FDA Proposes to Delete Warning Label on Hormone

FDA finds that there is no reliable evidence showing that drugs with progesterone cause birth defects.

FDA has proposed that drugs that contain the sex hormone progesterone should no longer carry special labeling that warns pregnant women against their use during the first four months of pregnancy.

In a proposed rule published in the April 13, 1999, Federal Register (64 FR:17985–17988), the agency says that based on a review of scientific data, there is no need for all progestogens to carry that warning. "The diversity of drugs that can be described as progestational, and the diversity of conditions these drugs may be used to treat, make it inappropriate to consider these drugs a single class for labeling purposes," the proposal states. "This action is intended to provide customers with more-accurate labeling for certain drug products."

The current regulation requires that drug companies print a box warning on professional labeling against progesterone use during the first four months of pregnancy as well as a patient package insert containing a "brief discussion of the nature of risks of birth defects resulting from the use of these drugs during the first four months of pregnancy." The warning applies to all drugs containing natural progesterone or synthetic progestins, with the exception of contraceptives and advanced cancer drugs in oral dosage forms.

When the regulation was first written in 1977, it was believed that there was an association between progestogens and congenital heart and limb-reduction defects. By the late 1980s, the evidence indicated that that was not the case, but that there could be an association between the drugs and an increased risk of certain genital abnormalities.

In 1989, the agency deleted the heart and limb warnings and replaced them with the genital abnormality warnings. Specifically, the drugs were thought to increase the risk of hypospadias in male babies—a condition in which the opening of the penis is on the underside rather than at the tip—and of masculinization of the external genitalia in female babies.

However, FDA recently reviewed the evidence for that link and found it to be weak. Much of the evidence came from individual case histories, and in many cases it was unclear what drug the mother had taken or whether she was taking drugs in addition to progestogens. The studies that were done often failed to control for the condition being treated.

According to the agency, "The reliable evidence, particularly from controlled studies, shows no increase in congenital abnormalities, including genital abnormalities in male or female infants, from exposure during pregnancy to progesterone or hydroxyprogesterone."

Since the 1970s, some uses of progestogens, such as a hormonal pregnancy test and a treatment for spontaneous abortion, have been abandoned. But other safe and effective uses have emerged, such as that for luteal-phase support with in vitro fertilization. There is no point in warning people away from an effective treatment if the caution is not justified, the agency says. In fact, the American College of Obstetricians and Gynecologists had objected because the warning was needlessly disturbing infertility patients.

When the rule becomes final, those who hold approved applications for progestational drug products will have to remove both the affected text in the patient labeling and the entire box warning on the professional labeling, which includes a contraindication as a diagnostic test for pregnancy (even though hormonal pregnancy tests have not been sold in the United States for years). The revisions will not have to be reported separately but can be included in the manufacturer's next annual report to the agency.

FDA also plans to revoke its guidance texts for patient and professional labeling for progestational drug products.

The comment period lasts until July 12, 1999. The proposal calls for the final rule to be effective one year after the date of its publication in the Federal Register.

For more information, contact Diane V. Moore, Center for Drug Evaluation and Research (HFD-580), FDA, 5600 Fishers Ln., Rockville, MD 20857, 301/ 827-4260.

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