| The
Power of Accutane:
The Benefits and Risks of a Breakthrough Acne DrugBy
Michelle Meadows (staff writer for FDA Consumer) Acne
plagued Julie Harper throughout high school and college. She depended on makeup
and wore her hair down over the side of her face. She gave up chocolate and french
fries, only to find that neither made a difference. And she went through medicine
after medicine, from over-the-counter creams to oral antibiotics.
These
were not occasional pimples that vanish after a couple of days. This acne covered
her face and left scars on her neck. "I had tried everything and felt frustrated
all the time," says Harper, now a physician and assistant professor of dermatology
at the University of Alabama-Birmingham--a career she chose due in large part
to her struggle with acne. Harper
finally found a successful treatment nine years ago at the age of 22. She took
a drug called isotretinoin (trade name Accutane) and watched her skin improve
in just a couple of months. By the third month, her acne had disappeared. She
says with clearer skin came more self-confidence and higher self-esteem. Considered
the biggest breakthrough in acne drug treatment over the last 20 years, Accutane
is the only drug that has the potential to clear severe acne permanently after
one course of treatment. (See "Why Acne Forms, and How Accutane Knocks It
Out.") One course, which is typically five months, results in prolonged remission
of acne in up to 85 percent of patients. A member of a class of drugs known as
retinoids, Accutane is highly effective. But it doesn't work for everyone, and
some patients need more than one course of treatment. Dr. Harper took a second
course of Accutane one year after the first and has been free of severe acne ever
since, now only occasionally using a topical medication. No
other acne medicine works as well for severe acne. Patients generally have to
keep using other medications because they only suppress acne temporarily. But
as powerful as Accutane can be in improving patients' lives, its adverse effects
can be just as powerful. The drug is known to cause miscarriage and severe birth
defects. Patients taking Accutane may develop potentially serious problems affecting
a number of organs, including the liver, intestines, eyes, ears, and skeletal
system. And some patients taking Accutane have developed serious psychiatric problems,
including depression. More rarely, patients have developed suicidal behavior and
killed themselves.
Because
it is a high-risk drug, Accutane should be reserved for cases of "severe
recalcitrant nodular acne," according to the product's labeling. This type
of acne is resistant to standard acne treatment, including oral antibiotics, and
is characterized by many nodules or cysts--inflammatory lesions filled with pus
and lodged deep within the skin. These lesions can cause pain, permanent scarring,
and negative psychological effects. "Sometimes
people tend to dismiss the impact of acne because it's not life-threatening, says
Kathy O'Connell, MD, PhD, a medical reviewer for Accutane in FDA's division of
dermatologic and dental drug products, Center for Drug Evaluation and Research
(CDER). "But patients with severe acne know all too well the very real suffering
caused by this disfiguring disease." FDA
approved Accutane in 1982, and since then, about 5 million people in the United
States and 12 million worldwide have been treated with it, according to its manufacturer,
Hoffmann-La Roche of Nutley, N.J. The number of patients taking the drug has increased,
and half are females, most of whom are in their childbearing years (age 15-44).
Because of concern about the drug's risks, FDA continues to evaluate Accutane
and work with the manufacturer to maximize safe use of the drug. Warning
about Pregnancy Risks
When FDA approved Accutane, the drug was known to be
teratogenic--able to cause birth defects. It was designated as Category X, meaning
that it must be avoided under all circumstances during pregnancy. Nursing mothers
also should not use Accutane. Though
not every fetus exposed to Accutane becomes deformed, the risk of birth defects
among pregnant women is extremely high. These defects include hydrocephaly (enlargement
of the fluid-filled spaces of the brain) and microcephaly (small head), heart
defects, facial deformities such as cleft lip and missing ears, and mental retardation.
