Mifepristone 100 mg in abortion regimens

doi:10.1016/S0029-7844(01)01462-4

Obstetrics & Gynecology

Volume 98, Issue 3, September 2001, Pages 434-439

https://doi.org/10.1016/S0029-7844(01)01462-4 Get rights and content

Abstract

OBJECTIVE:

To examine the clinical efficacy of mifepristone 100 mg followed 2 days later by misoprostol 400 μg orally or 800 μg vaginally in women at up to 49 days’ gestation.

METHODS:

Eighty participants received mifepristone 100 mg and then were randomized to misoprostol, administered 48 hours later, at a dose of 400 μg orally (group 1) or 800 μg vaginally (group 2). Women returned for follow-up evaluations 24 ± 1 hour after using the misoprostol and then 2–3 weeks later. If abortion still had not occurred and the pregnancy was nonviable, the subject returned again after an additional 3 weeks.

RESULTS:

Twenty-four hours after receiving misoprostol, 34 (85%; 95% confidence interval [CI] 71%, 94%) of the 40 women in group 1 and 38 (95%; 95% CI 85%, 99%) of the 40 women in group 2 had complete abortions. Overall, complete abortion without surgical intervention occurred in 34 women in group 1 (85%; 95% CI 71%, 94%) and 40 women in group 2 (100%; 95% CI 91%, 100%; P = .03). Four women in group 1 required suction aspiration for continuing pregnancy at the second follow-up, compared with none in group 2 (P = .12). Side effects occurred with similar frequency in both treatment groups.

CONCLUSION:

Low-dose mifepristone (100 mg) combined with vaginal misoprostol 800 μg may be an effective alternative to regimens using 200 or 600 mg of mifepristone with misoprostol.

Section snippets

Materials and methods

This clinical trial was approved by the Institutional Review Board of Magee-Womens Hospital of the University of Pittsburgh Health System. Entry criteria included 1) age at least 18 years, 2) a singleton intrauterine pregnancy not exceeding 49 days’ gestation as documented by vaginal ultrasound, 3) request for an abortion, 4) willingness to comply with the visit schedule, 5) willingness to have a surgical abortion if indicated, 6) adequate venous access for multiple phlebotomies, and 7) access

Results

Patient characteristics are presented in Table 1. All 80 subjects used the misoprostol, although histories obtained at first follow-up suggested that two women in group 1 and one woman in group 2 might have aborted before using the misoprostol. All but one of the women in group 1 (98%) and 38 (95%) of the women in group 2 used the misoprostol 48 hours ± 30 minutes after administration of mifepristone. The three women who did not use misoprostol during this time inserted the misoprostol tablets

Discussion

Mifepristone at doses less than the 600 mg, standardly used throughout most of the world, is known to be clinically effective. Two randomized studies demonstrated equal efficacy of regimens using either 200 or 600 mg of mifepristone followed in 48 hours by a misoprostol dose of 400 μg orally6 or 600 μg orally.7 In addition, a retrospective analysis by Ashok et al8 of data from 2000 women using mifepristone 200 mg followed in 48 hours by misoprostol 800 μg vaginally demonstrated complete

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Cited by (29)

