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Issues Relating to the Safety of Accutane
Subcommittee on Oversight and Investigations
Lynn Martinez
Dear
Sirs: OTIS
(Organization of Teratology Information Services) is a non-profit, North
American network of 22 state or regional Teratology Information Services (TIS),
14 individual members and four services in Canada. Each TIS is staffed with a minimum of a Medical Director and
TIS specialist. TIS' are
telephone consultation services that provide health care professionals and their
patients with up-to-date, authoritative information regarding the effects of
drugs and chemicals on the human embryo and fetus.
As a constellation of services, OTIS receives approximately 56,000 calls
per year. Half of these calls are
initiated by patients or the general public while the remainder come from health
care professionals. OTIS is organized exclusively to stimulate and encourage
research, education, and the dissemination of knowledge in the field of
teratology, and to improve the abilities of TIS' to provide accurate and
timely information about prenatal exposures, with the overall objective of
preventing birth defects and improving the public health. At
its 14th Annual Meeting in 2000, members of OTIS discussed the
disturbing trend of continued occurrence of isotretinoin-exposed pregnancies.
Data compiled from 16 of our TIS' for the period of 1995-1999 indicated
that there was an increase in the numbers of women who called our services
because they had become pregnant while undergoing treatment with isotretinoin
(see Appendix A). Many of our
members reported receiving calls from pregnant women who were being treated with
isotretinoin, but had not been appropriately counseled by their health care
professional regarding effective contraception.
These reports were consistent with data subsequently published by the
Centers for Disease Control and Prevention 1.
These continued pregnancy exposures to isotretinoin despite
implementation of the Pregnancy Prevention Program (PPPÔ),
and more recently the S.M.A.R.T. program, by the manufacturers are a great
concern given the high teratogenicity of isotretinoin.
Women who conceive during treatment with isotretinoin have a high risk
for pregnancy loss or for having babies with severe birth defects.
Anomalies of the brain, face, ears, heart, and thymus are present in
about one-third of children whose mothers were exposed to isotretinoin during
the first trimester of pregnancy. In
some cases, the mothers had been treated with isotretinoin for less than a week.
Subnormal intelligence with or without structural defects has also been
observed in children prenatally exposed to isotretinoin. Background
As
you know, to prevent fetal exposure to Accutane
(isotretinoin), Roche instituted the PPP
in 1989 with aggressive marketing to heath care providers and pharmacists.
The PPPÔ
instructed prescribing physicians that women of childbearing potential should: ·
Have two negative
pregnancy tests ·
Use two forms of
birth control simultaneously, starting one month before the prescription.
The drug should be started only after the second or third day of the next
cycle. ·
Be capable of
carrying out the instructions herein ·
Receive both verbal
and written warnings of the risks of exposing the fetus to the drug. However,
the use of the PPPÔ
by physicians was voluntary. To assess the effectiveness of the PPPÔ,
Roche commissioned a Survey of Accutane
Use in Women by the Slone Epidemiology Unit in 1989. Women treated with Accutane
were
encouraged to enroll in the survey through their physician, by filling out a
form in the medication package, or by calling a toll-free telephone number. They
were randomly assigned to be followed by telephone or by mail 2.
Women who were followed by telephone were interviewed at the beginning of
Accutane therapy, in
the middle, and six months following cessation of treatment.
Those who were followed by mail were sent questionnaires six months after
treatment ended. As of August 2000,
the survey reported results on 494,915 women 3. The pregnancy rate
among these women was 2.8 per 1000 140-courses of isotretinoin.
Among 28,016 women evaluated between 1995 and 2000, 195 identified
themselves as being sexually active and not practicing contraception.
Nearly all women in the Survey were advised to avoid pregnancy while
taking Accutane and
75% of the sexually-active women had signed a consent form.
Nevertheless, only 67% of these women postponed starting treatment until
the results of a pregnancy test were known and only 57% of the women surveyed
postponed treatment until their next menstrual period as instructed by the PPPÔ.
These results clearly illustrate that compliance to the PPMÔ
was poor. Between
the entire period of 1982-2000, Roche received reports of 1,995 Accutane-exposed
pregnancies 1. Roche
reported that between 1982-1989, 71 infants were born with congenital
malformations following prenatal exposure to Accutane
4. In addition, since
the PPPÔ
went into effect in 1989 through 2000, the FDA's Adverse Events Reporting
System database has reported 20 cases of congenital anomalies and 89 abortions
(both induced and spontaneous) per year on average following prenatal exposure
to Accutane 5.
