B6
Uses of Antiprogestins After 63 Days of Amenorrhea

ANDRÉ ULMANN, M.D., Ph.D., and LOUISE SILVESTRE, M.D.

Roussel-Uclaf, Romainville, France

RU 486 (mifepristone), the first antiprogestin available for clinical purposes, has been synthesized by Roussel-Uclaf. It possesses both antiprogesterone and antiglucocorticoid properties (Philibert et al., 1985; Ulmann et al., 1990). It is now marketed in France, the United Kingdom, and Sweden as a medical abortifacient, but has many other potential uses linked to its antiprogesterone activity. In addition, the antiglucocorticoid activity of this compound is of potential clinical interest and is currently being evaluated.

Based on the results of a large body of experience reviewed elsewhere (Bygdeman, Appendix B5), it has been recognized that RU 486 can be used as an alternative to vacuum aspiration for early pregnancy termination (up to 63 days of amenorrhea). It is given as a single oral dose of 600 mg followed 36–48 hours later by the administration of a small dose of a prostaglandin (PG) E1 analogue (gemeprost or misoprostol). In the three countries where RU 486 is currently marketed, it is approved with the following conditions:

  • It must be prescribed only in centers registered for pregnancy termination.

  • Its distribution must be strictly controlled.

  • Each patient must sign a form indicating that she is aware that the method does not ensure a 100 percent success rate, hence, the need for a mandatory control visit 8–10 days after RU 486 intake.

Availability under these conditions allows RU 486 to be studied and approved for administration at other times during pregnancy (i.e., after 63 days of amenorrhea), which are reviewed in this paper.



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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda B6 Uses of Antiprogestins After 63 Days of Amenorrhea ANDRÉ ULMANN, M.D., Ph.D., and LOUISE SILVESTRE, M.D. Roussel-Uclaf, Romainville, France RU 486 (mifepristone), the first antiprogestin available for clinical purposes, has been synthesized by Roussel-Uclaf. It possesses both antiprogesterone and antiglucocorticoid properties (Philibert et al., 1985; Ulmann et al., 1990). It is now marketed in France, the United Kingdom, and Sweden as a medical abortifacient, but has many other potential uses linked to its antiprogesterone activity. In addition, the antiglucocorticoid activity of this compound is of potential clinical interest and is currently being evaluated. Based on the results of a large body of experience reviewed elsewhere (Bygdeman, Appendix B5), it has been recognized that RU 486 can be used as an alternative to vacuum aspiration for early pregnancy termination (up to 63 days of amenorrhea). It is given as a single oral dose of 600 mg followed 36–48 hours later by the administration of a small dose of a prostaglandin (PG) E1 analogue (gemeprost or misoprostol). In the three countries where RU 486 is currently marketed, it is approved with the following conditions: It must be prescribed only in centers registered for pregnancy termination. Its distribution must be strictly controlled. Each patient must sign a form indicating that she is aware that the method does not ensure a 100 percent success rate, hence, the need for a mandatory control visit 8–10 days after RU 486 intake. Availability under these conditions allows RU 486 to be studied and approved for administration at other times during pregnancy (i.e., after 63 days of amenorrhea), which are reviewed in this paper.

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda RU 486 FOR SECOND-TERM PREGNANCY TERMINATION Second-term pregnancy termination can be achieved through either surgical means (dilatation and evacuation) or medical treatment (with local or systemic prostaglandins). Prostaglandins, although efficient, induce many side effects. These side effects can sometimes be severe, hence the importance of using doses as low as possible. Previous studies with RU 486, including studies of first-term pregnancy termination, indicate that RU 486 treatment sensitizes the myometrium to the action of prostaglandins, allowing a decrease in the amount of prostaglandin necessary to induce expulsion. This observation led to several clinical trials in which the effect of RU 486 treatment prior to PG administration was evaluated as a means to allow a decrease in PG doses and to accelerate expulsion in second-term pregnancy termination. The results of the trials are summarized in Table B6.1. These studies indicate that treatment with RU 486 prior to PGs allows a significant decrease of the PG doses and significantly shortens the induction to abortion interval. This finding is of great clinical value for the comfort of patients. In one study (Roussel-Uclaf, data on file), the duration of hospitalization was shortened by one day in the group given RU 486. In another study (Thong and Baird, 1992), which compared RU 486 and laminaria tent (Dilapan) in gemeprost-induced abortion, RU 486 resulted in a significantly shorter induction-abortion interval than Dilapan. RU 486 FOR INTRAUTERINE FETAL DEATH (IUFD) After a pilot study suggested that the compound alone seemed efficient to induce expulsion of the dead fetus, a placebo-controlled study was undertaken to evaluate the efficacy of RU 486, given as 600 mg for two consecutive days, in this condition. Results of this study, published elsewhere (Cabrol et al., 1990), are summarized in Table B6.2. These results show that RU 486 alone was able to induce labor in patients with IUFD and that expulsion took place significantly earlier than in patients given a placebo. CERVICAL RIPENING WITH RU 486 PRIOR TO SURGICAL ABORTION Animal studies have demonstrated that RU 486 is able to mature the cervix, evidenced by an increase in cervical diameter and a decrease of cervical resistance to mechanical dilation (Stiemer and Elger, 1990; Cabrol et al., 1991). It has also been shown that RU 486 triggers the biochemical modifications that characterize the normal process of cervi-

