Report 8 of the Council on Scientific Affairs (A-02)
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Use of Misoprostol for Cervical Ripening

Resolution 514, introduced by the American College of Obstetricians and Gynecologists and adopted as amended at the 2001 Interim Meeting asked:

That the American Medical Association (AMA) ask the Council on Scientific Affairs to report on the safety, efficacy and value of misoprostol use in the third trimester of pregnancy, post partum period, and for fetal death in utero.

This informational report responds to that resolution.

Background

Misoprostol (CytotecÒ ) is a synthetic prostaglandin E₁ analog with antisecretory and gastric mucosal protective properties. It is indicated for reducing the risk of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers in patients at high risk of complications from gastric ulcer. This includes the elderly and patients with debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with a history of ulcers.¹

Because of its ability to promote cervical ripening and to stimulate uterine contraction, the drug also has been used off-label for a wide range of obstetric and gynecologic indications including labor and delivery, evacuation of the uterus after pregnancy failure, and induced abortion. Clinical use was facilitated by the fact that the drug is relatively inexpensive compared with other regimens, and is stable at room temperature. Several recent reviews have been published that have examined both the intravaginal and oral use of misoprostol and that support the safe and effective off-label use of misoprostol for cervical ripening, evacuation of the uterus in cases of embryonic or fetal death, and induction of labor.^2-5

Resolution 514 was submitted because clinical use of misoprostol for off-label indications had been hampered by the product labeling which specified that misoprostol was contraindicated, because of its abortifacient property, in women who are pregnant. This contraindication was reinforced in August 2000 via a "Dear Doctor" letter.⁶ This warning had a chilling effect on the availability of the product in some hospitals.

Labeling Change

On April 17, 2002, the Food and Drug Administration (FDA) announced that the product labeling for misoprostol had been revised. The major changes to misoprostol labeling were as follows:

• Removed the contraindication and precaution that misoprostol should not be used in women who are pregnant based on the rationale that the drug is widely used by obstetricians and gynecologists to induce labor and delivery, and is part of the FDA approved regimen for use with mifepristone to induce abortion in pregnancies of 49 days or less.

• Clarified that the contraindication is for pregnant women who are using misoprostol to reduce the risk of NSAID-induced gastric ulcers. Therefore, this contraindication now refers to the drug’s labeled indication, and does not contraindicate off-label uses related to the practice of medicine.

• Created a new labor and delivery section of the labeling and provided safety information related to those uses. Thus, the label now complies with 21CFR 201.57.f.7, which requires labeling to include information if a drug has a recognized use for labor and delivery, whether or not the use is included in the "Indications" section of the label. Language in this section of the labeling now notes:

• Provided new information regarding risk factors for uterine rupture, an adverse event reported with misoprostol. These risk factors include later trimester pregnancies, larger doses of the drug, prior Cesarean section or uterine surgery, and a history of five or more previous pregnancies. This information may allow physicians to better identify patients at risk for uterine rupture and thereby improve the safe use of misoprostol.

Conclusion

Changes in the official product labeling for misoprostol (CytotecÒ ) remove impediments to the off-label use of this agent. Therefore, the Council on Scientific Affairs does not believe that a comprehensive report on the safety and efficacy of misoprostol for off-label indications is necessary. This practice should continue to be guided by the best available published evidence.

RECOMMENDATIONS

Because this is an informational report, it does not contain recommendations.

References

1. Cytotec® (Misoprostol). Skokie, IL: G.D. Searle & Co; 2002. Package Insert.
2. Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med. 2001;344:38-47.
3. Blanchard K, Clark S, Winikoff, Gaines G, Kabani G, Shannon C. Misoprostol for women’s health: a review. Obstet Gynecol. 2002;99:316-322.
4. Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev. 2001(3):CD000941.
5. Alfirevic Z. Oral Misoprostol for induction of labour. Cochrane Database Syst Rev. 2000;(4):CD001338.
6. Letter issued by Searle & Co. Important Drug Warning Concerning Unapproved Use of Intravaginal or Oral Misoprostol in Pregnant Women for Induction of Labor or Abortion. August 23, 2000.