Hospitals Restrict Misoprostol Use

OB/GYN News, Nov 15, 2000 by Greg Borzo

The off-label use of an antiulcer drug is threatening to curtail the widespread availability of medical abortions--right on the eve of mifepristone's closely watched rollout.

A recent warning from Searle not to use misoprostol (Gytotec) in pregnant women has unnerved hospitals, some of which are pulling the drug from their formularies for obstetrics. Meanwhile, some physicians are rethinking plans to begin offering medical abortions because of the controversy.

Misoprostol was approved by the Food and Drug Administration in 1988 for preventing and treating peptic ulcers. For years, it has been used off label for labor induction and cervical ripening--despite being contraindicated in pregnant women. More recently physicians began using it to manage third-stage labor. The latest use, for medical abortions, has thrust Searle and the drug squarely into the abortion war.

The arduous debate about medical abortions has focused on mifepristone (Mifeprex), but mifepristone must be used with misoprostol.

Shortly before the Food and Drug Administration approved mifepristone in September, Searle sent health care professionals a warning reminding them that misoprostol is contraindicated in pregnant women. But Dr. Charles Lockwood, chair of the American College of Obstetricians and Gynecologists' Committee on Obstetric Practice, said it is "unprecedented for a drug company to question the off-label use of its drugs."

Critics say that Searle's attempt to distance itself from off-label uses of misoprostol gives ground to antiabortion forces. "Searle is running scared," said Dr. George Huggins, chair of ob.gyn. at Johns Hopkins University, Baltimore. "It's afraid of a boycott organized by those who are trying to stop the provision of abortion services."

Not so, said a spokesman for Pharmacia, Searle's parent company. "The letter had nothing to do with mifepristone's pending approval. It was prompted by adverse events reported to Searle and the FDA through postmarket surveillance and had been in the works for over a year."

Regardless of Searle's motive, the sharply worded warning has hospital administrators, lawyers, risk managers, and pharmacy and therapeutics committees scrambling. An informal survey of more than a dozen hospitals found that one-third to one-half have pulled misoprostol from their formularies, according to Dr. Lockwood. Another one-fourth have restricted its use.

Los Angeles County/University of Southern California Women's and Children's Hospital restricted misoprostol use to investigational protocols in pregnant women as a result of Searle's letter. And Brigham and Women's Hospital, Boston, removed the drug from its formulary.

The Population Council, which holds the U.S. rights to mifepristone, said that such steps will have little bearing on whether medical abortions become readily available once mifepristone hits the market, since the new drug will be used in clinics and physicians' offices rather than in hospitals. "Mifepristone is designed to be used during the first trimester, and very few hospitals do first-trimester abortions," said spokeswoman Sandra Waldman.

Nevertheless, physicians say Searle's letter could prompt a rebuke of misoprostol across the board, and thereby severely limit the availability of medical abortions before the procedure is even available.

"Since this letter came out, most physicians are staying away from misoprostol," said Dr. Andrei Rebarber, an ob.gyn. at New York University, New York. "When we tell patients about the warning, most opt not to use the drug, and I believe these attitudes will carry over to the use of misoprostol with mifepristone."

"Searle's letter won't have much of an impact on those already providing abortions, but it will have a significant impact on the potential new providers of medical abortions," Dr. Huggins speculated.

In any event, Searle's tough stance has exposed a deep divide within obstetrics about the safety and efficacy of misoprostol. ACOG calls the drug safe and effective in inducing labor. In November 1999, it published guidelines endorsing the use of misoprostol to induce labor. In October 2000, after reviewing the literature and reports to the FDA regarding adverse events due to misoprostol, ACOG's Committee on Obstetric Practice concluded that safety fears are unfounded, said Dr. Lockwood, also of New York University. "The bulk of the problems occurred when the drug was used inappropriately."

Still, some institutions, including the University of Washington, have shunned the use of misoprostol in pregnant women. Due to concerns about safety and the lack of data about dosing and route of delivery the hospital limits the drug to investigational protocols.

Some cite teratogenesis as a possible adverse outcome. Searle's letter also lists maternal or fetal death; uterine hyperstimulation; rupture or perforation requiring surgical repair, hysterectomy or salpingooophorectomy; amniotic fluid embolism; severe vaginal bleeding; retained placenta; shock; fetal bradycardia; and pelvic pain.