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda TABLE B6.1 Results of Several Controlled Studies of RU 486 Followed by a Prostaglandin for Second-Term Pregnancy Termination     Units of PG Necessary (range) Induction to Abortion Interval (hours, range) Reference PG Used (units, route) RU 486 (or none) Placebo RU 486 (or none) Placebo Rodger and Baird (1990) Gemeprost (1 mg pessary every 3 hours) 3a (1–10)   5a (2–10) 6.8 (2–67.8)   15.8 (5.9–95.6)       P < 0.01     P < 0.01   R.-U.b Sulprostone (0.5 mg IM every 6 hours) 2a (1–4)   4a (2–9) 9.5 (2.2–25.8)   22.3 (10–84)       P < 0.01     P < 0.01   Hill et al. (1990) PGE2 (1.5 mg extraamniotic once) —   — 8.5 (5.3c)   18.5 (10.1)             P < 0.02   Urquhart et al. (1989) Prostin E2 infusion (extraamniotic infusion) 11d (5–30)   18d (5–45) 9.3 (4–14.3)   12.3 (6.6–22.4)       P = 0.01     P < 0.01   NOTE: IM = intramuscular. a Median. b Roussel-Uclaf, data on file, report of study FFR/88/486/03. c Standard deviation. d Mean of total dose infused (mg).

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda TABLE B6.2 Results of Double-Blind Placebo-Controlled Study of RU 486 (600 mg/day for two consecutive days) for IUFD   RU 486 (N = 46) Placebo ( N = 46) P Days of amenorrhea 199.1 (7.8a) 197.5 (6.7a) NS Duration of retention (days) 18.2 (4.1a) 15.1 (2.5a) NS Progesterone levels before treatment (ng/ml) 61.5 (12.1a) 57.1 (7.6a) NS Number (%) of women in whom labor occurred within 72 hours after first drug intake 29 (63) 8 (17) < 0.001 NOTE: NS = not significant at .05. a SEM = standard error of the mean. SOURCE: Cabrol et al. (1990). cal maturation (i.e., increase in water content and hyaluronic acid, and collagenase activation) (Ikuta et al., 1991). Data obtained during first- and second-term pregnancy termination, and in IUFD, have shown that RU 486 is also able to induce cervical maturation in humans. Several placebo-controlled studies have been performed to evaluate the efficacy of RU 486 in cervical ripening prior to vacuum aspiration. Their results are summarized in Table B6.3. The table shows that except in two studies [Rådestad et al., 1988, where the compound was given at a relatively small dose, 100 mg bid (twice a day), with measurements 24 hours after the last dose, and study FCH/85/486/21, where RU 486 was given only 12 hours prior to the measurements], RU 486 always induced a significant increase in the cervical diameter. Information obtained from trials other than those described above includes the following: The time lag between the last RU 486 intake and the measurement of cervical diameter is an important factor. In a Canadian study (Lefèbvre et al., 1990) where several doses of RU 486 were evaluated, the cervical modifications were always significantly more important after 48 hours than after 24 hours. A similar finding was reported by Rådestad et al. (1990). There is a dose-response relationship between dose of RU 486 and cervical diameter 24 to 48 hours after administration. The optimal dose of RU 486 was studied in the aforementioned Canadian study, in which different groups received either a placebo or 50, 100, 200, 400, or 600 mg of RU 486, as a single administration 24 or 48 hours prior to cervical calibration. For all doses of RU 486 studied, there was a significant increase of cervical diameter, which was linearly related to dosage up to 400 mg. Interestingly, in this study the duration of the subsequent vacuum aspiration was significantly decreased in parallel with the dose

