Studies continue in methotrexate use

While American women wait for final federal Food and Drug Administration (FDA) approval and U.S. release of mifepristone, research continues in the use of an already-available drug, methotrexate, for early medical abortions.

Researchers are working with various doses and administration routes of the drug, says Mitchell Creinin, MD, assistant professor and director of family planning at the University of Pittsburgh. Methotrexate is cleared by the FDA as a cancer medication and now is being used "off-label" in trials with the prostaglandin misoprostol for abortions. "Right now we are looking at techniques of adjusting either the methotrexate or the misoprostol to try and improve outcome," Creinin says. "There has been a lot of information coming out in publication."

Planned Parenthood Federation of America in New York City is processing data on its clinical trial of the methotrexate/misoprostol regimen, reports Michael Burnhill, MD, vice president for medical affairs. Once data analysis is complete, a report demonstrating the safety and efficacy of the regimen for early medical abortion will be submitted to the FDA. This documentation is needed before the agency will consider a labeling change.

The multi-center clinical trial has called for an extra effort by participating Planned Parenthood clinics, Burnhill says. "We are pushing them to complete a complex research protocol, and we haven't given them any money to do that, so for them, it has been a labor of love or basically a staff burden. If they were just providing it as a service, it probably would be no more or less difficult than early abortion. But there is a research protocol, and there is a lot of paperwork to fill out and guidelines to follow."

Testing regimens

In the last five years, much research has focused on intramuscular administration of methotrexate, followed by vaginal administration of misoprostol. A number of published studies have shown the safety and efficacy of the method, using 50 mg/m2 injection of methotrexate, followed by vaginal insertion of 800 µg of misoprostol tablets.1-5 This regimen has proven effective in over 90% of cases.

A study published early in 1998 has sparked renewed interest in oral administration of metho trexate with vaginal administration of misopros tol.6 A team of Spanish and Cuban investigators demonstrated more than 90% efficacy with an oral dose of 50 mg of methotrexate. The 300 women in the study received four capsules of methotrexate in one visit, then were randomly assigned to self-administer four tablets of 200 µg of misoprostol vaginally on either days 3, 4, or 5 after the methotrexate dose. Creinin, who has worked with oral administration of methotrexate,7 is collaborating with the study's lead researcher, Josep Lluis Carbonell, MD, of the Clinica Mediterrania Medica of Valencia, Spain, in further exploring oral administration of the drug.

Common side effects encountered with the methotrexate/misoprostol regimen include nausea, vomiting, diarrhea, and dizziness. In a multi-center acceptability study, 93% of women did not have a negative experience, and 83.5% said they would choose the method again.8

The main advantage of any form of medical abortion, whether it be achieved with mifepristone, methotrexate, or misoprostol alone, is that it gives a choice to those women who do not want a surgical abortion.

The desire for a choice is important in a direct comparison between surgical and medical methods, says Creinin. Surgical abortions can be done just as early in the pregnancy as medical abortions, he notes, and they are faster and more effective.

As the wait continues for the U.S. debut of mifepristone, researchers are continuing to gather information on methotrexate abortions. These figures may be helpful in comparing the two regimens, says Creinin, who also participated in the U.S. trial of mifepristone. "In looking at the two, I used to say you can't compare them, because one has had hundreds of thousands cases and the other had a few hundred, but now we are getting to the point where there have been thousands of methotrexate abortions, and we can talk a little bit in comparison. I think if both were available, mifepristone, assuming that costs and availability are truly equal, is definitely the better regimen."

While there appears to be little difference in overall efficacy between the two regimens, an important factor is the timetable in which efficacy is achieved, Creinin says. Most women complete their abortion with mifepristone within a few days, while methotrexate regimens may be completed within a few weeks. Abortion providers will have to factor in additional education time and extra telephone calls for women who choose either route of medical abortion.

"I think by the time mifepristone comes out, and our final work is completed on methotrexate, the public and certainly the profession will have a clear idea of what the risks, benefits, and disadvantages of this method are," Burnhill says. "It does do some things for some people, and it certainly extends women's options. But it is not a panacea."

References

1. Creinin MD, Darney PD. Methotrexate and misoprostol for early abortion. Contraception 1993; 48:339-348.

2. Creinin MD, Vittinghoff E. Methotrexate and misoprostol vs. misoprostol alone for early abortion. A randomized controlled trial. JAMA 1994; 272:1,190-1,195.

3. Creinin MD, Vittinghoff E, Galbraith S, et al. A randomized trial comparing misoprostol three and seven days after methotrexate for early abortion. Am J Obstet Gynecol 1995; 173:1,578-1,584.

4. Schaff EA, Eisinger SH, Franks P, et al. Combined methotrexate and misoprostol for early induced abortion. Arch Fam Med 1995; 4:774-779.

5. Creinin MD, Vittinghoff E, Keder L, et al. Methotrexate and misoprostol for early abortion: a multicenter trial. 1. Safety and efficacy. Contraception 1996; 53:321-327.

6. Carbonell JL, Varela L, Velazco A, et al. Oral methotrexate and vaginal misoprostol for early abortion. Contraception 1998; 57:83-88.

7. Creinin MD. Oral methotrexate and vaginal misoprostol for early abortion. Contraception 1996; 54:15-18.

8. Creinin MD, Burke AE. Methotrexate and misoprostol for early abortion: a multicenter trial. Acceptability. Contraception 1996; 54:19-22.