More FDA regulations, designed to protect patients, are coming for acne drug

Roche's Accutane draws new regs from FDA




More FDA regulations, designed to protect patients, are coming for acne medication

When Accutane (isotretinoin, Hoffmann-La Roche) won clearance in 1982, the secretary of Health & Human Services and the head of the Food & Drug Administration hailed the United States as "the first nation to approve this important new drug.'' Their joint statement did not mention the acne drug's potential for teratogenicity, a warning that the FDA had required in its labeling. Nor did they, or anyone else—at least from the public record—mention or even know then of a potential link between isotretinoin and suicide.

But in the nearly two decades since isotretinoin's introduction as a treatment for severe recalcitrant cystic acne, the dangers of birth defects and psychiatric disorders possibly associated with the drug have increasingly stalked patients, providers, regulators, and the manufacturer. Isotretinoin "continues to be one of the FDA's most difficult challenges in the area of postapproval risk management," noted Jonca Bull, deputy director of the FDA's office of drug evaluation.


The FDA expects to have a MedGuide mandated for isotretinoin patients this month. Also anticipated is an enhanced informed-consent form and a registry required for both patients and prescribers. The emphasis will continue to focus on pregnancy prevention and the requirement for females of childbearing age to use two effective forms of birth control simultaneously. But discussion of psychiatric events—including depression and suicide—among some users also will be covered. Further study of a causal link between isotretinoin and psychiatric events also is likely.

The possible association with suicide was given widespread public visibility in October when Rep. Bart Stupak (D, Mich.) appeared on NBC-TV's "The Today Show" and blamed the drug for the death of his 17-year-old son. He said his son, B.J., had been using isotretinoin for seven months when he died of a self-inflicted gunshot wound. "B.J. had not shown signs of depression, and if we'd known this drug could cause depression or suicide, he never would have come into contact with Accutane," Stupak said in a news conference with families of other isotretinoin users who had killed themselves. "The warnings on B.J.'s Accutane package contained none of these risks." The FDA has received reports of 41 suicides among isotretinoin users, most of them male teenagers.

At a Congressional hearing last month, several parents of isotretinoin users who had committed suicide said that their physicians and pharmacists had not warned them about the potential for depression, much less suicide. That troubled Rep. Dan Burton (R, Ind.), chairman of the House Government Reform Committee, who struggled to understand why, despite extended publicity, the doctors and R.Ph.s did not know of isotretinoin's dangers. He challenged the American Academy of Dermatology to "fax all the dermatologists in the country" warning them of the risks. He said if the academy did not do it, he would, "because I don't want other people coming before our committee with their kids being dead because possibly Accutane caused it."

Douglas C. Jacob, M.D., an associate professor at Harvard Medical School who has served as a consultant to Roche, said "the current scientific evidence does not support a link between isotretinoin and depression, suicidal ideation, or suicide."

James O'Donnell, Pharm.D., assistant professor, Rush Medical College, who has been an expert witness for plaintiffs in suits against Roche, said isotretinoin is "overwhelmingly prescribed for minor and moderate conditions, despite existing warnings to the contrary in the package insert."

About 400,000 patients used isotretinoin, a derivative of vitamin A, in the first nine months it was stocked in pharmacies. But then women who took the drug during pregnancy started reporting birth defects. Soon, Roche and the FDA began what has become a lengthy and continuing series of struggles over strengthened warnings and restrictions on isotretinoin. The initial worries about birth defects were later joined by concerns for the potential for depression. Roche amended the package insert in 1985 to list depression among the adverse events reported. In 1986, the firm again amended the insert to state: "Depression has been reported in some patients on Accutane therapy. In some patients, this has subsided with discontinuation and recurred with reinstitution of therapy."

By early 1998, the FDA required a bold-faced warning on psychiatric disorders, including suicide attempts and suicide. "Discontinuation of Accutane therapy may be insufficient," it noted. France had taken a similar step a year earlier, unbeknownst to the FDA. Burton questioned the FDA's Bull on whether makers are legally required to report such labeling changes. She indicated they are not, but the agency was developing a rule to change that.

Michael F. Conlan


Mike Conlan. More FDA regulations, designed to protect patients, are coming for acne drug. Drug Topics 2001;1:49.