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda TABLE B6.3 Results of Placebo-Controlled Studies of Cervical Ripening with RU 486     Cervical Diameter (mm)   Reference RU 486 (Placebo) Dose, Time Before Measurement (number of patients per group, mean duration of amenorrhea) RU 486 (or none) Placebo P R.-U.a 50 mg bid × 2 days, 48 hours (N = 20, 63 DA) 6.4 (1.2b) 4.3 (1.2) 810-4 R.-U.c 600 mg once, 12 hours (N = 20, 70 DA) 6.4 (1.6b) 6.3 (1.6) NS Rådestad et al. (1988) 100 mg bid × 1 day, 24 hours (N=20, 8.5 WA) 5.5 (3–11) 4.4 (3–6) NS R.-U.d 600 mg once, 48 hours (N=20, 76 DA) 7.5 (5–9) 6 (3–8) <.001 R.-U.e 600 mg once, 30 hours (N=38, 68 DA) 7.0 (5–10) 6 (5–7) <.001 Gupta and Johnson (1990) 600 mg once, 48 hours (N=15, 68 DA) 5 (2.0b) 3 (1.2) .002 Henshaw and Templeton (1991) 200 mg once, 36 hours (N=30, 75 DA) 6.8 (6.3–7.3 f ) 5.0 (4.7–5.4) 810-5 NOTE: DA = days of amenorrhea; WA = weeks of amenorrhea; NS = not significant. a Roussel-Uclaf, data on file: study FCH/85/486/25. b Standard error of the mean. c Roussel-Uclaf, data on file: study FCH/86/486/21. d Roussel-Uclaf, data on file: study UK/88/486/04. e Roussel-Uclaf, data on file: study UK/88/486/05. f 5% confidence interval. of RU 486 administered. For the 600-mg dose, the duration of the procedure was the shortest (8.2 minutes versus 12.3 minutes in the placebo group). A second study, undertaken by the World Health Organization, evaluated the effects of three doses (50, 100, or 200 mg) of RU 486 and a placebo on cervical diameter 12 and 24 hours after drug intake. All three doses of RU 486 significantly increased the cervical diameter, although there were no significant differences among doses (WHO, 1990). Given the short time between drug intake and cervical calibration, it is likely that the maximal effect was not observed. In this study, the ease of complementary mechanical dilation was linearly related to the dose of RU 486 (dilatation was considered easy in 10, 17, 22, and 35 percent of the patients for the placebo and in the 50-, 100-, and 200-mg groups for RU 486). RU 486 significantly reduces the mechanical resistance of the cervix. In the study of Rådestad et al. (1988), the mean force necessary to introduce a Hegar dilator No. 9 was 21.6 N in the RU 486-treated patients versus 31.4 N in patients given the placebo (P < .05). Similarly, the force necessary to dilate the cervix to 8 mm was significantly reduced in women given RU 486 compared to those given placebo in several

