Mifepristone/misoprostol regimen

• Overview and history
• Mifepristone worldwide
• Mifepristone in the US
• Mechanism of action of mifepristone
• How to use mifepristone/misoprostol
  • French regimen
  • US: FDA approved regimen
  • Other evidence-based regimens
• Efficacy
• Eligibility
• Contraindications
• Side effects and complications
• Acceptability
• Additional uses of mifepristone
• Citations in this section
• Links

Overview and history

Mifepristone was developed during the early 1980s by researchers at the French pharmaceutical company Roussel Uclaf. While investigating glucocorticoid receptor antagonists, investigators discovered that some of the compounds blocked the similarly shaped progesterone receptor. Refinement of the compound led to the production of RU 486, the medication now known as mifepristone.

Clinical testing of mifepristone began in Europe in 1982. The results from the clinical trials showed that mifepristone, when used alone, induced a complete abortion in 60% of women with pregnancies up to 49 days' gestation. Investigators then discovered that by adding small doses of a prostaglandin analog on the last day of mifepristone treatment, the complete abortion rate increased to over 95%. France became the first country to license the mifepristone/prostaglandin analog regimen for early abortion in 1988 [1].

Mifepristone worldwide

Since 1988, Mifepristone has been registered for medication abortion use in over thirty five other countries worldwide including Albania, Armenia, Austria, Azerbaijan, Belarus, Belgium, China, Denmark, Estonia, Finland, Georgia, Germany, Great Britain, Greece, Guyana, Hungary, India, Israel, Latvia, Luxembourg, Moldova, Mongolia, the Netherlands, New Zealand, Norway, Portugal, Romania, Russia, Serbia, South Africa, Spain, Sweden, Switzerland, Tunisia, Ukraine, the United States, Uzbekistan, and Vietnam. In 2009, the Therapeutic Goods Administration in Australia granted a number of clinicians and facilities access to mifepristone for the purpose of early pregnancy termination.

Mifepristone may also be available in additional countries through the black market. In unregulated markets, the quality of mifepristone may vary and thus the reliability of the source should be examined.

Worldwide over 30 million women have used mifepristone and a prostaglandin analog to terminate pregnancy with impressive safety and efficacy. In France, Sweden, and Great Britain, where mifepristone has been available for more than 15 years, there has been an increase in the proportion of abortions performed at earlier gestation [2].

Mifepristone in the US

In September 2000, the US Food and Drug Administration (FDA) approved the use of mifepristone in combination with misoprostol for early pregnancy termination. Since the approval of the mifepristone/misoprostol regimen, medication abortion has become an integral component of abortion care in the US. Over one million women in the US have used mifepristone/misoprostol to terminate a pregnancy and the method accounts for approximately one in five early abortions [3]. The number of abortion providers offering medication abortion also has steadily increased [4]. In the US, the brand names of mifepristone and misoprostol are Mifeprex™ and Cytotec®, respectively.

Mechanism of action of mifepristone

Mifepristone (a synthetic steroid) is an anti-progestin that blocks the action of progesterone, a hormone necessary to maintain a pregnancy. By blocking the action of progesterone, mifepristone alters the endometrium (the uterine lining), induces menstrual bleeding, and causes the uterine lining to shed. Mifepristone also causes the cervix to soften and initiates uterine contractions.

Mifepristone is used in conjunction with misoprostol. Misoprostol is an analog of prostaglandin E₁. By interacting with prostaglandin receptors, misoprostol causes the cervix to soften and the uterus to contract, resulting in the expulsion of the uterine contents.

How to use mifepristone/misoprostol

France: Labeled regimen

The mifepristone/misoprostol regimen is approved up to 49 days' gestation. Women are required to orally take 600mg of mifepristone (Mifegyne™). Thirty-six to forty eight hours later, women are required to either orally take 400µg (micrograms) of misoprostol or 1mg of vaginally administered gemeprost (also a prostaglandin analog). Ten to fourteen days after taking mifepristone, the patient is required to return for a follow-up visit to determine whether the pregnancy has been terminated [5].

US: FDA approved regimen

The research that the FDA reviewed for approval was based on the original French regimen, developed two decades ago. In the US, the mifepristone/misoprostol regimen was FDA approved up to 49 days' gestation and specifies that a woman orally take 600mg of Mifeprex™ and 400µg (micrograms) of misoprostol two days later (orally). Approximately fourteen days after taking mifepristone, the patient is required to return for a follow-up visit to determine whether the pregnancy has been terminated.

