Accutane (isotretinoin) has been commercially available since 1982 for the treatment of resistant cystic acne. Since its introduction, the use of Accutane has increased dramatically, with up to nearly 600,000 patients treated in 1999 according to recent testimony by Roche at an FDA hearing. While Accutane has arguably improved the outlook for patients with treatment-resistant acne, it has come at a price. At issue at the moment is how large the price has been and what the FDA should do about it.

There appear to be two significant issues that clinicians should consider when prescribing Accutane. The first is the possible link between Accutane use and depression and suicide. This potential side effect has been the subject of both FDA and Congressional hearings. From August 1982 through May 2000, 37 reports of suicide reached the FDA. Twenty-four of the reported cases occurred during therapy with Accutane. Thirteen occurred after stopping of the drug. Eighty-four percent of the suicides were reported in males with a median age of 17 years.

A total of 110 hospitalizations for depression were registered during this timeframe coincident with Accutane use. In contrast to the gender distribution for suicide, 56% of those patients hospitalized for depression were females with a median age of 17 years, with 44% having a history of a psychiatric disorder. Based on case reports involving dechallenge and rechallenge (41 positive results reported to the FDA), the temporal relationship between drug administration and the hospitalization and the pharmacology of Vitamin A derivatives, it would appear that there is sufficient evidence to provoke further study. At the moment, a causal relationship has not been established, however. Most experts suggest that depression is underdiagnosed in primary care. The underdiagnosis may be especially problematic in adolescents.

While recent Congressional hearings have focused on the relationship between depression and suicide in teenage patients treated with Accutane, a second, potentially larger, clinical issue is that of fetal abnormalities. Accutane is one of the few drugs commercially available with a Category X teratogenicity rating. There is no question that fetal abnormalities can and do occur with Accutane administration in women of child-bearing potential. Since 1982, Roche has issued no fewer than 10 "Dear Doctor" letters advising physicians about the unique prescribing requirements for Accutane. (see regulatory history at: http://www.fda.gov/ohrms/dockets/ac/00/slides/3639s1.htm) Here is what prescribers should be doing:

1. Restrict Accutane use to severe nodular acne resistant to standard therapies.
2. Insure that the patient will be reliable in understanding and carrying out instructions.
3. Insure that the patient will be capable of complying with the mandatory contraceptive measures required for therapy (2 forms of effective contraception should be used simultaneously unless abstinence is the chosen method or patient has had a hysterectomy) and understand behaviors associated with an increased risk of pregnancy.
4. Insure that the patient has received both oral and written warnings of the risk of taking Accutane during pregnancy and the possibility of contraception failure, and that she acknowledges this understanding in writing. A consent form is attached.
5. Obtain a negative serum pregnancy test with a sensitivity of at least 50MIU/mL when first considered for therapy and a second negative serum or urine pregnancy test on the second day of the next normal menstrual period or 11 days after last act of unprotected sexual intercourse.
6. Have patient begin therapy the second or third day of her next normal menstrual period.

In 1988, Roche introduced a Pregnancy Prevention Program for Accutane. During 1995-99, Roche surveyed women enrolled in the program to determine their level of understanding of the risks of Accutane use. The results are as follows:

Forty percent of women surveyed are sexually active: 39% of those sexually active women were using some method of birth control, 25% did not have a pregnancy test performed prior to initiation of Accutane therapy, and 40% did not have a pregnancy test at any time during therapy.

To date, the FDA and Roche have reported 958 exposed pregnancies to Accutane. These pregnancies have resulted in 834 pregnancy terminations and 111 live births. The live births experienced a 13% incidence of malformations.

While the FDA has yet to indicate how it will respond to this ongoing rate of pregnancy exposures and fetal malformation, the recent withdrawal of Lotronex, Propulsid and Rezulin may force the Agency into action. While withdrawal from the market is a possibility, a program of restricting prescribing authority for Accutane is more likely. In the meantime, prescribers would be well advised to screen their patients on Accutane for signs of depression and to adhere to the FDA recommendations for use in women of child-bearing potential. Documentation of the pregnancy status and discussion about the need for birth control measures are also advisable.

Here is the FDA-approved Accutane Patient Consent form from the Package Insert:

PATIENT CONSENT FORM:

To be completed by the patient, her parent/guardian * and signed by her prescriber.

Please read each item below and initial in the space provided to indicate that you understand each item and agree to follow your prescriber's instructions. DO NOT SIGN THIS CONSENT AND DO NOT TAKE ACCUTANE IF THERE IS ANYTHING THAT YOU DO NOT UNDERSTAND. A parent or guardian of a minor patient must also read and understand each item before signing the consent.