Bioavailability of mifepristone in capsule versus tablet form in healthy nonpregnant women
2008, Contraception
Citation Excerpt :
In China, 150 mg mifepristone po combined with 600 mcg misoprostol po is common, and the regimen is also effective for the termination of pregnancy of up to 49 days' gestation [4]. Even a 100-mg dose of mifepristone could achieve the efficacy [5–7]. So far, some research effort has been made to find the optimal dose of mifepristone.
The study was conducted to assess the bioavailability of two formulations of mifepristone in capsule and tablet forms at a single dose of 75 mg (half the registered dose in China).
A randomized two-way crossover study was conducted in 18 healthy nonpregnant women. Each subject was orally given a single dose of mifepristone at 75 mg in capsule or tablet form on an alternate basis. Serial blood samples were collected over a period of 96 h and assayed for the plasma concentration of mifepristone by high-performance liquid chromatography. Paired t tests were used to compare the capsule and tablet forms in terms of maximum concentration (C_max), time to maximum concentration (T_max) and area under the curve over 96 h (AUC_0–96h). Relative bioavailability (capsule/tablet) was derived from AUC_0–96h. Bioequivalability was analyzed by two one-sided t tests.
The major pharmacokinetic parameters were as follows: C_max values were 1.26±0.38 and 1.25±0.40 mcg/mL, T_max values were 0.94±0.34 and 0.89±0.47 h, T_1/2Ke values were 36.2±21.0 and 33.4±12.3 h and AUC_(0–96h) values were 19.7±6.4 and 19.6±9.9 mcg·h/mL for mifepristone in capsule and tablet forms, respectively. No significant difference was observed among these parameters. The relative bioavailability was 109.4±34.8%.
This study suggests that the two formulations of mifepristone are bioequivalent, which provides pharmacokinetic evidence for further reducing the dosage of mifepristone in clinical use.
Update on Medication Abortion
2007, Journal of Midwifery and Women's Health
Citation Excerpt :
Both were conducted with the goal of decreasing the costs associated with abortion. Comparison of these studies is complicated by the fact that they varied in the dose of mifepristone as well as the type, dose, and route of administration of misoprostol.32,33 Creinin et al. studied the efficacy of a 100-mg dose of mifepristone given in pregnancies up to 49 days gestation.32
This article provides an overview of medication abortion in the United States 6 years after the approval of mifepristone (RU486; Mifeprex; Danco Laboratories, LLC, New York, NY) by the US Food and Drug Administration (FDA). The adoption of mifepristone is considered in the context of epidemiologic data on abortion, abortion access, and the safety of abortion. The risks of medication and aspiration abortion are discussed in the context of abortion-related mortality, recent experience with obstetric and gynecologic infection with Clostridium sordellii, and the limits of scientific knowledge on the incidence of this infection in women. Innovative protocols studied since FDA approval of mifepristone are presented, and implications for clinical practice are discussed.
Simultaneous very low dose mifepristone and vaginal misoprostol for medical abortion
2006, Contraception
This pilot study was designed to evaluate the outcome of medical abortion following simultaneous mifepristone (100 mg) and misoprostol (800 μg).
Enrollees had gestational ages up to 56 days and desired a medical abortion. They received 100 mg of mifepristone orally and 800 μg of misoprostol vaginally. Follow-up examination occurred in 2–7 days. A phone call 3 weeks later assessed symptoms and acceptability. A 95% success rate, as seen in higher dose studies, gives a 95% confidence interval of 88–100% for 40 subjects.
Forty women were enrolled; 39 women had follow-up visits. Completed medical abortion was confirmed for 35 (90%) of 39 women. Four women had uterine aspiration. Two patients required repeat misoprostol. Median time from medication to abortion was 7 h. Most women (92%) strongly preferred taking all medications in the clinic.
The simultaneous administration of vaginal misoprostol with 100 mg of oral mifepristone had the outcome of completed abortion within the predicted confidence interval. In addition, simultaneous dosing was highly acceptable.
Mifepristone 100mg for early medical abortion
2005, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
Évaluation de l’efficacité et de la tolérance de la mifépristone à la dose de 100 mg relayée 48 heures plus tard par du misoprostol à la dose de 400 μg par voie orale dans l’interruption volontaire de grossesse de moins de 57 jours d’aménorrhée.
Étude rétrospective sur 8 mois et demi de 762 cas d’interruption volontaire de grossesse. La mifépristone est utilisée à la dose de 100 mg à J1 après un examen clinique et une échographie pelvienne. Le misoprostol est donné par voie orale à la dose de 400 μg à J3. La patiente est gardée en observation les 4 premières heures suivant le misoprostol. Une visite de contrôle à J15 est systématiquement réalisée. Le critère de jugement principal est l’efficacité du protocole définie par l’expulsion totale sans recours à une aspiration chirurgicale.