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda studies (Gupta and Johnson, 1990; Henshaw and Templeton, 1991; Roussel-Uclaf-monitored studies UK/88/486/04 and UK/88/486/05). In one study (Henshaw and Templeton, 1991), which compared RU 486 to gemeprost (1 mg pessary 3–4 hours prior to calibration), both RU 486 and gemeprost induced an identical increase in cervical diameter and a similar reduction in the resistance to mechanical dilatation. However, abdominal pain was significantly (P < .001) more frequent in the group treated with gemeprost (43 percent of the patients) than in the group treated with RU 486 (10 percent of the patients). Overall, RU 486 is well tolerated. The most frequently reported side effects are abdominal pain (23.9 percent of the patients on RU 486 versus 10.9 percent on placebo), and nausea and vomiting (20.5 percent on RU 486, 13.0 percent on placebo). Approximately one-quarter of the patients in whom the drug is used for cervical ripening prior to surgical abortion experienced uterine bleeding after RU 486 intake, which was always reported as minimal or moderate but never necessitated specific treatment. Blood loss during vacuum aspiration was usually identical in patients given RU 486 or the placebo, except in two studies (Roussel-Uclaf, data on file, study UK/88/486/04; Henshaw and Templeton, 1991) in which blood losses were significantly lower in RU 486-treated than in placebo-treated patients. In one of these studies, blood loss was 225 ml (range: 110–825 ml) in the placebo group, and 115 ml (range 60–500 ml) in the group given 600 mg of RU 486 (P = .001). In the second study, blood loss was 320.8 ml [95 percent confidence interval (CI): 243.2–398.5 ml] in the group given placebo, 137.3 ml (95 percent CI: 96.7–178.0 ml) in the group given 200 mg of RU 486, and 115.3 ml (95 percent CI: 93.2–143.6 ml) in the group given 1 mg gemeprost (P < .0001). Abdominal pain tended to be less frequently reported postoperatively in patients given RU 486 than in those given placebo (27.1 versus 40.4 percent of the cases). Postoperative bleeding was semiquantitatively assessed in some studies and was comparable in RU 486- and placebo-treated patients. Similarly, there was no difference in the duration of postoperative bleeding. Thus, RU 486 appears to be a safe and efficient means for cervical ripening prior to vacuum aspiration. It seems better tolerated than prostaglandins, but must be given 36–48 hours prior to the surgical procedure, instead of 3–4 hours for PGs. RU 486 FOR LABOR INDUCTION Studies in ewes (Burgess et al., 1992) and monkeys (Wolf et al., 1989) indicate that at term, RU 486 induces uterine contractions and enhances the myometrial sensitivity to oxytocin. Newborns from mothers treated

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda TABLE B6.4 Induction of Labor with RU 486 (200 mg/day for two consecutive days) or a Placebo   RU 486 (N = 57) Placebo (N = 55) P N (% of women with spontaneous onset of labor) 31 (54.4) 10 (18.2) <.001 Interval between day 1 and onset of labor (hours, SD) 51.7 (26.7) 74.5 (39.5) <.001 Mean (SD) total dose (IU) of oxytocina 2.0 (2.2) 4.7 (3.0) <.0001 Number of cesarean sections 18 18 NS Neonatal tolerance N (% of infants)       • With Apgar score below 7       • At 1 minute 5 (8.8) 4 (7.3) NS • At 5 minutes 0 0   • With umbilical vein pH below 7.20 4 (7.0) 3 (5.4) NS NOTE: IU = intrauterine; NS = not significant; SD = standard deviation. a For women who delivered vaginally. SOURCE: Frydman et al. (1992). with RU 486 were normal and actually grew faster than newborns from untreated mothers. This can be explained by an increase in milk output in mothers treated with RU 486, which is likely to be secondary to the suppression of progesterone-induced inhibition of prolactin. In humans, it has been demonstrated that RU 486 crosses the placental barrier (Frydman et al., 1985), so it is mandatory to evaluate the consequences of cortisol blockade in the newborn. A pilot study (Frydman et al., 1992) evaluated the efficacy and safety of RU 486 for the induction of labor in cases of postdate pregnancies or other medical indications for labor induction. Table B6.4 summarizes the results of this study. The table confirms that RU 486 is able to induce labor. It was well tolerated by both the newborn and the mother, and in particular, the number of hypoglycemic episodes up to 48 hours after birth was identical in both groups (three and five episodes in the RU 486and the placebo-treated groups, respectively). Dose-finding studies are currently in progress to determine the minimal dose of RU 486 necessary to induce labor. Once the dose is determined, a large-scale study will be undertaken to confirm the good tolerance to the compound by newborns. In conclusion, it appears that the myometrial consequences of progesterone blockade can be utilized for various purposes during pregnancy, and antiprogestins such as RU 486 appear as interesting therapeutic innovations in an area where available efficient drugs are either