Reports
in the literature suggest that about 25 to 35 percent of babies will suffer a
malformation after exposure, and that doesn't account for other defects, such
as learning disabilities, that aren't detectable at birth. Miscarriages and premature
births have also been reported. Though
FDA approved labeling in 1982 that warned Accutane should not be used in pregnant
women, reports of severe birth defects associated with the drug began to arrive
in June 1983. Over the following years, a series of labeling changes and letters
to pharmacists and prescribers of the drug stressed pregnancy warnings and sought
to increase awareness about reported malformations. Then,
after an FDA review of pregnancy exposures to Accutane, Roche launched the Pregnancy
Prevention Program (PPP) in late 1988 to further educate women using Accutane
and their physicians about the dangers. The goal was to ensure that prescriptions
would only be given to women with severe recalcitrant nodular acne who could comply
with contraceptive requirements. Roche
sent PPP kits to physicians and encouraged them to review pregnancy prevention
materials with patients before starting the drug. Materials included a contraceptive
booklet, checklists to help assess whether patients could adhere to the drug's
requirements, and consent forms that patients sign to acknowledge their understanding
of the risk of birth defects. Roche also set up a toll-free line, made contraceptive
information available in 13 languages, and offered to pay for contraceptive counseling
and pregnancy testing by a specialist. To
further reinforce pregnancy prevention, Roche began packaging Accutane in blister
packs that include red and black warnings, along with a drawing of a malformed
baby and the "Avoid Pregnancy" symbol. Even
though Accutane's labeling recommended use of two reliable forms of contraception,
there have been reports of pregnancies occurring in patients who used hormonal
contraception, including pills, injectables, and implantables, while taking Accutane.
Accutane's labeling was updated in the summer of 2000. One change emphasized the
need for two reliable forms of contraception for at least one month before taking
Accutane, during treatment, and for one month after discontinuing Accutane, even
when one of the forms of contraception is hormonal. Evaluating
Compliance
Yolonda Lawrence of Santa Monica, Calif., says there was no way
she could miss the point about pregnancy prevention before she used Accutane for
severe adult-onset acne in 1998. "I got a pamphlet, I signed papers, the
doctor told me over and over, and the pictures of what can happen were very clear--babies
with no ears" and other deformities, she says. But
reports of Accutane-exposed pregnancies continue, and that's enough to make FDA
concerned, says Peter Honig, MD, director of FDA's office of postmarketing drug
risk assessment (OPDRA) in CDER. Shortly
after the Pregnancy Prevention Program began, Roche sponsored a survey of women
taking Accutane to assess compliance with the program, and the company encouraged
doctors to enroll patients. Run by the Slone Epidemiology Unit at Boston University's
School of Public Health, the survey set out to track pregnancy rates and outcomes,
patients' awareness of risks, and patient and physician behavior. Of
the 500,000 women enrolled in the Slone survey from 1989 to 1998, there have been
958 pregnancies, 834 of which were terminations (either elective, spontaneous
or due to ectopic pregnancies), 110 that resulted in live births, and 14 patients
that had unknown outcomes. Of the 60 infants with available medical records, eight
had congenital abnormalities. Since Accutane's approval, Roche has received close
to 2,000 reports of Accutane-exposed pregnancies, 70 percent of which occurred
after the PPP began. According
to FDA, exactly how well the PPP has worked is unclear. Experts say the PPP is
a significant program that has prevented many pregnancies and is the first of
its kind initiated by a pharmaceutical company. Roche has made extraordinary efforts
to educate patients that they must not become pregnant while taking Accutane,
says a Roche spokesperson. At
a September 2000 meeting of FDA's Dermatologic and Ophthalmic Drugs Advisory Committee,
a Roche representative reported that from the company's perspective, pregnancy
rates have declined. Amarilys Vega, MD, an FDA medical officer, agreed. However,
because use of the product has increased over the years, the actual number of
pregnancies occurring while taking Accutane has not declined. One limitation is
that the survey is voluntary and only captures about 30 to 40 percent of all patients
on Accutane. So there's no way to know exactly how many pregnancy exposures there
have been, according to FDA experts. Of serious concern is that women who enroll
in the survey may be more likely to comply with the contraceptive requirements
than those who don't enroll in the survey. This leaves open critical questions
about how representative the PPP group is and about unreported pregnancies among
women who don't enroll in the PPP. Most
patients in the Slone survey have reported that they understood Accutane may cause
birth defects. And according to Roche, the percentage of female patients who reported
they were pregnant when they began Accutane dropped from 30 percent of pregnancies
reported in 1989 to 11 percent of pregnancies reported for the period of 1991
to 1997. But substantial noncompliance with the PPP continues to be reported. For
example, a 1997 report on the survey shows that 25 percent of women in the program
did not report having a pregnancy test before starting Accutane, and 33 percent
did not report postponing the start of Accutane until a pregnancy test result
was known. It is estimated that 40 percent of women taking Accutane are sexually
active. The
only patients exempt from Accutane's contraceptive requirements are men, and women
who have had a hysterectomy or who say they will abstain from sex during treatment.
