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Current program ineffective: tighter isotretinoin restrictions appear likely.

GAITHERSBURG, MD. -- The current risk management program for isotretinoin has failed, and a more stringent program is needed to reduce fetal exposures to the drug, members of two Food and Drug Administration advisory panels agreed at a recent meeting here.

At a 2-day meeting of the FDA's Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, panel members voted 16 to 8 in favor of adopting a more restrictive risk management program that was proposed by Accutane manufacturer Roche and generally agreed upon by the three manufacturers of generic isotretinoin.

The FDA usually follows the recommendations of its advisory panels, which are not binding.

The proposed program, based in part on the risk management programs for clozapine and thalidomide, would include a centralized registry of patients, physicians, and pharmacists; a link between all three; and a patient identification number for each patient, which registered pharmacists could use to check pregnancy test results before filling the prescription.

The eight dissenting panelists--mostly dermatologists--supported a proposal that the manufacturers first study the cost and effectiveness of Roche's proposed plan before nationwide adoption, as recommended by Dr. Michael Wilkerson, a dermatologist in Tulsa, Okla.

"The [proposed] program does not, in my view, add anything but more layers of complications that may actually lead to less compliance," he said, adding that despite 22 years on the market, he was "astounded" by the lack of information about what kind of program would best reduce fetal exposures and the fact that "we don't have a better way of dealing with this problem.

Dr. Sharon Raimer, professor and chair of dermatology at University of Texas Medical Branch, Galveston, pointed out that while the System for Thalidomide Education and Prescribing Safety (STEPS) has been highly effective in an older, sicker population, a pilot study would be needed to learn whether similar elements would be as effective in the younger, healthier population of isotretinoin users.

STEPS also requires registration of physicians and pharmacists; mandatory registration of patients; weekly pregnancy tests during the first month; and pregnancy tests every 2 or 4 weeks thereafter.

The panel unanimously agreed that there should be only one risk management program for isotretinoin, with one name, one registry, one survey, and one set of forms, instead of the four programs currently in the marketplace. Roche's System to Manage Accutane Related Teratogenicity (SMART), which was the first of the programs, was fully implemented in April 2002, and is virtually interchangeable with programs for the three generics.

How long it would take to implement a new program is uncertain. "Doing nothing and making no change, in our opinion, is not an option," and if changes are made, they need to be made quickly, said Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs.

Data presented by the FDA and manufacturers at the meeting showed that the risk management programs have failed to achieve what so far has been an elusive goal--despite efforts to address and manage the risks of isotretinoin dating back to 1983, when the first isotretinoin-exposed baby was born with malformations. The goal of the current program is that no woman who is already pregnant should be prescribed isotretinoin, and no woman should become pregnant during treatment with the drug. Isotretinoin, which is uniquely effective for severe, cystic acne, is associated with retinoid embryopathy in about 28% of exposed fetuses.

But the number of isotretinoin-exposed pregnancies reported to the FDA during the years before and after the current risk management program was implemented remained about the same, while the total number of prescriptions written for isotretinoin dropped by 23%, according to Marilyn Pitts, Pharm.D., of the FDA's Office of Pharmacoepidemiology and Statistical Science.

In the year before SMART was implemented, 127 isotretinoin-exposed pregnancies were reported, compared with 120 in the year after. (An additional 78 exposed pregnancies were reported at some point during that 2-year period.) The FDA believes that the total of 325 cases reported was "a fraction" of the actual number, Dr. Pitts said.

Of the 127 pregnancies that occurred before the program, 12 (9%) were reported in women who were pregnant before starting treatment, compared with 7 (6%) of the 120 pregnancies that occurred during the current risk management program; 83 (65%) conceived during treatment before the program, compared with 80 (67%) after. Before the current program, 31 (24%) women conceived within 30 days of stopping treatment, when birth defects are still a risk, compared with 31 (26%) under the current program.

SMART and its equivalents were designed to link a negative pregnancy test with each dispensed isotretinoin prescription, requiring physicians to affix a yellow "qualification sticker" on all prescriptions, with the date of the test written on the sticker. Patients are required to commit to using two forms of effective contraception for at least 1 month before, during, and for 1 month after stopping treatment.

Pharmacists were instructed to fill a prescription only if the yellow sticker is present, within 7 days of the date on the sticker, for one 30-day course at a time, with no refills.

The stickers have been used in over 90% of prescriptions, but they have not been an accurate predictor of compliance with the program's requirements for pregnancy testing.

A Roche survey of a random sample of pharmacists determined that the stickers were affixed to 97% of prescriptions and almost all were properly completed. The number of pregnancy case reports, acquired from the Accutane patient survey and from spontaneous reports from health care professionals and consumers, increased during the first year of SMART, to 183 cases, from 150 the year before.

Pregnancies were associated with incomplete compliance with the risk management guidelines, said Dr. Martin Huber, vice president and global head of drug safety risk management at Roche, who said the increase was more likely a reflection of greater awareness and increased reporting.

Of those exposures, there was a moderate reduction in the number of patients who were pregnant when they started treatment, dropping from 19% before SMART to 13% with SMART. The year before SMART, 51% of patients who became pregnant did so during treatment, dropping to 41% with SMART. The proportion of women who became pregnant within 30 days of stopping treatment remained the same, at about 30%. Timing of exposure was not known for 14% of the pregnancies reported during the SMART program, compared with less than 1% of those before SMART.

A total of 19 pregnancies have been reported in patients on generic isotretinoin products since they have become available, with 18 reported for Amnesteem (Bertek), one for Claravis (Barr), and none for Sotret (Ranbaxy). Of these, three were pregnant when they started treatment, six became pregnant after starting treatment, and five became pregnant within 30 days of stopping treatment.

Maintaining that SMART has "clearly" been a failure, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, told the panel that his organization would be filing a citizen's petition requesting that isotretinoin be withdrawn from the market and made available only as an investigational new drug, with restrictions that include requiring photographic proof of severe cystic acne, confirmed by an independent group of dermatologists.
Isotretinoin-Exposed Pregnancies

 Prior RMP Current RMP
 (n=127) (n=120)

Conceived within 30 days of 24% 26%
stopping treatment
Pregnant before starting treatment 9% 6%
Conceived during treatment 65% 67%

RMP=risk management program

Note: Table made from bar graph.

 Pregnancy Testing in Women
 With Isotretinoin-Exposed Pregnancies

 Prior RMP Current RMP
 (n=127) (n=120)

Before Isotretinoin Use (Baseline)
 [greater than or equal to]1 test 63 (50%) 60 (50%)
 No test 4 (3%) 2 (2%)
 Not reported 60 (47%) 58 (48%)

During Isotretinoin Use
 [greater than or equal to]1 test 45 (35%) 47 (39%)
 No test 4 (3%) 2 (2%)
 Not reported 78 (61%) 71 (59%)

Notes: RMP=risk management program. Percentages may not add up to 100%
due to rounding.
Source: Food and Drug Administration


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Title Annotation:Focus on Skin Disorders
Author:Mechcatie, Elizabeth
Publication:Internal Medicine News
Geographic Code:1USA
Date:Apr 1, 2004
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