Other evidence-based regimens

A number of studies have shown that alternative regimens to the FDA approved protocol are effective and safe. The most common modification involves decreasing the dose of mifepristone to 200mg [6]. Studies have also shown that misoprostol can be vaginally administered either one, two, or three days after mifepristone use, with no loss in efficacy, compared to the FDA approved two-day protocol [7]. Other studies have shown that the mifepristone/misoprostol regimen can be extended up to 63 days' gestation [8]. Vast experience also supports the safety, efficacy, and acceptability of home-administration of misoprostol. Studies have also called into question the need for a routine, in-person post-abortion visit, especially for terminations occurring < 49 days' gestation [9]. Results from a mifepristone/misoprostol clinical trial conducted in China, Cuba, and India suggest that women who experience an incomplete abortion are able to identify their condition correctly [10]. Investigation into possible alternatives to universal in-person follow-up, such as telephone follow-up with home pregnancy testing and in-person follow-up for selected patients, is ongoing.

The following table compares the labeled French regimen, the FDA approved protocol, and the other evidence-based regimens.

	French labeled protocol	FDA approved protocol	Other evidence-based regimens
Mifepristone Dosage	600mg (Day 1)	600 mg (Day 1)	200 mg (Day 1)
Misoprostol Dosage	400µg, PO (Alternative: 1mg gemeprost, PV)	400µg, PO	400µg, PO or 800µg, PV
Gestational Limit	<49 days	<49 days	<63 days
Location of misoprostol administration	At medical office/clinic	At medical office/clinic	At medical office/clinic or at home
Timing of misoprostol administration	Day 2 or 3	Day 3	Day 2, 3, or 4
Timing of initial follow-up examination	Day 10 to 14	Day 14	Day 4 to 14
Number of clinic visits required	Three or more	Three or more	Two or more

Regardless of which regimen is used, there are several steps involved in obtaining a medication abortion with mifepristone/misoprostol.

• Step I: A clinician counsels the woman, takes a medical history, performs a physical exam, and performs laboratory tests. Accurate dating of the pregnancy is critical and can occur through either clinical assessment or ultrasound. If the woman is eligible for a medication abortion using mifepristone/misoprostol she takes mifepristone orally. Pain medication is commonly prescribed at this time, in case the woman needs it later.
• Step II: One to three days after taking mifepristone, the woman takes misoprostol to complete the abortion. This can be taken at home or in the clinic, depending on the protocol. Rarely, a woman may abort after the mifepristone alone.
• Step III: Several to fifteen days later, the woman returns to the doctor's office or clinic for an evaluation to make sure the abortion is complete. Completion is often clinically evident, but sometimes an ultrasound is necessary for confirmation. The only ultrasound finding which reliably demonstrates incompletion is the presence of a persistent gestational sac. If the abortion is not complete, the clinician will discuss treatment options with the patient. These options may include waiting and reevaluating for a complete abortion, administering additional misoprostol, or performing a vacuum aspiration to empty the uterus.

Efficacy

Numerous studies have now overwhelmingly demonstrated the efficacy and safety of the mifepristone/misoprostol regimen. Approximately 95% of women will have a successful abortion when using mifepristone/misoprostol within 49 days from the onset of the last menstrual period. Medication abortion completion rates appear are higher at earlier gestational ages [11]

With respect to the timing of the abortion, approximately, 67% of women will have a complete abortion within four hours of using misoprostol and approximately 90% of women will have a complete abortion within 24 hours of using misoprostol.

For women who do not experience a complete abortion an aspiration intervention may be required. Reasons for an aspiration intervention include prolonged or excessive bleeding, incomplete abortion (remnants of fetal tissue in the uterus), or an ongoing pregnancy. An aspiration termination may also be performed at the request of the woman or the provider. Ongoing pregnancy occurs in fewer than 1% of cases, when treatment has been started <49 days' gestation.

Eligibility

Most women with a pregnancy of <63 days' gestation can use the mifepristone/misoprostol regimen. If the use of mifepristone/misoprostol does not result in a complete abortion, vacuum aspiration or dilation and curettage (D&C) may be necessary. Women considering the mifepristone/misoprostol regimen should be willing to undergo an aspiration procedure, if indicated.

Contraindications

According to the label, there are a number of contraindications to mifepristone/misoprostol use. These include: confirmed or suspected ectopic (extra-uterine) pregnancy; a history of allergy to either mifepristone or misoprostol; chronic systemic use of corticosteroids; chronic adrenal failure; coagulopathy or current therapy with anticoagulants; and inherited porphyria. Further, if an intrauterine device (IUD) is present, the device must be removed before a mifepristone/misoprostol termination can be performed [12]. In addition, women with chronic medical conditions, including hypertension, severe hepatic or renal disease, and severe anemia, should be evaluated individually.