But the challenge is that going from sexually inactive to active can happen overnight.
Possible
Psychiatric Link
Many patients say they feel better about themselves after
receiving successful treatment for acne. Evelyn Germanakos, of Los Angeles, Calif.,
struggled with acne as an adult, and says she felt like her old self after Accutane
cleared up lumpy blemishes in 1997. "I had gotten to the point where I didn't
even want to go outside or be with people, let alone look in the mirror,"
she says. But while Accutane may help lift psychosocial distress such as embarrassment,
evidence suggests that it may actually cause serious psychiatric disorders in
some people. Though
the drug's label previously listed depression as a possible reaction, FDA strengthened
the label warning in 1998 after reviewing cases with serious outcomes reported
in the years after the drug was approved. The new labeling states that Accutane
may cause depression and psychosis, and that in rare cases it may cause suicidal
ideation (thoughts of suicide), suicide attempts, and suicide. The
label also advises providers that simply discontinuing the drug may not remedy
any psychiatric problems and that further evaluation may be necessary. "In
some cases, stopping Accutane alone may not be enough to relieve the mood changes,"
says Jonathan Wilkin, MD, director of CDER's division of dermatologic and dental
drug products. "Psychiatric treatment may also be needed." The
relationship between Accutane and depression remains unproven, but some patients
have reported that their depression subsided when they stopped the medication
and came back when they resumed taking it. And some who have reported problems
with depression while taking Accutane had no previous psychiatric history. FDA
considers the number of reports of serious depression associated with Accutane
high compared to other drugs in its database. From
1982 to May 2000, FDA received reports of 37 U.S. Accutane patients who committed
suicide, 24 while on the drug and 13 after stopping the drug. In addition to suicides,
FDA received reports of 110 U.S. Accutane users hospitalized for depression, suicidal
ideation, and suicide attempt during the same time period. As of May 2000, FDA
had received reports of 284 Accutane users with non-hospitalized depression. Several
factors make it hard to definitively link depression with Accutane. Depression
is a common problem, and some patients may be suffering from it before starting
Accutane therapy. Additionally, some patients who reported depression with Accutane
had previous courses of the drug without depression. Even so, it is recommended
that doctors act as if Accutane could have psychiatric effects until there is
more information, says FDA's Wilkin. The
Future of Accutane
Roche does not want to have any Accutane-exposed pregnancies,
a company spokesperson says, and plans to continue educational efforts. This year
Roche launched a targeted Pregnancy Prevention Program that focuses on women who
are at highest risk of becoming pregnant while taking Accutane. Experts
agree that pregnancy prevention education should remain a key part of risk management
for Accutane use. But more labeling changes and letters are not likely to make
a significant difference, according to FDA's Honig. "During all the time
the drug has been on the market and after all of those labeling changes, there
are still pregnancies," he says. "It is not expected that another labeling
change or 'Dear Doctor' letter will change behavior at this point." Psychiatric
adverse events have also continued after labeling changes. FDA's
Dermatologic and Ophthalmic Drugs Advisory Committee met in September 2000 to
discuss options for Accutane, and to evaluate whether a framework for safer use
of the drug can be developed. One change since then is that all Accutane prescriptions
now come with a new Medication Guide that contains warnings about pregnancy and
psychiatric issues, plus other important warnings and precautions regarding potentially
