, Cuba, & China found versus surgical abortions there was “significantly more blood loss” associated with medication abortions.

• A similar study in the U.S. found:– 4 medication abortion patients required surgery for

acute bleeding versus 0 surgical abortion patients

– 14 medication abortion patients received surgery for persistent bleeding versus 8 surgical abortion patients


Reference 12

Key Complications:Cardiopulmonary

• Mifepristone + misoprostol has caused life-threatening cardiovascular complications & at least 1 fatality (prostaglandins induces potent vasodilator action & affect heart contraction).

• In U.S. trial:– Hypotension (low BP) in 0.3%-1.4%– Hypertension (high BP) in 1.5%-1.7%– Change in heart rate by >20% in 30%-35.4%


Key Complications:Failure to Follow-Up

• Maternal risk d/t incomplete abortion, infection, hemorrhaging, & so forth.– 106 (5%) women failed to follow-up in U.S. trial. – A Seattle abortion provider, Suzanne Poppema, stated

they are "lucky if 30-40% of patients" return.

• Risk to those born after RU-486 use. – Specific birth defects are associated with misoprostol.

References10, 20

Key Complications: Emotional/Psychological Reactions

• The former Roussel Uclaf chairman stated “A woman has to 'live' with her abortion for at least a week using this technique. It's an appalling psychological ordeal.”

• Spokeswomen of Roussel Uclaf said, "When [women] take a pill, they have the feeling they are truly responsible for the abortion…”

• Christian Frenpzel, abortion facility nurse, called viewing embryos in surgical dishes “upsetting… like looking at a little row of people” & stated “women too were shocked when they looked at what they had expelled.”

Reference 19

Maternal DeathsMifepristone + Misoprostol

• Lack of Centralized Tracking

• Danco’s Reported Rate

Maternal DeathsNo Centralized Tracking In U.S.

Emerging Clostridial Disease Workshop:• Due to 2 previous cases in California heightened

regional awareness potentially “stimulated reports of additional cases that may have not been detected in other states.”

• “No centralized reporting system has been developed for pregnancy-associated infections or deaths...”

• “Laboratory confirmation of C. sordellii in these [California] cases resulted from extraordinary efforts...”

Reference 16

Maternal DeathsNo Centralized Tracking In U.S.

A young women in California died of septic shock following RU-486. After her father contacted the FDA, the state health dept. began investigating & in response:

• Officials at the hospital stated they did not feel the death qualified as an ‘unusual occurrence’.

• The abortion clinic operator stated the death was not reported by the clinic because her death occurred at the hospital.

Reference 30

• Danco reported 575,000 mifepristone users – Based on units shipped, not units used– FDA approved regimen is for 3 tablets of mifepristone, but

Danco used “denominators” to achieve an “estimated range” with the assumption most providers use 1 tablet

• Given the 575,000 “users” the known mortality rate was approximately 1.39 per 100,000.

– This rate is nearly 14 times greater than surgical abortion – H1N1 (Swine Flu) U.S. mortality rate 0.9-1.27 per 100,000

References 11, 21, 37

Maternal Deaths Reported Mortality Rate vs. Reality

Mifepristone vs. Surgical Abortion

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Mifepristone vs. Surgical Abortion

• More adverse effects & complications w/ RU-486:– Inc. pain during & at follow up (77.1% vs 10.5%)– More nausea & vomiting (68.6% vs 0.6%)– Inc. bleeding risk requiring surgery (12.5% vs 0%)– Longer post-procedure bleeding (average of 9.6 days longer)– Greater risk of death d/t infection (10 x higher)

• Higher failure rate was reported w/ RU-486: – US 18.3% vs 4.7%– China 8.6% vs 0.4%

References12, 22

– Cuba 16% vs 4%– India 5.2% vs 0%

Mifepristone vs. Surgical AbortionsU.S. FDA Medical Officer’s Review Revealed:

RU-486 requires at least 3 office visits & has a short clinically useful window plus:

• It is not an alternative to surgical abortions

• It is not more effective than surgical abortions

• It is not safer than surgical abortions

Reference 12

Real World ConsequencesLax Regulation

Image downloaded from http://www.owczarek.com.pl/blog/category/economy/

Blatant Improper Use Summit Medical Department

AP News Article: “State health officials say that in February a Summit staff member performed an ultrasound on a woman seeking an abortion and determined she was six weeks pregnant, when in fact she was nearly full-term. She was given RU-486 even though the patient’s blood pressure was dangerously high. The state health department said the woman went to an emergency room six days later with the baby's head protruding and ‘delivered a stillborn six pound, four ounce baby.”

Investigations found, 5 women had second trimester abortions (one was 19 wks pregnant & another was 21 wks pregnant).

