Restylane® is a new form of injectable
filler. It has many advantages over traditional options like
collagen and fat injections such as durability. Restylane® is a
transparent hyaluronic acid, biodegradable gel that is injected
into facial tissue to smooth wrinkles and folds, especially
around the nose and mouth. Hyaluronic acid is a protective,
lubricating and binding gel substance that is produced
naturally by body moisture. Also, Restylane® is non-animal
based, which eliminates transmission of animal based diseases
and pretesting to determine allergic reaction.
What is the treatment procedure?
Depending on each individuals needs and the amount of area the
needs treatment, the procedure will generally last anywhere
from a few minutes to half an hour. Using a thin gauge needle,
small amounts of Restylane® is injected into areas of the
facial tissue where moderate to severe facial wrinkles and
folds occur. Restylane® enhances your appearance with a minimal
amount of pain. To help minimize pain, patients can request a
topical anesthetic and for lip sculpting, a local
anesthesia will likely be used.
Choosing a qualified doctor or nurse
practicioner trained in the use of Restylane® injection is
important in achieving the best results
What are the results?
Restylane® temporarily shapes facial contours, smoothes
wrinkles and sculpts lips, adding volume to facial tissue and
restoring a smoother appearance to the face. The effects of
Restylane® are practically instantaneous and last for about 6
months or sometimes longer. Restylane® will help smooth
moderate to severe facial wrinkles and folds. In a clinical
study, most patients needed one injection to achieve optimal
wrinkle smoothing; about one-third of patients needed more than
one injection to get a satisfactory result. Skin type,
age, and daily activities can affect how long the results will
Restylane® restores natural volume under the wrinkle,
lifting the skin up to smooth out the surface of the
- Facial Contours
Restylane® lifts up the skin from the cheeks and chin and
corrects deep folds, allowing for a fuller shaped chin and
a more shapely contour along the cheeks.
- Lips Augmentation
Restylane® is injected into the inside of the upper and/or
lower lip and also along the lip line to add more volume
and an overall more youthful look.
*Two treatments a year are allowed and follow up treatments
that are administered before the effects of the latter
disappear will help the results to last. If further
treatments are not scheduled, the pre-treatment facial state
will gradually reappear.
What are the side effects?
Any side effects that may occur generally only
last for one or two days, then dissipate. These effects may or
may not include:
provide the best results?
- Choosing a qualified doctor or nurse practicioner
trained in the use of Restylane® injection is important in
achieving the best results
Though no pre-testing is needed, aspirin, Vitamin
E supplements and other medications should be avoided before
treatment because they can increase bruising or
Restylane® should not be used in patients who
- severe allergies marked by a
history of anaphylaxis ( hypersensitivity to the
ingestion or injection of a drug or protein) ,
- multiple severe allergies,
- severe allergies to
gram-positive bacterial proteins,
Restylane® should not be used for:
- breast augmentation,
- implantation into bone,
tendon, ligament, or muscle, or
- implantation into blood
vessels, because it may obstruct blood flow.
For additional information:
SUMMARY LEAD REVIEW
Restylane® consists of non-animal, stabilized, hyaluronic acid
(NASHA) at a concentration of 20 mg/ml, suspended in a
physiological buffer pH 7. It is a clear, transparent, viscous
and sterile gel, supplied in a disposable glass syringe. Each
syringe contains 0.4 or 0.7 ml gel. The contents of the syringe
are sterile. The syringe consists of a plunger stopper, finger
grip and plunger rod. The syringe is packed in a blister
together with a sterile 30 G needle.
Restylane® acts by adding volume to the tissue, thereby
restoring the skin contours to the desired level of
Indication for Use:
Restylane® is intended for temporary correction of moderate to
severe facial wrinkles and folds, such as nasolabial folds.
Restylane® was first approved for marketing and sale in
September 1996 in the European Union including EES.
Registration was obtained in Canada,
Brazil, Hungary and Russia in 1998. In 1999 the product was
registered in Australia, Argentina, Peru, Poland and Korea. In
2000 Ecuador, Mexico, Uruguay, Turkey and Singapore were added
to the list of countries in which Restylane® is approved.
Approval was obtained in Bulgaria, Columbia. Czech Republic,
and Jordon in 2001.
Sales for 1997 amounted to 67,050 syringes and 457,385 syringes
sold worldwide in 2001.
Restylane® has not been marketed in the United States was the
subject of a clinical trial in the U.S.