The
Slone Epidemiology Unit has also evaluated the effectiveness of the S.T.E.P.S.
Program, a pregnancy prevention program initiated in 1998 for another highly
teratogenic medication, thalidomide. This
program differs from PPPÔ
in that it requires mandatory registration of prescribing physicians, patients,
and dispensing pharmacies, and mandatory compliance with the program.
So far, no pregnancies among 360 sexually-active women who are of
reproductive age and currently taking thalidomide have been reported 3.
Because
the number of Accutane
prescriptions to women of child-bearing age had tripled from 70,000/year in 1989
to estimates of almost 210,000 in 1999,
there was concern that an increasing number of pregnant women were being
exposed to Accutane 6.
The FDA held a meeting of its Dermatologic and Ophthalmic Drugs Advisory
Committee in September, 2000 to discuss what additional measures might help
prevent further fetal exposures to Accutane.
OTIS was also invited to participate in this meeting.
At that time, OTIS made the following recommendations to FDA: 1.
Increased regulatory safeguards concerning the use of Accutane
in reproductive age women using the thalidomide S.T.E.P.S. program as a template
to include: A.
Mandatory enrollment of physicians, pharmacists and patients by the
manufacturer. B.
An improved monitoring system for reporting a greater proportion of
Accutane exposed
pregnancies, including a substantial increase in the use of the patient survey C.
Increased patient accessibility to the use of two reliable forms of
contraception. D.
Continued educational activities provided for physicians, pharmacists and
patients concerning the teratogenic potential of Accutane. 2.
Incorporate OTIS toll-free number and web site information in all
Accutane packaging so
that direct access to risk assessment and counseling concerning the use of
Accutane prior to and
during pregnancy is available to the consumer. 3.
Amend marketing strategies to include pregnancy warnings in all direct to
consumer advertising. 4.
Continued evaluation of the effectiveness of this program and
modification if necessary. Introduction of
the S.M.A.R.T. Program
In
accordance with the recommendations made by the FDA's Dermatologic and
Ophthalmic Drugs Advisory Committee, Roche developed the S.M.A.R.T. program in
April 2002 to further enhance the safe use of Accutane
in women of reproductive age. In
addition to the requirements of the PPPÔ,
the S.M.A.R.T. program also requires that women receive a pregnancy test each
month before refilling their prescription.
Physicians must register with Roche and agree to follow the new
guidelines for prescribing Accutane.
They are also expected to provide patient counseling or referrals about
effective contraception and write prescriptions for no more than a one-month
supply. A bright yellow
qualification sticker supplied by Roche must be applied to each prescription
form for Accutane,
signifying that the patient has had negative pregnancy tests, education about
risks associated with the use of Accutane,
and counseling regarding effective contraception.
Pharmacists are expected to fill only those prescriptions for Accutane
that bear the yellow sticker, dispense a one-month supply at a time, and refuse
to fill prescriptions that are more than seven days old. Furthermore, unlike the PPPÔ,
the S.M.A.R.T. program prohibits call-in prescriptions (http://www.fda.gov/cder/drug/infopage/accutane/smart.pdf). Limitations of
the S.M.A.R.T. Program
Patient/Physician
Compliance to the Program
The
S.M.A.R.T. program is to be commended for its stricter control over the
prescribing and dispensing of Accutane;
however, there is still concern that the regulations do not go far enough to
prevent unintended pregnancies. For example, although physicians are required to register
with Roche, no consequences have been specified for those who fail to register.
Also, patients are strongly encouraged to enroll in the Accutane
survey, but patient enrollment is not mandatory.
No safeguards are in place to ensure that pharmacists only fill
prescriptions that bear a yellow sticker. For
these reasons, it is likely that compliance to Roche's pregnancy prevention
program for Accutane
will continue to be less than optimal. Indeed,
pregnancies still continue to occur even under the tighter restrictions.
Since April 2002, 17 cases of pregnancy exposure to Accutane
have been reported to 13 North American TIS'.
Also, several of the women who called their local TIS reported that no
yellow sticker appeared on the prescription form when they got their
prescription filled. Although these
reports are anecdotal and the S.M.A.R.T. program has not been in effect for very
long, they nevertheless suggest that compliance to the requirements specified in
the S.M.A.R.T. program continues to be a problem.