State officials closed this center

Reference 24

Slipped to Women

• U.S. New York: Physician injected partner with methotrexate after she refused to have an abortion (2000).

• Canada: During sexual relations a man inserted misoprostol vaginally after his girlfriend refused to have an abortion & as a result pregnancy was terminated (2003).

• U.S. Wisconsin: After a 2nd miscarriage a women became suspicious of her married boyfriend & a lab confirmed RU-486 in a smoothie he made her. Upon investigation the man had a stash of RU-486 reportedly from India (2007).

• U.S. Virginia: a man crushed 2 misoprostol tablets & put them in his 19 yr old girlfriend's drink, which caused pregnancy termination (2007).

References23, 25, 26, 27, 28, 29, 44

Slipped to Women

• U.S. Maryland: A man spiked his girlfriend's drink with a cattle hormone. She went to the hospital complaining about the foul drink that burned her throat (2007).

• Britain: A husband purchased mifepristone & misoprostol over the internet & laced his wife’s food on 2 occasions (2008).

• Sweden: After refusing to abort, a man spiked his girlfriend's yogurt w/ misoprostol. Subsequently, the women aborted the baby out of fear of birth defects (2008).

• U.S. Pennsylvania: At high school a pregnant juvenile was given a drink spiked with Prostomate (cow medication). Apparently, a couple men sexual assaulted the girl at an underage drinking party (2008).

References23, 25, 26, 27, 28, 29, 44

Slipped to Women

• U.S. California: A man reportedly put a powder into his girlfriend’s vaginal area resulting in an abortion of the 13 week-old fetus (2009).

• U.S. Alaska: An Airman had a friend obtain misoprostol then placed the crushed tablets in his wife’s food, resulting in a miscarriage (2009).

• London: a physician spiked his mistress’ drink w/ “drugs” (2009).• U.S. New York: A pharmacist allegedly inserted misoprostol

during sexual intercourse with his girlfriend on 2 occasions, which resulted in a miscarriage (2010).

• U.S. Utah: A man placed misoprostol in her girlfriend's food twice, resulting in her delivering a 16-week stillborn baby (2010).

References23, 25, 26, 27, 28, 29, 44

Ulipristal(Ella®, EllaOne®)

Image downloaded from http://www.pharmacytimes.com/media/image/Ella.jpg

Ulipristal: “structurally related” to mifepristone

Substitution on the 17th carbon resulted in a compound (ulipristal), “which exhibited antiprogestational and antiglucocortocoid activity similar to mifepristone”

References31, 38

Mifepristone Ulipristal

Mechanism of Action How It Works

Ulipristal: Progesterone Receptor Antagonist• Ulipristal & mifepristone can suppress the release

of an egg at low doses thus preventing ovulation. • Ulipristal & mifepristone have an effect on the

lining of the womb, which can discourage/prevent implantation.

• Ulipristal & mifepristone powerfully block progesterone, which is needed for pregnancy to begin and continue.

References32, 33

Mechanism of Action How They Work

Progesterone

Mifepristone & Ulipristal

The Lock = Progesterone Receptor(must be open to begin & continue pregnancy)


Mechanism of Action How They Work

Ulipristal: Selective Progesterone Activity? • “CDB 2914 [ulipristal] has shown progesterone

antagonist without agonist activity in all studies published”

• Ulipristal “prevents progesterone from occupying its receptor… and the proteins necessary to begin and maintain pregnancy are not synthesized.”

• Ulipristal & mifepristone “act as pure antagonist” of progesterone


Ulipristal: Indicated for emergency contraception • Two trials indicated ulipristal was “not inferior” or

no worse than Plan B® for preventing pregnancy.

• Use after >72 hours: − Fine et al: “sample sizes in the intervals of 72-96 hours

and 96-120 hours warranting further investigation with larger numbers”

− Glasier et al: had an insufficient no. of participants >72 hours to prove safety & efficacy

Point: gaps in the available data still exist



Ulipristal: Gaps in Available Data • Efficacy & safety after >72 hours• Maternal & fetal consequences if used during pregnancy • Maternal & fetal safety if pregnancy continues • Potential immune suppression (ulipristal displays anti-

glucocorticoid activity as detected by elevated cortisol)• Implications of the longer duration of action than

levonorgestrel & activity of metabolites (CDB-3877A) • Better generalisability to women in the ‘real world’ • Establish safety of repeated use

References42, 43


Ulipristal: Medication Abortion Post Implantation?

• In animal studies, ulipristal was found to be more potent than mifepristone at terminating pregnancies in rats and equally potent in monkeys & guinea-pigs.

