Early Options: Evidence-Based Variations of the Standard Regimen

Early Options - A Provider's Guide to Medical Abortion

This page contains the following sections:

Lower Doses of Mifepristone
Vaginal Versus Oral Misoprostol
Buccal and Sublingual Administration of Misoprostol
Medical Abortion After 63 days' Gestation
Gestational Age and Outcomes
Home Use of Misoprostol
Timing Variations
Ultrasound

A number of evidence-based alternative treatment regimens, or off-label treatment regimens not included in the FDA-approved label, have emerged as researchers have attempted to optimize the mifepristone/misoprostol regimen.

Investigators have studied the impact, safety, and efficacy of different mifepristone doses, administration of vaginal misoprostol, home use of misoprostol, extension of the gestational age limit, and variations in the timing of the regimen. In addition, researchers have conducted studies of safety and efficacy with and without routine use of ultrasonography.

Lower Doses of Mifepristone
After oral administration, mifepristone is absorbed rapidly. The serum half-life is about 30 hours. In serum, mifepristone is bound to alpha 1-acid glycoprotein. The blood contains relatively small amounts of this glycoprotein, and binding sites on this carrier molecule are quickly saturated. As a result, for doses greater than 100 mg, serum levels correlate with concentration of the carrier protein, and not with the dose administered.¹³

Based on the pharmacological characteristics of mifepristone, lower doses of the drug could theoretically provide similar serum levels and efficacy while decreasing costs and side effects.

Several trials have investigated the effect of the mifepristone dose on the efficacy of medical abortion. In the early 1990s, the World Health Organization (WHO) conducted a randomized study using mifepristone doses of 200 mg, 400 mg, or 600 mg in women with gestations of ≤ 56 days.¹⁴ Women in this study received vaginal gemeprost 1 mg, rather than 400 µg oral misoprostol, 2 days after administration of mifepristone.

The study found nearly identical rates of complete abortion (~94%) and continuing pregnancy (< 1%) with all three doses of mifepristone.

In a study by McKinley and colleagues,¹⁵ women with pregnancies of ≤ 63 days' gestation were randomized to a single dose of either 600 mg or 200 mg mifepristone followed 2 days later by a single oral dose of misoprostol 600 µg. The percentage of women who had a complete abortion was virtually identical in the two groups (93.6%).

The authors concluded that the recommended dose of mifepristone could be reduced from 600 mg to 200 mg without loss of clinical efficacy. This study, however, used an oral dose of misoprostol higher than that used in the FDA-approved regimen.

In one randomized trial,¹⁰ WHO compared outcomes in women up to 63 days' gestation who received 600 mg or 200 mg mifepristone followed in 2 days by 400 µg oral misoprostol, the same dose as used in the FDA-approved regimen.

The overall complete abortion rate with the lower dose of mifepristone (89.3%) was similar to that with the higher dose (88.1%). In both groups, however, efficacy decreased with advancing gestational age. The failure rates were 8% at ≤ 42 days' gestation, 11% at 43 to 49 days, 13% at 50 to 56 days, and 20% at 57 to 63 days.

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After reading this section, you should be able to answer the following question:
Comparisons between oral and vaginal dosing of misoprostol reveal differences in pharmacokinetics and in effects. Which "differences" are true?

Vaginal Versus Oral Misoprostol
A comparison of oral and vaginal dosing of misoprostol reveals significant differences in pharmacokinetics. Following oral dosing, plasma levels peak at around 30 minutes and drop off sharply within 2 hours. In contrast, after vaginal administration, plasma levels peak later (at around 80 minutes) and remain relatively high for 4 hours.¹⁶ Click here to view Figure 9.

In theory, higher peak levels with oral dosing might be associated with a higher rate of GI side effects, while the more sustained plasma levels following vaginal administration could positively affect efficacy.

These predictions are supported by results of randomized trials and large case series of regimens using vaginal misoprostol. El-Refaey and colleagues¹⁷ published a randomized controlled trial in which women with gestations of ≤ 63 days received 600 mg of mifepristone followed by 800 µg of misoprostol either orally or intravaginally.

Notably, the difference in success rates between the vaginal and oral routes of administration was statistically significant (95% vs. 87%, respectively; p = .03), as was the difference in time until abortion. Ninety-three percent of those in the vaginal misoprostol group aborted within 4 hours, whereas only 78% of the oral misoprostol group aborted within this time period (p < .001). The incidence of vomiting (31% vs. 44%; p = .04) and diarrhea (18% vs. 36%; p = .002) was significantly lower among women receiving vaginal misoprostol, but there was no significant difference in the rate of nongastrointestinal side effects (tiredness, headache, hot flashes, dizziness).