Two clinical studies have been performed in order to evaluate
the safety and efficacy of Restylane® for the treatment of
facial wrinkles and folds. The pivotal study is the primary
evaluation of safety and effectiveness. The open-label
extension is considered only for additional safety data. Only a
very brief summary of the clinical studies is provided here.
Please see the FDA clinical summary memo for complete summary
information on the clinical study.
1. Pivotal Study: A Randomized,
Evaluator-Blind, Multi-Center U.S. Study Comparing the Safety
and Efficacy of Restylane® and Zyplast® for the Correction of
Study Design: Randomized, double-blind, multi-center clinical
study on Restylane® vs. Zyplast®. A total of 138 patients at 6
centers were randomized to obtain the optimal cosmetic result.
The response of the initial treatment was evaluated after 2
weeks and in case of non-optimal cosmetic results a touch-up
treatment could be performed. This procedure was repeated every
two weeks until optimal response was achieved.
2. An open tolerance and efficacy study- A Non-Randomized Open
Study of 112 Patients Receiving Restylane® for the Treatment of
Depressed Cutaneous Scars, Wrinkles and Folds
This study was done at four clinics with 112 patients treated
and followed for four months. The naso-labial folds were the
most commonly treated site but the study also included
treatment of facial wrinkles, scars and lips.
The original submission contained the results of the pivotal
clinical study out to 6 months and an open-label extension to
the study. The pivotal study is considered by FDA to be the
primary study of safety and effectiveness. The open-label
extension is considered only for additional safety data. For
ease of review, it is helpful to understand the chronology of
the submission. FDA determined that the 6-month follow-up data
were inadequate to make a judgment on the safety of the product
and requested that the sponsor provide 12 month data that were
being collected. Additionally, we requested that the sponsor
provide all safety data from all sources, including those from
Europe and patient diaries. Based on the data in the original
submission, FDA sent the sponsor a major deficiency letter on
November 18, 2002 requesting information addressing overall
safety data and data regarding hypersensitivity. The sponsor
submitted an amendment (i.e., Amendment 3) in response to the
major deficiency letter of November 18, 2002. The sponsor was
sent another major deficiency letter on May 5, 2003, to address
the issues of biocompatibility/toxicology of the cross-linker
component, hypersensitivity, and lack of minority
representation in the study. In response to that letter, the
sponsor submitted another amendment (i.e., Amendment 5). These
letters and the sponsor’s responses to the deficiencies are
included on the CD ROM in the panel pack.
Restylane® contains small amounts of BDDE (1,4 butanediol
diglycidulether), a potential sensitizer. Hypersensitivity was
therefore a concern. The IDE protocol had specified that
patients developing sensitivity reactions were to be skin
tested. The sponsor pointed out that none of the investigators
noted sensitivity reactions and therefore none of the patients
were skin tested. FDA is concerned that some of the reactions
noted during the study could be hypersensitivity reactions. The
panel will be asked to comment on this issue.
In addition to questions about the overall effectiveness of
Restylane®, FDA questions whether or not the data show
Restylane® as superior to the control (Zyplast™). The sponsor
bases their superiority claim on the majority of individual
patient successes achieving a one-point improvement over the
control in the Wrinkle Severity Rating Scale (SRS) from
baseline at 6 months. The alternative approach is to look at
the entire cohort of Restylane® versus Control and note that a
full one-point improvement could not be achieved in the
aggregate case (D = 0.58). The panel will be asked to discuss
if Restylane® is superior to the Control.
In addition to questions about the overall safety of
Restylane®, FDA has concerns about the lack of minority
representation in the study. Minorities, particularly those
with darker skin, may have more severe reactions to injections
than populations with lighter skin. Noting that the study only
included two African-Americans and ten patients listed as
“other”, dark skin populations may have an increased risk of
adverse reactions or poor cosmetic outcome. The panel will be
asked to discuss if the sponsor should be required to conduct
further studies on the issue and if Restylane® should include
language in the labeling to address the lack of minorities in
FDA also questioned whether the data in the PMA supported the
proposed indications. The sponsor had only injected nasolabial
folds bilaterally (i.e., control and treatment sides) yet the
proposed indications include “…correction of moderate to severe
facial wrinkles and folds...” FDA will also ask the panel to
comment on the adequacy of the data for these proposed
Botox Restylane and Injectables - Before and After
Facial Refinement / Restylane
Restylane (Hyaluronic Acid)
injection gave this middle aged woman the desired
wrinkle reducer around the mouth and
Add to 'My Interests'
Science Meets Beauty: Using Medicine to Improve
By Carol Rados
A smaller nose. Bigger breasts. Slimmer thighs. Plumper
lips. Less hair on the body. More hair on the head. Whether
we're looking to tighten our tummies or lighten our laugh
lines, America's fascination with youth and beauty has long
fueled the development of medical products for cosmetic
purposes. And if such "vanity drugs" can be shown to be safe
and effective, the Food and Drug Administration just may
The ongoing fight to delay or reverse the aging process has
dermatologists and cosmetic plastic surgeons responding with
products like Restylane (hyaluronic acid), one of a handful of
soft tissue fillers recently approved by the FDA to treat
facial wrinkles. Restylane is an injectable gel that acts as a
filler to remove the wrinkle, producing instantaneous results.
