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Misoprostol Use as Potent Induction Agent Grows : The drug's pharmacokinetics vary with the route of administration; sublingual onset of action is fastest.


 

ASHEVILLE, N.C. — Six years after its manufacturer, G.D. Searle, warned against using the drug in pregnancy due to litigation and political concerns, misoprostol is finding off-label use throughout pregnancy, Dr. Wendy Hansen said at the Southern Obstetric and Gynecologic Seminar.

Dr. Hansen, of the University of Kentucky, Lexington, said misoprostol is being used as an abortifacient in first- and second-trimester pregnancy failures, as an induction agent in the third trimester, and to manage postpartum hemorrhage.

The drug's pharmacokinetics are dependent on its route of administration. Orally, it is rapidly absorbed with a peak concentration in 12 minutes and a half-life of 21 minutes. The drug has the shortest onset of action and greatest bioavailability when given sublingually. There is also great bioavailability when misoprostol is given vaginally or rectally, but the absorption is not as consistent, said Dr. Hansen. Peak concentration with vaginal administration is 1 hour, with a slow decline over the 4 hours post administration.

However, vaginal dosing has been shown to be superior to oral regimens in hastening delivery time and reducing the need for oxytocin (Obstet. Gynecol. 1997;89:392–7; Am. J. Obstet. Gynecol. 1999;180:1155–60). That route also decreases side effects, which include nausea, vomiting, diarrhea, abdominal pain, chills, shivering, and fever.

Misoprostol is usually given in 25-mcg doses vaginally, though it comes in a 100-mcg tablet. Dr. Hansen says she has her pharmacy cut the 100-mcg tablets into quarters and then weigh each to be sure of providing the right dose. Doses should be reduced for women with hepatic disease.

The drug fell out of favor in the late 1990s after Searle issued its warning, but the American College of Obstetricians and Gynecologists countered with a letter to members stating that the evidence backed use of misoprostol in pregnancy. Use picked up, but it was tempered with caution after there were many sporadic reports of uterine rupture in the presence of a uterine scar, said Dr. Hansen. A retrospective study of 20,000 women with a prior cesarean delivery found that prostaglandins such as misoprostol did increase the rupture risk (N. Engl. J. Med. 2001;345:3–8).

Dr. Hansen recommends considering a repeat cesarean if induction is necessary in a woman with a uterine scar.

A relatively new use of misoprostol is in the first trimester for women who have missed a therapeutic abortion or have a pregnancy failure. Expectant management has been the customary approach, but the interval to spontaneous expulsion is unpredictable, which leads to sadness and uncertainty, noted Dr. Hansen. Misoprostol gives more control over timing and provides prompter evacuation, she said. A large randomized, controlled trial found that success rates for misoprostol ranged from 71% at day 3 to 85% at day 15, compared with nearly 100% success for surgical management (N. Engl. J. Med. 2005;353:761–9).

Patients who had an incomplete or inevitable abortion were administered 800 mcg of misoprostol vaginally on day 1 and again on day 3 if expulsion was incomplete (491 patients) or given electric or manual vacuum aspiration (161 patients). The pain was worse in the group given misoprostol, as was nausea, vomiting, and diarrhea. But the acceptability was the same, and 78% of women said they'd try misoprostol again, compared with 75% of the surgical group.

Women considering misoprostol for first-trimester failure should be told that success diminishes with parity, and that success can't be predicted by the biometry of the sac or the gestational age of the fetal pole, said Dr. Hansen. And, misoprostol does not seem to affect long-term fertility (Hum. Reprod. 2005;20:3355–9).

Misoprostol has become a standard treatment for second-trimester terminations or induction for intrauterine fetal demise, Dr. Hansen said. Two regimens are used, but it is not clear which is better: 400 mcg vaginally every 4 hours up to a maximum of five doses, or 800 mcg every 6, 8, or 12 hours for 24 hours. Oral routes are sometimes used also: 400 mcg every 2 hours for 24 hours or 200 mcg every hour for 8 hours. Several studies have now shown that it is safe to use in the second trimester, even in women who have had previous cesareans or uterine ruptures, said Dr. Hansen.

The drug has a history of being used successfully to manage postpartum hemorrhage, she said, adding that the rectal route is best for this purpose. Patients are given 600–800 mcg rectally, 200 mcg orally, or 400 mcg sublingually.

Dr. Hansen was asked if there had been any reports of infections with Clostridium sordellii. There have been at least five deaths attributable to that pathogen in women who took misoprostol in combination with mifepristone. But Dr. Hansen said she had not heard any such reports with misoprostol alone or outside the setting of elective medical abortion.

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