A meta-analysis of 54 studies that were published from 1991 to 1998 on the efficacy of mifepristone/misoprostol abortion supports the hypothesis that vaginal administration of misoprostol is associated with a lower rate of incomplete abortion than oral administration (2.1% vs. 6.4%, respectively; p = .05).¹⁸

Extensive clinical trial evidence also confirms the safety and efficacy of mifepristone combined with vaginal misoprostol 800 µg for women with gestations up to 63 days.¹⁸

In 1998, Ashok and colleagues¹⁹ published a retrospective analysis of 2,000 women with gestations of ≤ 63 days who received low-dose mifepristone (200 mg) followed 36 to 48 hours later by 800 µg of misoprostol intravaginally.

The overall success rate of this regimen was 97.5%, and 86% aborted within 6 hours of receiving misoprostol, further validating the efficacy of vaginal misoprostol. Roughly 3% of women aborted before receiving misoprostol, which is comparable to the percentage of women aborting before misoprostol in studies using the 600-mg dose of mifepristone.^7,9

This lends support to the hypothesis that the 200-mg and 600-mg doses have an equivalent biologic effect. Schaff and colleagues²⁰ used the same regimen and reported success rates of 97% for women with gestations of ≤ 49 days and 96% for those at 50 to 56 days' gestation. A similar study published by Schaff and colleagues²¹ in 2000 showed that the same regimen was also highly effective (96% success rate) from 57 to 63 days' gestation.

Buccal and Sublingual Administration of Misoprostol

Despite the success with vaginal dosing, studies suggest that women prefer an oral route⁶⁰. Both buccal and sublingual regimens have been investigated with success, although the magnitude of the literature is much smaller than that for vaginal misoprostol.

Use of buccal misoprostol appears equivalent to use of vaginal misoprostol. Middleton and colleagues⁶¹ randomized 442 women with gestations of 56 days or less to 200 mg mifepristone orally followed one to two days later by 800 µg misoprostol given by the vaginal or buccal route. Buccal administration consisted of allowing the tablets to dissolve for 30 minutes after which the remaining fragments were swallowed. The complete abortion rate was 95% in the buccal group and 93% in the vaginal group (p=0.51). With the exception of diarrhea, which occurred more frequently in the buccal group (36% vs. 24%, p=0.006), the side effect profiles were similar. Overall satisfaction rates were high in both groups (92% buccal vs. 95% vaginal, p=0.18). When women were queried regarding their preferences for the route of administration, 16% of women in the buccal group would have preferred vaginal administration compared with 11% in the vaginal group who would have preferred buccal. A recent study confirmed this high efficacy and acceptability of mifepristone and buccal misoprostol through 63 days' gestation⁶²(Winikoff, B., Dzuba, I.G., Creinin, M.D., Crowden, W.A., Goldberg, A., Gonzales J. In-the-mouth applications of misoprostol in mifepristone medical abortion. [Unpublished Manuscript]).

Limited research has been conducted on the use of the sublingual route of misoprostol following mifepristone for medical abortion. A few smaller clinical trials^63-65 as well as the current pharmacokinetic research^52-59 suggest that although there is a higher rate of unpleasant side effects with the sublingual route, efficacy may be equivalent to that of vaginal use when reduced dosages are repeated at shorter intervals (for example, every 3 to 6 hours up to a maximum dose).

Medical Abortion After 63 days' Gestation

All studies investigating the use of mifepristone and misoprostol to achieve abortion beyond 63 days' gestation have not only used multiple-dose regimens of misoprostol at short intervals (typically three hours), via variable routes, but have included ongoing observation of patients in the clinic or hospital until completion of the abortion (either by medication or vacuum aspiration) has been assured. Failure rates in these cases have been reported to vary from 5-10%.⁶³^{, 66-68}

Click here to check your understanding.

Gestational Age and Outcomes
The three pivotal trials by the Peyron, Aub�ny, and Spitz groups^7-9 employing the standard FDA-approved regimen of mifepristone 600 mg followed 2 days later by oral misoprostol 400 µg found an inverse relationship between efficacy and gestational age (i.e., medical abortion is more effective in earlier pregnancy).

The aforementioned randomized trial by WHO¹⁰ also found decreased efficacy with increasing gestational age when mifepristone was combined with oral misoprostol 400 µg. The authors concluded that failure rates were too high after 49 days' gestation (> 13%) to recommend use of these mifepristone/oral misoprostol regimens.

