The Power of Accutane:
The Benefits and Risks of a Breakthrough Acne Drug
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.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.
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.
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