• In humans, 2 trials reported pregnancy outcomes after using ulipristal for EC: The result was 90% ended in miscarriage for those w/ known outcomes that did not choose to abort (limited no).

References 34, 35, 36 , 39, 40, 41


Ulipristal: U.S. New Drug Application• “Data on pregnancy outcomes after EC failure with

ulipristal were too limited to draw any definitive conclusions regarding the effect of ulipristal”.

• Reproduction studies in pregnant rats & rabbits at exposures comparable to human dosage:

− Caused “embryofetal lethality”

− Drug exposure evaluations were “severely limited by the difficulty in maintaining pregnancy”

Reference 42

•Very Common (≥ 1/10)– Abdominal Pain – Menstrual Disorder

•Common (<1/10 but ≥1/100)– Infection – Mood Disorders – Headache – Dizziness – Nausea/Vomiting – Dyspepsia– Muscle Spasm – Back Pain– Menstrual Changes – Fatigue

When used within 120 hours of sexual intercourse

Reference 33

Adverse EffectsDuring U.S. Clinical Trials for EC Use

Closing Opinion

As a woman & healthcare professional, I hope we will

begin to proactively address unplanned pregnancy rather than

continually resort to jeopardizing women’s health with afterthought solutions.

References

1. Foster AM. Medication Abortion: A Guide for Health Professionals. Ibis Reproductive Health. Cambridge, MA: 2005.

2. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: Pharmacokinetic profiles, effects on the uterus and side-effects. International Journal of Gynecology and Obstetrics. 2007;99: 160-67.

3. Norman JE, Thong KJ, Baird DT. Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet. 1991;338:1233-36.

4. Jain J, Dutton C, Harwood B, Meckstroth K, Mishell D. A prospective randomized, double-blinded, placebo-controlled trial comparing mifepristone and vaginal misoprostol to vaginal misoprostol alone for elective termination of early pregnancy. Human Reproduction. 2002;17(6):1477-82.

5. Baird DT. Mode of Action of Medical Methods of Abortion. J Am Med Womens Assoc. 2000;55(3):121-26.

6. Ibis Reproductive Health. Medication Abortion Facts and Information for Health Care Professionals, Misoprostol Alone. www.medicationabortion.com/misoprostol/index.html (accessed Jan 12, 2011).

7. G.D. Searle LLC. Cytotec® misoprostol tablets. Medication Guide. Revised Sept 2009.8. Medication Guide, Mifeprex, FDA.

www.fda.gov/cder/drug/infopage/mifepristone/mifeprexMedguide20050719.pdf (accessed April 13, 2007).

9. Elia D. The Antiprogestin Steroid RU 486 and Human Fertility Control. New York, New York, Plenum Press: 1985;211-20.

References

10. Spitz IM, Bardin CW, Benton L, Robbins A. Early Pregnancy Termination with Mifepristone and Misoprostol in the United States. New England Journal of Medicine. 1998;338(180):1241-47.

11. The FDA and RU-486: Lowering the Standard for Women’s Health. Staff Report prepared for the Hon. Mark Souder, Chairman, Subcommittee on Criminal Justice, Drug Policy and Human Resources, October 2006.

12. Medical Officer’s Review of Amendments 024 and 033, Final Reports for the U.S. Clinical Trials Inducing Abortion up to 63 Days Gestational Age and Complete Responses Regarding Distribution System and Phase 4 Commitments, Finalized Nov 22, 1999 (dated Jan 27, 2000), www.fda.gov/cder/foi/nda/2000/20687_Mifepristone_medr_P1.pdf (accessed Sept 28, 2008).

13. Rarick L. Transcript of Testimony before the FDA Reproductive Health Drugs Advisory Committee. July 19, 1996;134.

14. Government Accountability Office. Drug Safety: Improvement Needed in FDA's Postmarket Decision-Making and Oversight Process. Report to Congressional Requesters. GAO-06-402 March 31, 2006.

15. Woodcock, J. Testimony on RU-486:Demonstarting a Low Standard for Women’s Health. US Department of Health and Humans Services. Washington, DC; May 2006.

16. Department of Health and Human Services. Emerging Clostridial Disease Workshop. Transcript of Proceedings. May 11, 2006. www.fda.gov/cder/meeting/clostridial/meeting_transcrript.pdf (accessed May 10, 2007).

17. Gary MM, Harrison DJ. Analysis of severe adverse events related to the use of mifepristone as an abortifacient. Annals of Pharmacotherapy . 2006;40(2):191-97.

References

18. Nakano J, McCurdy, RJ. Cardiovascular Effects of Prostaglandin E1. Journal of Pharmacology And Experimental Therapeutics.1967;156(3):538-47.