Corroborating these findings, a meta-analysis of 54 medical abortion trials using mifepristone and misoprostol published from 1991 to 1998 indicated that the efficacy of the procedure declines from 96% at ≤ 49 days' gestation to 85% at 57 days' gestation and above (typically 57 to 63 days in most studies).¹⁸

In contrast, extensive clinical evidence shows that the success rate through 63 days' gestation may exceed 95% when mifepristone is followed by vaginal misoprostol 800 µg.^19,21-22

Home Use of Misoprostol
Studies involving mifepristone/misoprostol regimens have confirmed the safety and efficacy of home administration of misoprostol.^20-24 These studies have reported success rates comparable to those of regimens involving misoprostol administration in a clinical setting.^7-9

In 1997, Schaff and colleagues²⁴ reported a 98% complete abortion rate in 166 women with gestations of ≤ 56 days who received mifepristone 600 mg PO and self-administered vaginal misoprostol 800 µg at home 2 days later.

In 1999, Schaff and colleagues²⁰ reported a 97% success rate in a comparable population of 933 women who received 200 mg mifepristone PO and administered 800 µg misoprostol intravaginally at home 2 days later. Based on the results of the study and on surveys of the participants, the authors concluded that home administration of misoprostol was safe, highly effective, and acceptable to women.

Subsequent studies have confirmed the acceptability, safety, and efficacy of regimens involving home use of misoprostol.^21-23

Clinicians and counselors who prescribe misoprostol for intravaginal use at home should explain the proper technique. Women should first empty their bladder and then insert the misoprostol tablets one at a time as far into the vagina as they can using their fingers.

Resting after misoprostol insertion or using tampons is not necessary, although some women may feel more comfortable if they rest on their backs for approximately 30 minutes after insertion. It is not a problem if the tablets do not fully dissolve or drop out after that time, since enough of the medication will have already been absorbed.

Timing Variations
In the past decade much research has focused on the time interval between mifepristone and misoprostol administration. Acceptability is higher with shorter time intervals.⁷⁴

Regimens with non-oral misoprostol routes allow for high efficacy with a shorter interval. Schaff et al.⁷⁴ reported a multicenter randomized trial in 2,295 women up to 56 days' gestation who self-administered misoprostol 800 µg vaginally 24, 48 or 72 hours after taking mifepristone 200 mg orally. In a later trial, the same investigative team showed continued high efficacy of the combination of mifepristone and misoprostol 800 µg vaginally 24 hours later up to 63 days' gestation.⁶⁹

In 2004, Creinin et al.²² performed a multicenter, randomized trial of 1,080 women up to 63 days' gestation who received the misoprostol either six to eight hours (n=540) or 23 to 25 hours (n=540) following the mifepristone.

Subsequently, in 2007 Creinin et al.⁷² performed a multicenter, randomized trial of 1,128 women up to 63 days' gestation who received the misoprostol either within 15 minutes of the mifepristone administration (n=567) or 23 to 25 hours (n=561) following the mifepristone. Complete abortion rates were statistically equivalent (95% and 97%, respectively). Continuing pregnancy rates were 0.7% and 0.2%, respectively. Women who used simultaneous dosing had a lower likelihood of expulsion with a single dose of misoprostol as compared to the 23- to 25-hour interval (91% vs. 94% p=0.10. for non-inferiority). However, researchers proposed that simultaneous use of misoprostol has a practical advantage in that the misoprostol cannot be improperly placed or lost. Studies using buccal and sublingual misoprostol similarly have demonstrated that a 24-hour interval can be used with high success.^{70, 71} However, unlike vaginal misoprostol, buccal misoprostol is not effective when used simultaneously with mifepristone.⁷³

Ultrasound
Ultrasound is useful in medical abortion practice for dating pregnancy and assessing completion of medical abortion. However, this imaging modality is not mandatory for every medical abortion patient and is not used routinely in other countries, such as France.²⁵ Ultrasound use has been standard in clinical trials in the U.S.^9,20-24

The results of international trials, however, indicate that safety and efficacy are not reduced when this imaging modality is reserved for cases of uncertain dating and for assessing possible complications. Ngoc and colleagues¹¹ relied on clinical history (LMP) and bimanual examination to provide mifepristone medical abortions to women with gestations of ≤ 56 days, and reported high rates of efficacy (96%) and patient acceptability.

Ultrasound should be available when needed to assess a suspected ectopic pregnancy, to date a pregnancy when clinical assessment is difficult, or to evaluate the possibility of an ongoing pregnancy following treatment. Less-experienced providers may prefer to use ultrasound until they gain more confidence in dating pregnancies accurately on clinical grounds, and many providers in the U.S. may choose to use it routinely. (See Module 4, The Role of Ultrasound, hCG Assays, and Clinical Assessment in Medical Abortion, for a thorough discussion of this issue.)

Proceed to Alternatives to Mifepristone.

References for this module