Elsevier

Contraception

Volume 74, Issue 1, July 2006, Pages 48-55
Contraception

Review article
Mifepristone and misoprostol sequential regimen side effects, complications and safety

https://doi.org/10.1016/j.contraception.2006.03.016Get rights and content

Abstract

Exhibiting a strong affinity to the progesterone and the glucocorticoid receptors, mifepristone exert competitive antagonism to these hormones both in in vitro and in animal experiments. Due to its antiprogesterone activity, it was proposed that mifepristone be used for the termination of early human pregnancy. Mifepristone, at a dose of 600 mg initially used alone, was then used with a subsequent low dose of prostaglandin that led to a success rate of 95% as a medical method for early termination of pregnancy (TOP), and the occurrence of continuing pregnancy was reduced to ≤1%. Its use was extended to other indications, such as cervical dilatation prior to surgical TOP in the first trimester, therapeutic TOP for medical reasons beyond the first trimester and for labor induction in case of fetal death in utero. The efficacy and safety of this treatment have been confirmed based on its use for over 15 years since its first approval in France and with close adherence to the approved recommendations. This article describes the toxicology studies conducted in animals as well as the safety follow-up and side effects reported with use of the compound when used with misoprostol in the main indication that is currently approved in 31 countries. Special emphasis is given to the rare but relevant safety issues, that is, heavy uterine bleeding, pelvic infections and continuing pregnancies. The rationale for warnings and contraindications for use of the product are also explained.

Introduction

Mifepristone is an orally active synthetic steroid with antiprogesterone and antiglucocorticoid activities. To date, mifepristone is approved in several countries for use in four indications: early termination of pregnancy (TOP), cervical dilatation prior to surgical TOP, preparation for prostaglandin-induced TOP during the second trimester and expulsion of a dead fetus during the third trimester. When used in a sequential regimen with prostaglandins, it shows a high efficacy inducing TOP at an early stage. The combined regimen has now been used by millions of women all over the world, and provided the contraindications and warnings are respected, the method proved to be safe. Infection, hemorrhage and retained tissue are among the more relevant complications.

Section snippets

Safety studies in animals

Roussel Uclaf conducted a comprehensive toxicology program in the mid-1980s demonstrating the safety of the molecule and allowing for mifepristone's use in humans. Most of the program focused on the development of indications using single-dose administration of the compound. Therefore, toxicology studies were conducted with durations of animal exposure not exceeding 6 months [1]. The compound was shown to have no mutagenic potential and no toxic effect up to 1000 mg/kg in acute administration

Antiglucocorticoid effects

Mifepristone has antiglucocorticoid properties and has antagonized the effects of dexamethasone in a number of models: mifepristone totally inhibited the effects of dexamethasone, such as inhibition of ACTH secretion, as well as its thymolytic action and diuretic effects [3]. In humans, mifepristone also exerts antiglucocorticoid activity. The antiglucocorticoid effect of mifepristone is exerted both on the central actions of cortisol (inhibition of feedback control of cortisol over its own

Discussion of the key issues

Although the conclusions of large studies indicate good tolerability of mifepristone, some issues have been identified that require special attention.

Conclusion

Mifepristone exhibits a strong affinity to the progesterone and the glucocorticoid receptors. Consequently, it exerted competitive antagonism to these hormones both in in vitro and in animal experiments. The identification of antiprogesterone activity led to the proposition of mifepristone use for the termination of early human pregnancy. Mifepristone, at a dose of 600 mg initially used alone, was then used with a subsequent low dose of prostaglandin that led to a success rate of 95% as a

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