Side effects and complications

Some side effects, such as abdominal cramping and bleeding, are hallmarks of the abortion process itself. Many women and clinicians report cramps and abdominal pain similar to those associated with a heavy menstrual period. Vaginal bleeding can vary significantly in both duration and severity, and many report that the bleeding resembles a heavy period or a spontaneous miscarriage. One study of mifepristone used with a vaginal prostaglandin to treat women through 63 days' gestation found that median blood loss was about 75ml, compared with 50ml typically lost during menses [13]. The range of bleeding is correlated to the length of gestation and can extend up to several hundred milliliters. Light bleeding and spotting can last for 1-3 weeks. Reported median bleeding times range from 9-13 days. The heaviest period of bleeding typically occurs when the abortion is occurring and persists for 1 to 4 hours [14].

Side effects of the medications include nausea, vomiting, diarrhea, fever, and chills. In most cases, side effects can be managed with appropriate counseling and symptomatic treatments, such as oral analgesics for pain. Temperature elevation (defined as more than 100.4°F or 38°C) that is sustained (more than four hours) or begins more than 6 to 8 hours after misoprostol administration warrants clinical assessment.

To date, there is no evidence that mifepristone has teratogenic effects on the fetus. Several case reports have associated misoprostol use with limb defects and Mobius syndrome. However, an absolute causal relationship between misoprostol use and fetal deformities has yet to be demonstrated through prospective trials.

Complications

On rare occasions, uterine bleeding can be extremely heavy or prolonged. Some clinicians treat excessive bleeding with an ergot alkaloid such as methylergonovine maleate (Methergine) before resorting to aspiration. Bleeding significant enough to require transfusion is rare and is most likely to occur 1 to 3 weeks after taking the medications. Approximately 1% of women experience uterine bleeding that requires vacuum aspiration and about 0.1% require transfusion [15].

In 2% to 5% of cases, the medication abortion is incomplete. Patients may require vacuum aspiration, to resolve an incomplete abortion, end a continuing pregnancy, or control bleeding.

Acceptability

Studies in the US, Europe, Asia, Latin America, and the Middle East have demonstrated high rates of acceptability among patients using the mifepristone/misoprostol regimen [16]. Indeed, more than 90% of women in most studies reported being satisfied with the regimen. Several studies have found that more than 85% of women would choose the regimen again as well as recommend the regimen to a friend [17]. Even among women who experienced an incomplete abortion, more than two thirds reported that they would use the regimen again [18].

Women consistently report that the best features of the mifepristone/misoprostol regimen include:

1. The ability to avoid surgery and anesthesia;
2. The perception that the process is more "natural";
3. The perception of privacy; and
4. The convenience

Women also consistently report that the least liked features of the process include:

1. Length and degree of bleeding;
2. Number of clinic visits; and
3. Uncertainty as to whether or not the procedure had resulted in a complete abortion

Additional uses of mifepristone

Research is currently underway to study other beneficial uses of mifepristone. Issues under investigation include the use of mifepristone in labor induction, infertility treatment, and fibroid and meningioma tumors treatment. Studies have also shown that mifepristone when used in low doses serves as an effective post-coital contraceptive method [19].

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Citations in this section
[1] Creinin M, 2000.
[2] Jones R and Henshaw S, 2002.
[3] Finer L and Wei J, 2009.
[4] Finer L and Henshaw S, 2003.
[5] Mifegyne website
[6] Von Hertzen H, 2000.
[7] Schaff E et al, 2000.
[8] Newhall E and Winikoff, 2000.
[9] Grossman D et al, 2004; Harper C, Ellertson C and Winikoff B, 2002.
[10] Ellertson C, Elul B and Winikoff B, 1997.
[11] Spitz I et al, 1998.
[12] Ellertson C and Waldman S, 2001.
[13] Rodger M and Baird D, 1997.
[14] Spitz I et al, 1998.
[15] World Health Organization Task Force on Post-ovulatory Methods of Fertility Regulation, 1993; Spitz I et al, 1998.
[16] Clark S, Ellertson C and Winikoff B, 2000; Bygdeman M, Gemzell K and Marions L, 2000; Shangchun W, 2000; Coyaji K, 2000; Newhall E and Winikoff B, 2000; Elul B et al, 2001.
[17] Schaff E and Fielding S, 2000; Clark S, Ellertson C and Winikoff B, 2000.
[18] Clark S, Ellertson C and Winikoff B, 2000.
[19] XXX

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