Such products are not as invasive as facelifts, eyelid surgery,
and other reconstructive procedures. And they are more
effective and last longer than creams, lotions and other
topical products, whether over-the-counter or prescription. In
addition, the fact that the treatments result in little or no
downtime makes them more attractive to those seeking a quick
fix. Without making a single incision, doctors can erase
wrinkles, acne scars and sun damage in a matter of minutes.
"This is a huge industry," says Jonathan K. Wilkin, M.D., a
medical officer in the FDA's Division of Dermatologic and
Dental Drug Products. "The way people try to move the clock
back is through the skin." Basically, he says, through various
products and procedures, "they are addressing the effects of
gravity on the skin over time."
Aging Skin 101
An increased understanding of the structure and function of
the skin is helping to drive the development of products that
reduce the visible signs of facial aging, according to the
American Academy of Dermatology (AAD).
With aging, all skin cells begin to produce excess amounts
of free radicals--unstable oxygen molecules that, under ideal
circumstances, are removed by naturally occurring antioxidants
within the skin's cells. In aging skin cells, antioxidants are
in short supply. The free radicals generated are left unchecked
and cause damage to cell membranes, proteins, and DNA. These
free radicals eventually break down a protein substance in
connective tissue (collagen) and release chemicals that cause
inflammation in the skin. It is a combination of these cellular
and molecular events that leads to skin aging and the formation
of wrinkles, the AAD says.
As we get older, two components of our skin--collagen
and elastin--degenerate, setting the stage for the
appearance of wrinkles, creases, folds, and furrows. The
breakdown of these components, accelerated by sun exposure
and gravity, results in the sagging skin of old age.
Illustration by Renée Gordon.
Source: National Institute on Aging.
Considerable research has been done to understand the aging
process, and studies now show that products containing
bioactive ingredients (those that interact with living tissues
or systems) can benefit sun-damaged, discolored, and aging
skin, giving consumers new choices for restoring their overall
appearance. But why is the FDA reviewing products that simply
make people look and feel good when typically the agency
evaluates disease-fighting treatments?
"If something that is being implanted into the body could
have health consequences, we're concerned about it," says
Stephen P. Rhodes, M.S., chief of the FDA's Plastic and
Reconstructive Surgery Devices Branch. "Wrinkle fillers affect
the structure of the face and could have such health
Under the Federal Food, Drug and Cosmetic Act, the FDA
legally defines products by their intended uses. Drugs are
defined as products intended for treating or preventing disease
and affecting the structure or any function of the body. A
medical device is a product that also is intended to affect the
structure or function of the body, but which does not achieve
its primary intended purposes through the chemical action of a
drug--nor is it dependent on being metabolized.
The hyaluronic acid in Restylane, although biosynthetically
produced (formed of chemical compounds by the enzyme action of
living organisms), is almost identical to that in all living
organisms. Hyaluronic acid is a structural component of skin
that creates volume and shape. Concentrations of hyaluronic
acid throughout the body decline with age, causing undesirable
changes in the skin. Restylane binds to water and provides
volume to easily fill in larger folds of skin left by tissue
loss around the mouth and cheeks. "This makes it a structural
action," says Rhodes, "much like a chin implant."
In contrast, cosmetics are defined as substances that
cleanse, beautify, promote attractiveness, or alter the
appearance, without affecting the body's structure or function.
This definition includes skin-care products such as creams,
lotions, powders and sprays; perfume; lipstick; fingernail
polish; and more.
Different laws and regulations apply to each type of
product. Some products must comply with the requirements for
both cosmetics and drugs. This happens when a product has two
intended uses, such as an antidandruff shampoo. A shampoo is a
cosmetic because it is intended to clean hair. An antidandruff
shampoo is a cosmetic and a drug because it is intended to
treat dandruff (which affects the follicles where the hair is
formed) and clean hair.
