Misoprostol label change welcomed by Obstetricians: revisions acknowledge off-label uses

OB/GYN News, June 1, 2002 by Kate Johnson

Obstetricians are welcoming recent changes in the labeling for Cytotec that acknowledge the drug's off-label obstetric uses.

Cytotec (misoprostol) remains indicated solely for the prevention of gastric ulcers in people taking nonsteroidal anti-inflammatory drugs. But a previous contraindication for its use in pregnancy, which led some hospitals to forbid the use of Cytotec for obstetric purposes such as labor induction and cervical dilation, has been modified. The new label clarifies that the contraindication refers exclusively to the drug's approved indication: Pregnant women should not take Cytotec for the prevention of gastric ulcers. It does not contraindicate off-label uses related to the practice of obstetrics.

Indeed, the label now contains a new labor and delivery section that provides safety information related to the drug's unapproved use in cervical ripening and labor induction when administered vaginally, a practice that is widespread in the United States. The drug has also been used as an abortifacient.

Misoprostol's new labeling is a vast improvement over the previous version, but it remains "overly alarmist," said Dr. Charles Lockwood, chair of the American College of Obstetricians and Gynecologists Committee on Obstetric Practice.

"Ideally, I would have liked the new labeling to have stated that intravaginal Cytotec is safe and efficacious when employed for induction of labor and cervical ripening at the correct dosage and at the correct interval in the absence of absolute and relative contraindications," said Dr. Lockwood, professor and chair of obstetrics and gynecology at New York University, New York.

A spokesman for Searle, which manufactures the drug, said the company had been working with the Food and Drug Administration for more than 2 years on the label change. Searle has no plans to study Cytotec as a labor inducing agent or abortifacient and therefore cannot provide guidelines for these uses, he said.

But the label, which was revised in April, now provides information about risk factors associated with uterine rupture, which may guide safer use of the drug in pregnancy The label now lists the major adverse effects of Cytotec's obstetric uses, including hyperstimulation of the uterus, which may progress to uterine tetany with marked impairment of uteroplacental blood flow; uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy); or amniotic fluid embolism. Pelvic pain, retained placenta, severe genital bleeding, shock, fetal brady-cardia, and fetal and maternal death have been reported.

The label also notes that the risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including Cesarean delivery Grand multiparity also appears to be a risk factor for rupture.

Dr. Luis Sanchez-Ramos, who has studied the drug extensively, says the company's revised labeling of Cytotec reflects the overwhelming evidence supporting the drug's obstetric uses. "The favorable results of at least 60 randomized trials and several systematic reviews with meta-analyses could no longer be ignored," said Dr. Sanchez-Ramos, professor of obstetrics and gynecology in the maternal-fetal medicine division of the University of Florida Health Sciences Center in Jacksonville.

He said he's satisfied with the changes and that nothing further can be done unless the company requests approval for an indication of labor induction.

Dr. Lockwood, for his part, took issue with the drug's pregnancy category X classification. "It has been used in thousands of pregnancies without teratogenic sequelae. The adverse fetal effects noted following its use in failed self-induced abortions in South America reflect nearly a 1,000-fold higher dose than would be used clinically by U.S. physicians," he said.

The label change comes nearly 2 years after Searle sent a letter to physicians reminding them of possible adverse outcomes associated with Cytotec use in pregnancy The letter prompted a flurry of indignant responses from U.S. obstetricians, some of whom suggested that the company was trying to distance itself from the abortion issue shortly before the FDA approval of mifepristone (Mifeprex). ACOG sent a letter to the FDA reaffirming its previous committee opinion that misoprostol is safe and effective when used appropriately in pregnant women.

Dr. Lockwood emphasized that appropriate use means a dosage of 25 [micro]g given at intervals of every 3-6 hours, in the absence of absolute and relative contraindications, including prior C-section or other uterine surgeries, multiple gestation, grand multiparity of more than four prior deliveries, and macrosomia of more than 4,500-5,000 g.