Les avortements médicamenteux représentent 42 % de l’ensemble des avortements. Seize pour cent des grossesses étaient de moins de 43 jours, 76 % de 43 à 49 jours et 8 % de 50 à 56 jours ; 80,2 % des expulsions sont survenues dans les 4 premières heures suivant la prise du misoprostol. Une seule expulsion est survenue avant la prise du misoprostol. Le taux de succès dans notre série est de 94,4 %. Le taux d’échec augmente avec l’âge de la grossesse. Les effets secondaires sont dominés par les douleurs. Six cas d’hémorragie ont nécessité une aspiration chirurgicale en urgence. Aucune patiente n’a été transfusée. Quatre-vingt-seize pour cent des patientes se sont présentées à la visite de contrôle. Le taux d’acceptabilité a été de 94 %.
La mifépristone à la dose de 100 mg relayée 48 heures plus tard par du misoprostol à la dose de 400 μg par voie orale est une méthode efficace et sûre dans les interruptions médicales de grossesses précoces.
To assess the clinical efficacy of mifepristone 100mg followed two days later by misoprostol 400μg orally in women undergoing medical termination of pregnancy up to 56 days gestational age.
Retrospective study over 8.5 months of 762 cases early medical abortion. 100 mg mifepristone was used on day 1 after clinic visit and vaginal ultrasonography. Misoprostol 400μg was administered orally on day 3. Following administration of prostaglandin, women were observed in the ward for 4 hours. A control visit on day 15 was systematic. Success was defined as a complete uterine evacuation without the need for surgical intervention.
Medical terminations accounted for 42% of all abortions. 16% of women were pregnant for <42 days, 76% for 43 to 49 days and 8% for 50 to 56 days. Termination occurred within 4 hours after administration of misoprostol in 80.2% of the women. Only one woman aborted within 48 hours of mifepristone administration only. The success rate in this study was 94.4% and the failure rate increased with the gestational age. Pain was the predominant side effect. Six cases of bleeding required a surgical intervention. No patient required transfusion. 96% of patients attended a control visit on day 15. The acceptability rate of the method has been 94%.
Mifepristone 100mg followed two days later by misoprostol 400μg orally is safe and effective for early termination of pregnancy.
Randomized, double-blind, controlled trial of mifepristone in capsule versus tablet form followed by misoprostol for early medical abortion
2004, European Journal of Obstetrics and Gynecology and Reproductive Biology
Objective: To compare the efficacy and side-effects of mifepristone 75 mg in capsule form versus 150 mg in tablet form followed by misoprostol for medical termination of early pregnancy. Study design: In a prospective randomized, double-blind, placebo-controlled trial, a total of 480 women who were 49 days or less pregnant were randomized by means of a random number table to receive either two tablets in the morning and one tablet 12 h later for 2 days (group A) or three capsules orally twice daily for 2 days, the first dose being double all subsequent doses (group B). After a further 48 h, 600 μg misoprostol was given orally. Successful abortion was defined as complete abortion with no need for surgical aspiration. Results: There were no significant differences between the two study groups in the rates of complete abortion (95.4% in group A versus 96.3% in group B), incomplete abortion (3.8% in group A, 3.3% in group B) and continued pregnancy (0.8% in group A, 0.4% in group B). No significant difference in the duration and amount of vaginal bleeding was observed. The incidence of side-effects, such as vomiting, nausea, headache, diarrhea and lower abdominal pain was similar in the two groups. Conclusions: Our results indicate that 75 mg mifepristone in capsule form combined with 600 μg misoprostol is as effective and safe as 150 mg mifepristone in tablet form for the termination of pregnancy up to 49 days.
The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action
2003, Contraception
The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25–30 h, and high micromolar serum concentrations following ingestion of doses of ≥100 mg of the drug. The serum transport protein—α 1-acid glycoprotein (AAG)—regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4. The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges similar to those of the parent mifepristone. Thus, the combined pool of mifepristone—plus its metabolites—seems to be responsible for the biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ from those needed in emergency contraception—mifepristone is effective in emergency contraception at a dose of 10 mg, which results in linear pharmacokinetics. However, the ≥200 mg doses of mifepristone needed for optimal abortifacient effects of mifepristone result in saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2–5 mg, respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical arena.

View all citing articles on Scopus

^☆: Supported by the Departmental Research Fund, Magee-Women’s Research Institute Family Planning Research Fund.

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Original researchMifepristone 100 mg in abortion regimens☆

Abstract

Section snippets

Materials and methods

Results

Discussion

Am J Obstet Gynecol

Am J Obstet Gynecol

Contraception

Contraception

J Steroid Biochem

J Steroid Biochem

Contraception

Contraception

Am J Obstet Gynecol

Contraception

Fertil Steril

Contraception

Contraception

Am J Obstet Gynecol

Original research
Mifepristone 100 mg in abortion regimens☆