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With publication of a review article that identifies more than 200 studies involving more than 16,000 women who have used misoprostol, health care providers hope the evidence supporting the safe use of the drug in women at various stages of pregnancy will prompt a change in the medication’s labeling.1
The Washington, DC-based American College of Obstetricians and Gynecologists (ACOG) has filed a citizen’s petition with the Food and Drug Administration (FDA) outlining the reasons justifying the continued use of misoprostol and requesting a change in the drug’s current labeling. Other groups and individuals have a similar right to file petitions, states Stanley Zinberg, MD, vice president of practice activities at ACOG.
"We think the most important uses of misoprostol are one, facilitating delivery in post dates and high-risk pregnancies; two, increasing access to safe abortion; three, controlling uterine hemorrhage where access to other drugs is limited," states Philip Darney, MD, MSc, professor at the University of California, San Francisco, and OB/GYN department chief at San Francisco General Hospital Medical Center. Darney served as a co-author of the review article, which concludes that "misoprostol is one of the most important medications in obstetrical practice."
Misoprostol, marketed in the United States as Cytotec by G.D. Searle & Co. of Skokie, IL, was approved by the FDA in 1988 for the prevention of gastric ulcers associated with the use of non-steroidal anti-inflammatory drugs. Since that time, however, the drug has been used on an off-label basis, particularly for cervical ripening as a prelude to induction of labor and as the second component to early medical abortions using mifepristone.
The treatment of choice’
Indeed, use of the drug for cervical ripening prior to labor induction has been used so frequently and effectively that it has become the "treatment of choice," wrote Zinberg and Ralph Hale, MD, ACOG executive vice president, in an editorial accompanying the recently published review article.2 ACOG published a committee opinion and a practice bulletin in November 1999 as guidelines for appropriate use of misoprostol.3,4
However, Searle issued a letter to providers on Aug. 23, 2000 that cautioned that "Cytotec administration by any route is contraindicated in women who are pregnant because it can cause abortion."5 (Contraceptive Technology Update included information on the Searle letter in its December 2000 report of the FDA’s approval of mifepristone; see p. 141.) Many women’s health care advocates questioned the timing of the letter, issued about one month prior to the FDA’s approval of mifepristone (Mifeprex, marketed by Danco Laboratories of New York City).
Letter impacts care
Following the Searle letter, many hospitals, often on the advice of their legal counsel, removed misoprostol from their hospital pharmacies, states Zinberg.
"As a result, the best drug for cervical ripening prior to induction in full-term pregnancies was unavailable in these institutions," says Zinberg.
ACOG issued responses affirming the use of misoprostol for induction of labor and for medical abortion in combination with mifepristone.6,7
"Some hospitals restored misoprostol to their formularies after ACOG’s published reports supporting its continued off-label use," states Zinberg. "However, many have not done so."
Searle has issued a response defending its issuance of the provider warning letter, which states that it "resulted from lengthy discussions between Searle and the FDA after reports were received of uterine rupture in connection with the off-label use of Cytotec in pregnant women."8
In the response, Michael Friedman, MD, senior vice president for research and development at Searle, states "the FDA requested that Searle make a labeling change to clarify further the serious risks and to consider sending a letter to health care professionals." The timing of the provider letter was coincidental, he adds.
"We fully support the role of physicians, using their professional judgment, to prescribe an approved pharmaceutical product for a use outside of its FDA-approved indication in the best interest of their patients, on the basis of published research, expert clinical opinion, or their own clinical experience," notes the response.
The company says it is looking for a better dialogue with providers in the misoprostol issue. That sentiment is shared by ACOG, which seeks continued use of misoprostol in women’s health care.
"It is our hope that further evaluation by Searle and the FDA will result in a retraction of the letter of Aug. 23, 2000, and a recognition of the beneficial roles misoprostol can have during and after pregnancy," write Zinberg and Hale in their editorial. "Women in the United States should not be deprived of access to misoprostol."2
1. Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med 2001; 344:38-47.
2. Hale RW, Zinberg S. Use of misoprostol in pregnancy. N Engl J Med 2001; 344:59-60.
3. American College of Obstetricians and Gynecologists. Induction of Labor with Misoprostol. ACOG Committee Opinion 228. Washington, DC: ACOG; 1999.
4. American College of Obstetricians and Gynecologists. Induction of Labor. ACOG Practice Bulletin 10. Washington, DC: ACOG; 1999.
5. Cullen M. Dear Health Care Provider [letter]. Skokie, IL: U.S. Searle; Aug. 23, 2000.
6. American College of Obstetricians and Gynecologists. Response to Searle’s drug warning on misoprostol. ACOG committee opinion No. 248. Washington, DC: ACOG; December 2000.
7. American College of Obstetricians and Gynecologists. Mifepristone for Medical Pregnancy Termination. Washington, DC: ACOG; December 2000.
8. Friedman MA. Manufacturer’s warning regarding unapproved uses of misoprostol. N Engl J Med 2001; 344:61.