The Pregnancy Riskline, a TIS in Salt Lake City, Utah, has recently
received funding from a Cooperative Agreement between Association of American
Medical Colleges and the Centers for Disease Control and Prevention to
systematically study the reasons why Accutane-exposed
pregnancies continue to occur, despite the implementation of pregnancy
prevention programs by Roche and the FDA. The Danger of
Overprescribing of Isotretinoin
There
is evidence that isotretinoin is being used to treat conditions other than
severe, disfiguring nodular acne. A
survey of 670 dermatologists in the United States in 1992 found that
dermatologists were prescribing isotretinoin for indications other than those
contained in the official labeling 7. More recently, a study published by Wysowski et al. evaluated
prescription data from two pharmaceutical marketing research databases and two
health plan networks. The authors reported that between 1993 and 2000, the
proportion of prescriptions for isotretinoin for severe acne declined from 60%
to 46%, whereas the proportion of prescriptions for isotretinoin for mild and
moderate acne increased from 31% to 49% 8. Since the proportion of prescriptions was evenly distributed
between males and females, it is not likely that the increase in the proportion
of prescriptions for isotretinoin for mild and moderate acne was due to more
males receiving the prescriptions. Unfortunately,
it is not always clear from these studies if isotretinoin was used as a
first-line therapy or only after other treatments had failed. Some
dermatologists advocate using isotretinoin to treat even mild cases of acne that
are unresponsive to standard therapies, not just cystic acne 9,10.
Others believe that treatment with isotretinoin should be started in
patients with severe acne before scarring occurs.
These views illustrate the potential for more widespread use of
isotretinoin than was originally intended. Further
evidence that isotretinoin may be overprescribed can be found in articles in
popular women's magazines. For
example, in the September/October 2002 issue of Elle, the increased use of
Accutane by women is
discussed in the article, "Small Wonders". On the front page of the article, a photo of a beautiful, nude
woman with flawless skin is pictured. Accutane
is touted as "Hollywood's guaranteed panacea for the occasional blemish".
The health risks associated with the use of Accutane
are not discussed until the second page, and only one sentence is devoted to the
teratogenic risk of Accutane.
One dermatologist is quoted in the article as saying, "A very low dose
of Accutane is safe
to take indefinitely if a condition like this [rosacea or psoriasis] is chronic
and you have no intention of getting pregnant".
Since 50% of pregnancies in North America are unintentional, what happens
if a woman does become pregnant during chronic treatment with a low dose of
Accutane (however
that may be defined)? What are her
risks of giving birth to an infant with malformations or mental retardation?
Unfortunately, we have no epidemiological evidence that a low dose of
isotretinoin is safe to take during pregnancy in humans. The
Wysowski et al. study also found that dermatologists were not the sole
prescribers of isotretinoin. During
Accutane marketing in
the United States in 1982 through 2000, 8% of the physicians who prescribed
Accutane were family
and general practitioners and internists 8.
In many rural areas of the country, opportunities to visit specialists,
such as dermatologists, are infrequent. Since
the diagnosis of acne is not perceived to be difficult and the drug is not very
toxic to the adult, an increasing number of family practitioners prescribe
Accutane.
Although the S.M.A.R.T. prescribing guidelines for Accutane
recommend that Accutane
should be prescribed only by prescribers who have "demonstrated special
competence in the diagnosis and treatment of severe recalcitrant nodular acne
[and] are experienced in the use of systemic retinoids", Roche nevertheless
only requires that a physician sign the S.M.A.R.T. Letter
of Understanding certifying that he or she "knows how to diagnose and
treat the various presentations of acne".
Therefore, although it may be implicitly understood that the likely
prescriber would be a dermatologist, the S.M.A.R.T. program does not go so far
as to prohibit other health care professionals from prescribing Accutane.
In
addition, a generic form of Accutane
has recently been approved for marketing in the U.S. by the FDA; other generic
forms will surely follow. This, in
addition to the potential for overprescribing, will likely increase the number
of prescriptions filled for isotretinoin and consequently the number of
isotretinoin-exposed pregnancies. OTIS
Recommendations
OTIS
is supportive of the current efforts by the manufacturer, Roche Laboratories,
Inc. and the FDA to decrease the number of exposed, pregnant women.
However, our programs continue to receive calls from pregnant women who
have taken isotretinoin, even under the current S.M.A.R.T. guidelines.