Warning letters issued by the FDA recently to firms that
marketed hair care products with claims such as restoration of
hair growth and hair loss prevention illustrate an important
distinction between the legal definitions of cosmetics and
drugs. Warning letters officially inform companies that they
may be engaged in illegal activities, and instruct
manufacturers on how to bring their products into compliance
with the law. Hair growers and hair loss prevention products,
because of their mechanism of action, are considered drugs, not
cosmetics, and these firms were not meeting the legal
requirements for marketing a drug.
Unlike drugs and medical devices, neither cosmetic products
nor cosmetic ingredients are reviewed or approved by the FDA
before they are sold to the public. The agency only acts
against cosmetic products found to cause harm after they are on
Cosmetics or Drugs?
Much confusion exists about the status of cosmetic products
having medicinal or drug-like benefits, says Linda Katz, M.D.,
M.P.H., director of the FDA's Office of Cosmetics and Colors.
Although the FDA does not consider the term "cosmeceutical" to
be a valid product class, Katz says it is used throughout the
cosmetic industry to describe products that are marketed as
cosmetics but that have drug-like effects. Tretinoin (retinoic
acid), the biologically active form of vitamin A, for example,
is not prohibited from use in cosmetics. However, when it is
used topically for treating mild to moderate acne, sun-damaged
skin, and other skin conditions, it is recognized by the FDA as
a drug. This is because it acts deep at the skin's cellular
level by increasing collagen.
According to the AAD, the answer to whether or not
cosmeceuticals really work lies in the ingredients and how they
interact with the biological mechanisms that occur in aging
skin. The regulatory question the FDA faces when considering
such products, Katz says, "is whether or not a manufacturer is
making a structure or function claim."
The FDA uses different standards when evaluating the risks
and benefits of products used for cosmetic treatments than for
therapeutic uses of products. Steven K. Galson, M.D., M.P.H.,
acting director for the FDA's Center for Drug Evaluation and
Research, adds that products like tretinoin and Restylane that
are not indicated for serious or life-threatening conditions
are subject to close examination by the agency because of the
"Because these products are for cosmetic purposes, they must
be extraordinarily safe," Galson says. This means that the FDA
may allow someone to incur a greater risk from products that
treat medical conditions, rather than from those that are
intended for cosmetic purposes. "We generally won't tolerate
much risk for a drug whose primary use is cosmetic," he
Welcome Side Effects
Many cosmetic treatments are the result of common disease
therapies whose unexpected side effects were pleasant
surprises. Vaniqa (eflornithine hydrochloride), the first
prescription drug for removing unwanted hair, is a topically
applied version of a drug that was originally developed to
treat African sleeping sickness. Similarly, minoxidil
originally had been prescribed as an oral tablet to treat high
blood pressure. As a result of side effects that included hair
growth and reversal of male baldness, Rogaine (2 percent
minoxidil) was the first drug approved by the FDA for the
treatment of hair loss (androgenetic alopecia).
"There's a lot of serendipity in drug development," says the
FDA's Wilkin. A pill to help smokers quit, for example, evolved
out of the unexpected observation that a drug intended to treat
depression also seemed to take away the desire to smoke.
Bupropion was first marketed in 1989 by GlaxoSmithKline as an
antidepressant under the name Wellbutrin. After doctors noticed
that patients being treated with Wellbutrin gave up smoking
spontaneously, studies were done to show that the product could
help smokers quit, as well. As a result, the slow-release form
of bupropion, marketed as Zyban, was approved by the FDA in
1997 as an aid to smoking cessation treatment.
Some pharmaceutical companies, however, apparently aren't
ready to enter the vanity drugs arena. Patrick Davish, the
global product communications spokesman for Merck & Co.
Inc., says that the drug company has no "cosmetic" drugs in its
product pipeline at this time.
"The fact that we don't participate in that market right
now-I'm not sure that's reflective of any particular
deliberation or decision," he says. "That's just not where the
science has taken us."
Before electing to have a cosmetic procedure
- Discuss it with a physician who can refer you to a
specialist in the fields of dermatology and aesthetic
- Begin with a consultation to find the right doctor,
and select one who is qualified to do the procedure you
- Make sure the doctor you choose is certified by an
appropriate medical board.
- Have realistic expectations about the benefits you
want to achieve.
- Compare fees--insurance does not usually cover
According to the American Society for Aesthetic Plastic
Surgery (ASAPS), nearly 7 million Americans underwent surgical
and nonsurgical cosmetic procedures in 2002. Laura Bradbard was
one of them.