1. I, _________________________________________________,
   (Patient's Name)
   understand that Accutane is a very powerful medicine with the potential for serious Adverse Effects that is used to treat severe nodular acne that did not get better with other treatments including oral antibiotics.
   INITIALS: _________________
2. I understand that I must not take Accutane (isotretinoin) if I am pregnant. I understand that I must not take Accutane if I am able to become pregnant and I am not using the required two separate forms of effective methods of birth control.
   INITIALS: _________________
3. I understand from my prescriber that although not every fetus exposed to Accutane has resulted in a deformed child, there is an extremely high risk that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking Accutane in any amount even for short periods of time. Potentially any fetus exposed during pregnancy can be affected.
   INITIALS: _________________
4. I understand that I must avoid pregnancy during the entire time of my treatment and for 1 month after the end of my treatment with Accutane.
   INITIALS: _________________
5. I understand that if I am able to become pregnant and unless I absolutely and consistently abstain from sexual intercourse, I must use two separate, effective forms of birth control (contraception) AT THE SAME TIME.
   INITIALS: _________________
6. I understand from discussions with my prescriber that birth control pills and injectable/implantable birth control products are the most effective forms of birth control. I understand that there have been reports of pregnancy from women who have used birth control pills, as well as women who have used injectable/implantable birth control products and I understand that pregnancies occur more often when only a single method of birth control is used. Therefore, I understand that it is essential that I use two different methods, even if one of the methods I choose is birth control pills or injectable/implantable birth control products.
   INITIALS: _________________
7. I understand that the following are considered effective forms of contraception:
   Primary:Tubal ligation, partner's vasectomy, birth control pills, injectable/implantable birth control products, and an IUD
   Secondary:Diaphragms, latex condoms, and cervical caps; each must be used with a spermicide.
   I understand that at least one of my two chosen methods of birth control must be a primary method, and that any birth control method can fail, even when two forms are used at the same time.
   INITIALS: _________________
8. I understand that I may receive free initial contraceptive counseling and pregnancy testing from a consulting physician or family planning center. I understand that my Accutane prescriber can provide me with an Accutane Patient Referral Form for this consultation.
   INITIALS: _________________
9. I understand that I must begin actively avoiding pregnancy as described above at least 1 month before taking the first dose of Accutane, throughout treatment with Accutane and for 1 month after I have completed Accutane treatment.
   INITIALS: _________________
10. I understand that I cannot receive a prescription for Accutane unless I have 2 negative pregnancy test results. The first pregnancy test should be during the office visit when my prescriber decides to prescribe Accutane. The second test should be on the second day of my next menstrual cycle or 11 days after the last time I had unprotected sexual intercourse, whichever is later. I understand that I will have additional pregnancy testing, monthly, throughout my Accutane therapy.
    INITIALS: _________________
11. I understand that I should not start Accutane until I am sure that I am not pregnant and have negative results from 2 pregnancy tests.
    INITIALS: _________________
12. I have read and understand the materials my prescriber has given to me, including the brochure Important Information Concerning Your Treatment with Accutane® (isotretinoin) . I have watched and understand the Roche video provided to me by my prescriber about contraception. I have also been told about a confidential counseling line that I may call for additional information about birth control and I have received information on emergency contraception.
    INITIALS: _________________
13. I understand that I must not share my medication with anyone else and that I should not give blood until 1 month after taking my last dose of Accutane, because if I do, someone else's unborn baby may be exposed to Accutane.
    INITIALS: _________________
14. I understand that I must immediately stop taking Accutane and inform my prescriber if I become pregnant, miss my menstrual period, or stop using birth control.
    INITIALS: _________________
15. I have been given information about the confidential Accutane Survey by my prescriber and he/she has explained to me how important it is to join the Accutane Survey.

My prescriber has answered all my questions about Accutane and the Accutane information provided to me. I understand all the information I have received and that avoiding pregnancy during Accutane treatment is my responsibility.
INITIALS: _________________

I now authorize my prescriber to ______________________________ to begin my treatment with Accutane.

_____________________________________________________
Patient signature
_____________________________________________________
Parent/guardian signature
_____________________________________________________
Please print: Patient name and address
_____________________________________________________
Telephone (area code)

I have fully explained to the patient, __________________________, the nature and purpose of the treatment described above and the risks to females of childbearing potential. I have asked the patient if she has any questions regarding her treatment with Accutane and have answered those questions to the best of my ability.

_____________________________________________________
Prescriber signature Date

*if patient is a minor under the age of 18.

Roche Pharmaceuticals
Roche Laboratories Inc., 340 Kingsland Street, Nutley, New Jersey 07110-1199
Revised: May 2000