serious or life-threatening effects. FDA
has also proposed a mandatory registration of patients taking Accutane, prescribers,
and pharmacists. "The main reason is to ensure that pregnancy testing is
done before the drug is prescribed," says Julie Beitz, MD, of FDA's office
of postmarketing drug risk assessment. The goal would be to have doctors document
negative pregnancy tests and to have pharmacies dispense the drug only to women
who have had negative pregnancy tests. The program to track Accutane patients
is expected to be in place by summer 2001. The
registry for prescribers may involve a continuing education course that doctors
would have to take to be able to prescribe Accutane. According to Hoffmann-La
Roche, about 85 percent of Accutane prescriptions come from dermatologists and
15 percent come from primary care physicians. The course would be open to all
medical doctors. And all Accutane patients would have to sign a mandatory consent
form that would address both pregnancy and psychiatric issues, Beitz says. The
American Academy of Dermatology and the Dermatologic Nurses Association were among
those who testified at the September 2000 committee meeting in opposition to a
mandatory registration, saying that it would be a disservice to patients, making
it harder for them to obtain the drug. Others, including the March of Dimes and
the Public Citizen's Health Research Group, testified that they want to see stricter
measures for Accutane. FDA's
experts say it's a balancing act. The value of Accutane is clear, but when it
comes to even one report of death--whether it's suicide, miscarriage, or some
other cause--FDA must make choices that will best protect the public's health. To
learn more, visit FDA's Accutane page on the Internet: www.fda.gov/cder/drug/infopage/accutane.
To report adverse events related to Accutane, call Roche Medical Services at 1-800-526-6367
or FDA's MedWatch Program at 1-800-FDA-1088. -----------------------------------------------------
Monthly
Accutane Prescriptions Ensure Follow-Up
Evelyn Germanakos of Los Angeles,
Calif., recalls forgetting to have a blood test before returning to her dermatologist
for a monthly visit while taking Accutane. "He sent me right away to get
it and said he wouldn't renew the prescription without it," she says. Experts
say that kind of follow-up is critical. Doctors should only give one-month prescriptions
for Accutane and should conduct urine or blood pregnancy testing and contraceptive
counseling each month of treatment. Monthly
blood tests also allow doctors to monitor patients for other adverse effects.
Elevated triglyceride levels, which can be associated with pancreatitis, have
occurred in about 25 percent of patients in clinical trials for Accutane, and
about 7 percent of patients showed an increase in cholesterol levels. Alan
N. Moshell, MD, director of the skin diseases branch at the National Institute
of Arthritis and Musculoskeletal and Skin Diseases, says he's heard about severe
adverse effects such as liver damage in cases where a full dose of Accutane has
been prescribed with inadequate follow-up. "It has usually been a situation
in which the full five-month course has been prescribed at the first visit and
then the patient was not brought back, or simply failed to follow instructions
about follow-up visits and blood tests." In such cases, patients may keep
taking the drug and only return to the doctor when it's too late and they've experienced
an adverse effect. More
common side effects of Accutane include lip inflammation and drying of the skin
and mucous membranes. Germanakos says her mouth was incredibly dry. "I drank
about 15 to 16 glasses of water a day, and I was still thirsty," she says.
She also experienced skin peeling on her eyelids and dry nasal passages, and she
says her acne got worse before it got better. --M.M.
Reprinted
from FDA Consumer. This article originally appeared in the March-April 2001 FDA
Consumer
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