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda absent or poorly tolerated. Because of the controversy surrounding abortion in several countries, it is necessary that antiprogestins are first approved as medical abortifacients before being approved for their other obstetrical indications, as was the case for RU 486 in France, the United Kingdom, and Sweden. Since these other obstetrical indications are limited to inpatient use, the approved antiprogestins can be distributed and prescribed following the same procedures as those followed for medical pregnancy termination, which limits the risk of improper use. REFERENCES Burgess, K.M., Jenkin, G., Ralph, M.M., et al. Effect of the antiprogestin RU 486 on uterine sensitivity to oxytocin in ewes in late pregnancy. Journal of Endocrinology 134:353–360, 1992. Cabrol, D., Dubois, C., Cronje, H., et al. Induction of labor with mifepristone (RU 486) in intra-uterine fetal death. American Journal of Obstetrics and Gynecology 162:540–542, 1990. Cabrol, D., Carbonne, B., Bienkiewicz, A., et al. Induction of labor and cervical maturation using mifepristone (RU 486) in the late pregnant rat. Influence of a cyclooxygenase inhibitor (diclofenac). Prostaglandins 42:71–79, 1991. Frydman, R., Taylor, S., and Ulmann A. Transplacental passage of mifepristone. Lancet 2:1252, 1985. Frydman, R., Lelaidier, C., Baton-Saint-Mleux, C., et al. Labor induction in women at term with mifepristone (RU 486): A double-blind, randomized, placebo-controlled study. Obstetrics and Gynecology 80:972–975, 1992. Gupta, J.K., and Johnson, N. Effect of mifepristone on dilatation of the pregnant and nonpregnant cervix. Lancet 335:1238–1240, 1990. Henshaw, R.C., and Templeton, A.A. Pre-operative cervical preparation before first trimester vacuum aspiration: A randomized controlled comparison between gemeprost and mifepristone (RU 486) . British Journal of Obstetrics and Gynaecology 98:1025–1030, 1991. Hill, N.C.W., Selinger, M., Ferguson, J., et al. The physiological and clinical effects of progesterone inhibition with mifepristone (RU 486) in the second trimester. British Journal of Obstetrics and Gynaecology 97:487–492, 1990. Ikuta, Y., Matsuura, K., Okamura, H., et al. Effects of RU 486 on the interstitial collagenase in the process of cervical ripening in the pregnant rat. Endocrinologia Japonica 38:491–496, 1991. Lefebvre, Y., Proulx, L., Elie, R., et al. The effects of RU-38486 on cervical ripening. Clinical studies. American Journal of Obstetrics and Gynaecology 162:61–65, 1990. Philibert, D., Moguilewsky, M., Mary, I., et al. Pharmacological profile of RU 486 in animals. Pp. 49–68 in The Antiprogestin Steroid RU 486 and Human Fertility Control. Baulieu, E.E., and Segal, S.J., eds. New York: Plenum Press, 1985. Rådestad, A., Christensen, N.J., and Stromberg, L. Induced cervical ripening with mifepristone in first trimester abortion. A double-blind randomized biomechanical study. Contraception 38:301–312, 1988. Rådestad, A., Bygdeman, M., and Green, K. Induced cervical ripening with mifepristone (RU 486) and bioconversion of arachidonic acid in human pregnant uterine cervix in the first trimester. A double-blind, randomized biomechanical and biochemical study. Contraception 41:283–292, 1990. Rodger, M.W., and Baird, D.T. Pretreatment with mifepristone (RU 486) reduces interval

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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda between prostaglandin administration and expulsion in second trimester abortion. British Journal of Obstetrics and Gynaecology 97:41–45, 1990. Stiemer, B., and Elger, W. Cervical ripening of the rat in dependence of endocrine milieu: Effects of antigestagens. Journal of Perinatal Medicine (Berlin) 18:419–429, 1990. Thong, K.J., and Baird, D.T. A study of gemeprost alone, Dilapan or mifepristone in combination with gemeprost for the termination of second trimester pregnancy. Contraception 46:11–17, 1992. Ulmann, A., Teutsch, G., and Philibert, D. RU 486. Scientific American 262:42–48, 1990. Urquhart, D.R., Bahzad, C., and Templeton, A.A. Efficacy of the antiprogestin mifepristone (RU 486) prior to prostaglandin termination in pregnancy. Human Reproduction 4:202–203, 1989. Wolf, J.P., Sinosich, M., Anderson, T.L., et al. Progesterone antagonist (RU 486) for cervical dilation, labor induction and delivery in monkeys: Effectiveness in combination with oxytocin. American Journal of Obstetrics and Gynecology 160:45–47, 1989. World Health Organization (WHO). The use of mifepristone (RU 486) for cervical preparation in first trimester pregnancy termination by vacuum aspiration. British Journal of Obstetrics and Gynaecology 97:260–266, 1990.