19. RU486Facts Organization. Medical Information About RU-486 (Mifepristone). http://www.ru486facts.org/index.cfm (accessed Feb 14, 2008).

20. Glasow, R. Some Important Questions for “RU 486 Advocates”. Jan 2000. http://www.lifeissues.org/ru486/ru4862000/ru00-01.html (accessed Feb 12, 2011).

21. Brown, D. H1N1 death rate is elevated for Indians, Alaska natives. The Washington Post. Dec 11, 2009.

22. Shuping M, Harrison D, Gacek C. Medical Abortion with Mifepristone (RU-486) Compared to Surgical Abortion.

23. Wright W. Drug Like RU-486 May Be Approved as Morning-After Pill. http://www.cwfa.org/printerfriendly.asp?id=19109&department=cwa&categoryid=life (accessed Feb 10, 2011).

24. Associated Press. Alabama Abortion Clinic to Stay Shut. Washington Post online. http://www.washingtonpost.com/wp-dyn/content/article/2006/06/14/AR2006061402542.html (accessed Oct 23, 2008).

25. Jones, M. Man Accused of Causing Miscarriage. Milwaukee Journal Sentinel. http://www.jsonline.com/story/index.aspx?id=691665 (accessed Oct 23, 2008).

26. Gibbs, F. ‘Loner’ Husband Tried to Abort Child by Hiding Pills in Wife’s Breakfast. The Times (London). March 1, 2008.

27. Associated Press. Court: Man put abortion pills in lover's food. Feb 26, 2008 http://www.msnbc.msn.com/id/23358791/from/ET/ (accessed Feb 4, 2011).

References

28. Dyer, C. Misconduct panel investigates research of doctor convicted of lacing lover’s drink. BMJ 2009; 339:b4906.

29. KABC-TV/DT. L.A. man accused of causing miscarriage. October 29, 2009. http://abclocal.go.com/kabc/story?section=news/local/los_angeles&id=7088931&pt=print (accessed Feb 26, 2011).

30. Chronicle Staff and Wire Report. Abortion-pill death wasn’t reported to state as ‘unusual’. San Francisco Chronicle. Feb 27, 2004;A-25.

31. Larner JM, Reel JR, Blye RP. Circulating concentrations of the antiprogestins CDB-2914 and mifepristone in the female rhesus monkey following various routes of administration. Human Reproduction. 2000;15(5):1100-06.

32. Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM. Selective progesterone receptor modulators and progesterone antagonists: mechanism of action and clinical applications. Human Reproductive Update. 2005;11(3):293-307.

33. European Medicines Agency. CHMP Assessment Report for Ellaone. Document reference EMEA/261787/2009.

34. Glasier AF, Cameron ST, Fine PM, Logan SJ, Casale W, Van Horn J, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomized non-inferiority trial and meta-analysis. Lancet . Published online Jan 28, 2010.

35. Creinin MD, Schlaff W, Archer DF, Wan L, Frezieres R, Thomas M, et al. Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol. 2006;108(5):1089-97.

References

36. Fine PT, Mathe H, Ginde S, Cullins V, Morfesis J. Ulipristal Acetate Taken 48–120 Hours After Intercourse for Emergency Contraception. Obstet Gynecol. 2010;115(2):1–7.

37. Green MF. Fatal Infections Associated with Mifepristone-Induced Abortion. N Engl J Med. Dec. 1, 2005;353(22):2317-18.

38. Rao et al., 11β-Substituted 13β-ethyl gonane derivatives exhibit reversal of antiprogestational activity. Steroids. 1998;63(1):50-57.

39. Tarantal AF et al., Effects of two antiprogestins on early pregnancy in the long-tailed macaque. Contraception. 1996;54:107-15.

40. Poyser NL, Forcelledo ML. A comparison of the pregnancy-terminating potencies of three anti-progestins in guinea-pigs, and the effects of sulprostone. Prostaglandins, Leukotrienes and Essential Fatty Acids. 1994;50(5):245-47.

41. Teutsch G, Philibert D. History and perspectives of antiprogestins from the chemist’s point of view. Hum Reprod. 1994;9:12-31.

42. Food and Drug Administration’s Division of Reproductive and Urologic Products. Background Document for Meeting of Advisory Committee for Reproductive Health Drugs. NDA 22-474, Ulipristal Acetate. 20 May 2010.

50. Spitz IM. Progesterone Receptor Antagonist. Current Opinion in Investigational Drugs. 2006;7(10):882-90.

51. Pregnant girl slipped cow abortion drug, police say. The Tribune-Democrat online. April 12, 2008. http://tribune-democrat.com/local/x519161660/In-brief (accessed Feb 28, 2011).

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