Improving Patient Education and Reducing Risk

Marcia L. Buck, Pharm.D., FCCP

Pediatr Pharm. 2001;7(7) 

In This Article

Teratogenic Effect

The ability of isotretinoin to cause severe birth defects was first documented in humans in 1983,[3] the year of its introduction in Canada and a year after its approval for marketing in the United States.[2,4] The teratogenic effect of excessive doses of vitamin A derivatives (retinoic acids) had already been established and similar results were anticipated with isotretinoin. The drug has carried a category X pregnancy designation since its release. The embryopathies associated with isotretinoin use during the first trimester include central nervous system, craniofacial, cardiac, and thymic malformations.[5] It has been suggested that these defects result from an alteration of neural crest cell morphology and motility during critical stages of development.[6]

Initial attempts to educate women about the teratogenic effect of isotretinoin focused on a voluntary, manufacturer-supported Pregnancy Prevention Program.[7,8] The program, initiated in July 1988, consisted of printed educational materials for the patient, instructions for the prescriber about the scheduling of preliminary pregnancy tests, and information about enrollment in a patient-tracking survey. As part of the program, female patients were asked to sign a consent form acknowledging that they had received counseling.

While this program had considerable success, it was unable to achieve the goal of a zero pregnancy rate.[9,10,11] In a survey of women participating in the program from 1989 to 1993, nearly all knew the damage isotretinoin could produce in a developing fetus.[9] Of the 42% who were sexually active, 99% reported using contraception. Despite this level of compliance, there were 3.4 pregnancies per 1000 documented treatment courses. Of the pregnancies reported, nearly three-quarters were terminated. Thirty-two live births occurred, with data available on 30. Of those, 7 infants had malformations believed to be caused by isotretinoin.

In a more recent survey of women enrolled in the voluntary program in California over a two year period, 23 patients reported a pregnancy.[11] Of those women, 14 consented to be interviewed. These cases resulted in one infant born with major malformations, four infants born without defects, four miscarriages, and five terminations. Neither report was able to identify patient characteristics which might predict an increased risk for becoming pregnant.

The total number of pregnancies which have occurred during isotretinoin use remains unknown.[10,11,12] In a report to the FDA's Dermatologic and Ophthalmic Drugs Advisory Committee during their September 2000 meeting, Roche provided information on a total of 1,995 pregnancies which had occurred during isotretinoin treatment.[10,12] This number, while already unacceptably high, is likely an underestimate because of the voluntary nature of the program. It is estimated that only 40% of women taking isotretinoin enroll in the program.[11] The frequency of isotretinoin-exposed pregnancies might also be expected to rise as the drug is prescribed for increasingly larger numbers of women with milder disease.

Based on the growing concern over isotretinoin's teratogenic risk, Roche, working with the FDA, voluntarily completed an extensive revision of their Accutane® product labeling in May 2000.[12] The product insert now contains a strengthened series of boxed warnings in bold type (known as "black box" labeling). The warnings stipulate that all female patients must:

  • have severe acne resistant to other therapies

  • be capable of understanding instructions

  • be reliable in complying with all testing

  • receive written and verbal warnings on the risk of teratogenicity

  • receive written and verbal information on the need for two forms of contraception

  • have a negative serum or urine pregnancy test at the time of initial evaluation and a second test on the second day of the next menstrual period or 11 days after the patient's last sexual intercourse, whichever is later (free urine test kits are provided by Roche)

  • receive information on the Accutane® Survey and watch a videotape provided by Roche

The insert also highlights the need for monthly pregnancy tests and recommends that prescriptions be written without refills to encourage compliance with testing. The product insert also contains a revised patient consent form requiring women to document that they understand the potential risks of therapy. A copy of the product insert with the new consent form is available on the company's website.[2] With the May 2000 revision, the label was also changed to require all prescribers to present the Accutane® Survey enrollment form at the time of initiating therapy in a female patient.

It is recommended that prescribers use the Pregnancy Prevention Program kit provided by Roche to assist with counseling. The kit, revised in July 2000, contains a qualification checklist for the prescriber, a patient self-evaluation, the consent forms (with copies for both the prescriber and patient), the Accutane® Survey enrollment form, documentation for referral for pregnancy testing, and patient educational materials, including a toll-free phone number of a confidential contraceptive counseling service and a toll-free phone number for additional product information, available in 13 different languages. Kits may be obtained without cost by calling Roche at 1-800-937-6243.

Accutane® should only be dispensed in its original blister package. The box contains most of the warnings from the insert, as well as a drawing of an affected infant. The FDA has also developed a patient medication guide (MedGuide) for isotretinoin that provides information in a question and answer format at a sixth grade reading level.[13] The MedGuide was released in January 2001 and is expected to become a requirement for dispensing the drug within the next year. In addition to these resources, a supplement on counseling women taking teratogenic drugs was recently published in The Journal of Reproductive Medicine which may also aid clinicians in the discussion of these risks with patients.[14,15]

Female patients should know that the precautions against pregnancy must be continued for at least a month after treatment has ended. Patients also cannot donate blood during treatment or for one month after the completion of therapy. Blood from donors taking isotretinoin may pose a risk to pregnant recipients.[2]