Despite the sudden explosion of such "lunchtime" techniques
as Restylane for erasing wrinkles, and Botox (botulinum toxin
type A) for smoothing out frown lines, Bradbard, of
Gaithersburg, Md., opted for a longer-lasting reconstructive
facelift that included a chin implant, eyelid surgery, and
surprisingly, only a few days of pain-free recovery.
"None of this was medically necessary," admits Bradbard, a
48-year-old FDA press officer, "but I had been feeling worn out
and tired. What I saw in the mirror was sad." Bradbard says she
didn't get a facelift to look younger; she only wanted her face
to look more balanced. In the end, she says, "My doctor gave me
a chin that geometrically fit my face," and a look that she
says makes her feel better about herself.
Like Bradbard, others are spending a lot of money to look
good. "With patients living 90-plus years, today's anti-aging
modalities offer people noninvasive procedures that mimic true
facelifts," says Craig R. Dufresne, M.D., a plastic and
reconstructive surgeon in Chevy Chase, Md., who performed
Bradbard's surgery. However, Dufresne says he suggested
reconstructive surgery for Bradbard because "she wanted to deal
with structural changes to restore facial balance," which was
more than the chemical action of a drug could produce. "And
skin product application (such as wrinkle fillers) following a
facelift," adds Dufresne, "will actually allow the facelift or
any other reconstructive procedure to last longer and make a
great result even better."
Top 5 Cosmetic Nonsurgical
botulinum toxin injection (Botox®, Myobloc®)
laser hair removal
Source: American Society for
Aesthetic Plastic Surgery
Top 5 Cosmetic Surgical
Source: American Society for
Aesthetic Plastic Surgery
Seeking Professional Advice
Since it is often difficult for people to determine the
validity of claims made about topical products and to decide
among the overwhelming number of anti-aging procedures, how do
people know what's right for them?
"A good place to start is with a dermatologist," says
Arielle N.B. Kauvar, M.D., clinical associate professor of
dermatology at the New York University School of Medicine.
"Dermatologists are trained in the health, function and disease
state of the skin, and people could save time, money and
confusion by seeking the advice of a dermatologist rather than
guessing what might work for them."
Kauvar says a dermatologist's recommendations can help
consumers make informed decisions. "People shouldn't hunt and
peck for products," she adds. "Not knowing what type of skin
you have is why so many people try unnecessary products that
can often do more harm than good."
An expert in laser procedures, Kauvar says that, in the
past, techniques for improving aging skin required invasive
laser or surgical procedures, which produced open wounds and
required long recovery times. Today, she says, people can
choose from a variety of non-ablative (non-wounding) laser
treatments that are designed to reverse, improve or erase the
early signs of aging, take very little time to perform, and
have a minimal, if any, recovery time.
While Bradbard wasn't interested in removing wrinkles at the
time of her facelift, given what she knows about new
technologies and drug delivery systems today, she says, "I
would consider both non-invasive procedures and another
facelift down the road, depending on how much my skin changes.
I would ask my doctor what would give me the best results with
the longest-lasting effects."
Anti-aging products that promise to diminish wrinkles and
fine lines are found on many store shelves. However,
dermatologists recommend that people consider only those
procedures and products that have proven, over time, to be most
effective at reversing the aging process. Most doctors agree
that the leading product to prevent premature wrinkles and sun
damage is sunscreen. A broad-spectrum sunscreen that protects
the skin from both UVA and UVB rays, with a sun protection
factor (SPF) of 15 or higher, can prevent the skin from looking
older than it is.
According to the ASAPS, it's important to realize that
although certain products and procedures are effective, they
are also limited by the skin's normal aging process. A product
that has been deemed effective for erasing wrinkles doesn't
necessarily erase wrinkles--there are lots of variables that
determine its effectiveness.
For example, the active ingredient in a drug must be
delivered to the skin at a therapeutic concentration and remain
in the skin long enough to have an effect. Also, because the
composition of a man's body differs from a woman's, products or
procedures can have different effects. The facial area in men
contains hair, for example, and their skin is thicker. This
means the blood supply is greater--and so is the risk of
bleeding--but it also could mean better healing.
And cosmetic procedures come with risks. If a procedure is
performed poorly, the physical and emotional scars could be
carried for life. Understand the risks and side effects that
may be involved.
"My wanting to improve my appearance is like my husband's
desire to restore a vintage automobile," says Bradbard. "We
both want something to look good for as long as it can."
For More Information
American Academy of
PO Box 4014, Schaumburg, IL 60168-4014
for Dermatologic Surgery
5550 Meadowbrook Drive, Suite 120, Rolling Meadows, IL
for Aesthetic Plastic Surgery
11081 Winners Circle, Los Alamitos, CA 90720