And given recent trends to expand the number of skin conditions that can
be treated by isotretinoin and the arrival of generic forms of isotretinoin on
the market, OTIS cannot see how the current S.M.A.R.T. guidelines can possibly
prevent the continued and unacceptable
occurrence of isotretinoin-exposed pregnancies.
Therefore, further restrictions are essential to assure appropriate
protection for the embryo and fetus. For
this reason, OTIS recommends implementation of the following: 1.
Increased regulatory safeguards concerning the use of oral isotretinoin
in women of reproductive age, using the thalidomide S.T.E.P.S. program as a
template to include: A. Mandatory enrollment and compliance of physicians, pharmacists and patients with the S.M.A.R.T. program as set forth by the manufacturer. B. Mandatory participation of patients, prescribing physicians, and pharmacies in an independent registry established to monitor compliance and pregnancy outcomes of exposures to all forms of oral isotretinoin. C.
Increased patient accessibility to the use of two reliable forms of
contraception. D.
Continued educational activities provided for physicians, pharmacists and
patients concerning the teratogenic potential of isotretinoin. 2.
Availability of all forms of oral isotretinoin should be strictly limited
to only those women who meet the clinical criteria for severe recalcitrant
cystic acne. 3.
Prescribing of oral isotretinoin should be strictly limited to
dermatologists who have enrolled in the S.M.A.R.T. program and have agreed to
comply with the
guidelines. 4.
More effective and comprehensive contraceptive counseling techniques
should be used to eliminate common misconceptions about contraceptive methods
and to ensure that women understand their responsibility in
preventing pregnancy. 5.
Incorporate OTIS toll-free number and web site information in all
isotretinoin packaging so that direct access to risk assessment and counseling
concerning the use of oral isotretinoin prior to and during pregnancy is
available to the consumer. 6.
Continued evaluation of the effectiveness of this program and
modification if necessary. Given
the nature of human reproduction, OTIS is aware that all exposures to
isotretinoin cannot be prevented. However,
we feel that our combined efforts can make a significant impact on the number of
exposed pregnancies. Therefore, we
would like to see an increase in the use of TIS' to provide accurate risk
assessment and counseling for pre-,peri-, and post conception exposures to
isotretinoin. Specifically, the
potential teratogenic effects should be clearly discussed with those individuals
who have been exposed during pregnancy. Sincerely, Janine
E. Polifka, Ph.D. References 1.
Honein MA, Paulozii LJ, Erickson JD:
Continued occurrence of Accutane-exposed pregnancies.
Teratology 64:142-147, 2001. 2.
Mitchell AA, Van Bennekom CM, Louik C:
A pregnancy-prevention program in women of childbearing age receiving
isotretinoin. N Engl J Med
333(2):101-106, 1995. 3.
Scialli AR: Monitoring the
effectiveness of pregnancy prevention programs. Teratology 63(6):270, 2001. 4.
Dai WS, LaBraico JM, Stern RS: Epidemiology
of isotretinoin exposure during pregnancy. J Am Acad Dermatol 26:599-606, 1992. 5.
Brinker A, Trontell A, Beitz J: Pregnancy
and pregnancy rates in association with isotretinoin (Accutane).
J Am Acad Dermatol 47(5):798-799, 2002. 6.
Jones KL, Adams J, Chambers CD, Erickson JD, Lammer E, Polifka J:
Isotretinoin and pregnancy [letter].
JAMA 285(16):2079-2080, 2001.
7. Doering PL, Araujo OE,
Frohnaple DJ, LaMarre A, Flowers FP: Patterns
of prescribing isotretinoin: focus
on women of childbearing potential. Ann
Pharmacother 26(2):155-161, 1992.
8. Wysowski DK, Swann J,
Vega A: Use of isotretinoin (Accutane)
in the United States: Rapid
increase from 1992 through 2000. J
Am Acad Dermatol 46:505-509, 2002.
9.
Layton AM, Knaggs H, Taylor J, Cunliffe WJ:
Isotretinoin for acne vulgaris-10 years later: a safe and successful
treatment Br J Dermatol 129:292-296, 1993.
10. Cunliffe
WJ, van de Kerkhof PCM, Caputo R, Cavicchini S, Cooper A, Fyrand OL, et al.:
Roaccutane treatment guidelines: results of an international survey. Dermatology 194:351-357, 1997. Appendix A AGGREGATE DATA COLLECTED FROM PARTICIPATING TIS'
- 9/2000
TOTALS
558
143 *These numbers are incomplete because data have not been received from all TIS' as of December 9, 2002.
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