1 Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong SAR and 2 Shanghai Institute of Family Planning Technical Instruction, International Peace Maternity and Child Health Hospital, China Welfare Institute, Shanghai, People's Republic of China
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Abstract |
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Key words: medical abortion/mifepristone/misoprostol/sublingual
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Introduction |
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A pharmacokinetic study has also shown that the systemic bioavailability of vaginally administered misoprostol is three times higher than that of orally administered misoprostol when determined by the area under the plasma concentrationtime curve (AUC) for 360 min (Zieman et al., 1997). The marked difference in AUC between oral and vaginal administration is likely the result of presystemic gastrointestinal or hepatic metabolism that occurs with oral but not with vaginal misoprostol. The same study also showed that the absorption of misoprostol by the vaginal route was variable and it was not uncommon to find that the majority of the misoprostol tablet was still not completely dissolved several hours after vaginal administration (Ziemen et al., 1997; Singh et al., 1999
).
Recently, we have developed a new sublingual route of administration of misoprostol. Misoprostol, being very soluble in water, was put under the tongue; it was observed that the tablet took ~1015 min to dissolve. It is given by mouth and therefore can avoid the uncomfortable vaginal examination during the administration of vaginal misoprostol. The aim of this pilot study was to determine the complete abortion rate of sublingual misoprostol when given with mifepristone for termination of first trimester pregnancy up to 9 weeks gestation.
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Materials and methods |
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All women were given 200 mg of mifepristone (Mifegyne; Roussel UCLAF, Romainville, France) in the presence of the medical or nursing staff. Forty-eight hours after mifepristone administration, the women were admitted to the hospital and 800 µg sublingual misoprostol (Cytotec; Searle Pharmaceutical, Skokie, IL, USA) was given. They were instructed to put four tablets of 200 µg misoprostol under the tongue and allow them to dissolve. The misoprostol took ~1015 min to dissolve and during this period of time the subjects were told not to swallow the tablets. They stayed in the hospital for 4 h, and blood pressure and pulse rates were recorded hourly. A vaginal examination was performed at the end of the 4 h observation. The women were given a diary card to record the days and the amount of vaginal bleeding (in comparison with their usual menstrual periods) and any other side-effects.
The women returned to the hospital on day 15 (after mifepristone) and vaginal examination, measurement of blood pressure, pulse and haemoglobin level, and ultrasound of pelvis were carried out. If pelvic ultrasound showed the presence of an ongoing pregnancy, vacuum aspiration was arranged. If pelvic ultrasound examination showed that there was an incomplete or missed abortion, the women would be observed unless there was heavy bleeding.
The women were followed-up again on day 43. The examination and investigations on day 15 were repeated except the ultrasound examination of pelvis, which was only performed when it was clinically indicated. The side-effects and duration of bleeding as recorded in the diary card were checked during the follow-up visits. An extra follow-up visit was arranged if bleeding persisted or menstruation had not yet returned by 67 days after mifepristone. If no emergency or elective curettage was required during the interval up to the first menstruation, the outcome was classified as a complete abortion. All women were asked to use the barrier method for contraception.
The primary outcome was the complete abortion rate. The haemoglobin level, duration of vaginal bleeding and side-effects of the treatment were also studied.
Statistics for Social Sciences 10.0 for Windows was used for statistical analysis. Repeated measurements in haemoglobin levels were compared by Wilcoxon signed ranks test. P-values (two-tailed) of < 0.05 were considered as statistically significant.
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Results |
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Discussion |
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Oral misoprostol has been shown to be less effective and to result in more side-effects than vaginal administration in randomized trials (El-Refaey et al., 1995). Additionally, a pharmacokinetic study showed that the systemic bioavailability of vaginal administration, as indicated by the area under the serum level of misoprostol concentration versus time curve, was higher than oral misoprostol (Zieman et al., 1997
). However, the same study showed that there is a wide variation in the absorption of vaginal misoprostol, as shown by the large coefficients of variation of the AUC for vaginal misoprostol between individuals. Clinically, it was not uncommon to find that the majority of the misoprostol tablet was still not completely dissolved several hours after vaginal administration (Zieman et al., 1997
; Singh et al., 1999
). The action of vaginal misoprostol may be difficult to predict in individual patients. It has been suggested that adding water to the tablets may improve absorption (Carbonell et al., 1997
, 1999
). This, however, was not supported by a randomized trial (Ngai et al., 2000
).
Recently, we have investigated a new route of sublingual administration of misoprostol. The current study represents the first report on the use of sublingual misoprostol with mifepristone for medical abortion up to 63 days gestation. Misoprostol, being very soluble in water, was administered by putting the tablet under the tongue and allowing it to dissolve. It was observed that it could dissolve in 1520 min. It is convenient to administer and avoids the uncomfortable vaginal administration. Sublingual misoprostol is taken by mouth but it can avoid the first-pass effect through the liver as in the oral route and therefore, may result in a higher complete abortion rate. Absorption of misoprostol tablets may be easier to ascertain as the dissolution of the tablets can be easily observed during sublingual compared with vaginal administration. It has been shown that some women find vaginal administration painful and uncomfortable and would like drugs that can be taken by mouth (Ho et al., 1997). Sublingual misoprostol also has the potential of developing into an outpatient medical abortion regimen. This is especially convenient if repeated doses are required.
It was shown in this study that the complete abortion rate was 94% and this is similar to a previous study using vaginal misoprostol (El-Rafaey et al., 1995). The onset of action with sublingual administration may be faster as the induction to abortion interval was only 2.7 h, shorter than the 4 h reported in the other study using vaginal misoprostol (Ashok et al., 1998). However, the incidences of side-effects were higher in the present study with a relatively high percentage of women complaining of lower abdominal pain, diarrhoea and fever. Randomized studies are required to compare the efficacy of sublingual misoprostol with other routes of administration and work out the dosage of sublingual misoprostol that can give the highest complete abortion rate and lowest incidence of side-effects.
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Acknowledgements |
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Notes |
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References |
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Submitted on December 31, 2001; accepted on February 26, 2002.