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3/1/2004

Experts Advise Tougher Restrictions for Isotretinoin

Donna Young

Tighter restrictions, including a mandatory registry of pharmacists, prescribers, and female patients, must be imposed to ensure that women of childbearing age do not become pregnant while taking the acne drug isotretinoin, a joint panel of experts advised the Food and Drug Administration (FDA) on Friday.

Isotretinoin, first approved in 1982 for the treatment of severe recalcitrant nodular acne, is known to cause severe birth defects and spontaneous abortion.

F. Hoffmann-La Roche Ltd. markets isotretinoin under the brand name Accutane.

On November 8, 2002, the first generic version of isotretinoin was approved for marketing. Since then, two additional generic formulations have been approved, and other applications are pending, according to FDA.

Each of the drug makers have been required to provide an isotretinoin teratogenicity risk-management plan that requires pharmacists to dispense a 30-day supply of the drug only when presented with a prescription that bears a yellow qualification sticker.

The sticker, if on a prescription for a female patient, signifies that the patient has two negative urine or serum pregnancy tests before the initial prescription of the drug was written, according to FDA.

At the time the program was first implemented in April 2002, Roche was the only approved manufacturer of isotretinoin. Generic makers of the drug implemented programs with identical components in late 2002 and early 2003.

But a first-year evaluation of the program found that it has not decreased pregnancies among women taking the drug.

According to FDA, there were 127 pregnancies among isotretinoin users in the year before the program was implemented, and 120 pregnancies in the program's first year. Of the 120 pregnancies, more occurred during the first month of isotretinon therapy than during later months, and at least 7 women were already pregnant before taking their first dose.

About 90 percent of the prescriptions filled during the first year of the program bore the yellow sticker, the agency said.

However, FDA said that at least seven women reported that they took isotretinoin without medical supervision, and at least one woman obtained the drug at a "swap meet." Another patient obtained a prescription in January but did not take the drug until December of the same year. At least five women reported that they had saved doses of isotretinoin after stopping therapy and restarted treatment later when their acne flared up.

The advisory panel, a joint meeting of the Drug Safety and Risk Management and the Dermatologic and Ophthalmic Drug Advisory Committees, unanimously voted not to continue the current risk-management program, opting instead to adopt ideas presented last week by Roche, as a "core" to base a new program.

Roche's proposed plan includes the implementation of a required registry of patients, pharmacies, and prescribers, similar to a program used by Celgene for its thalidomide drug, Thalomid.

Under Celgene's System for Thalidomide Education and Prescribing Safety (STEPS) program, prescribers of the drug must confirm by using an interactive voice response system survey that the patient has been appropriately counseled and that there has been no fetal exposure to the drug.

Patients and pharmacists are also required to complete a separate telephone survey.

Celgene does not require that each pharmacist in a pharmacy register for the STEPS program, but allows a pharmacy to designate one pharmacist as a representative.

But panel members on Friday voted that pharmacists who dispense isotretinoin and not pharmacies should be registered for the program.

Some panel members objected to a new risk-management plan out of fears that its complexity could potentially introduce new problems.

Under Roche's proposed plan, patients of childbearing potential are required to undergo a pregnancy test in the prescriber's office, and a second test conducted by an off-site laboratory.

Registered patients are assigned a patient identification number (PIN), which identifies the patient in all transactions.

Laboratory pregnancy test results are transmitted to the registry system. After the prescriber determines that the patient qualifies to receive the drug, the prescriber enters the qualification information into the registry system and gives the patient a prescription bearing the yellow qualification sticker.

When presented with the prescription, the pharmacist checks with the registry by submitting the PIN and dispenses the drug if the registry system confirms the authorization.

But panel members Brian Strom, professor of biostatistics, epidemiology, medicine, and pharmacology at the University of Pennsylvania at Philadelphia, and Michael R. Cohen, president of the Institute for Safe Medication Practices, said that pharmacists should not carry the burden of explaining to a patient why a prescription was not authorized.

In a 16 to 8 vote, the advisory panel suggested that isotretinoin's risk-management plan include a mandatory registry for patients, prescribers, and pharmacists.

Some physicians on the panel suggested that prescribers should be required to submit photographs of patients who are prescribed isotretinoin so that FDA could determine if the drug was prescribed inappropriately. But other experts strongly dissented declaring that requiring photos would overburden the system and would put prescribing judgments in the hands of someone other than the prescriber.

An FDA official reminded panel members that the agency does not regulate medical practice or the prescribing of medications for off-label uses.