Restylane ®
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
last.
- Wrinkles
Restylane® restores natural volume under the wrinkle,
lifting the skin up to smooth out the surface of the
face.
- 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:
- bruising
- redness
- swelling
- pain
- tenderness
- itching
Who can
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
Important Information
Though no pre-testing is needed, aspirin, Vitamin
E supplements and other medications should be avoided before
treatment because they can increase bruising or
bleeding.
-
Restylane® should not be used in patients who
have:
- 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:
http://www.fda.gov/OHRMS/DOCKETS/AC/03/briefing/4004b1_04_Lead%20Summary%20Memo.htm
SUMMARY LEAD REVIEW
MEMO
Product Description:
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
correction.
Indication for Use:
Restylane® is intended for temporary correction of moderate to
severe facial wrinkles and folds, such as nasolabial folds.
Marketing History
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.
Clinical Studies:
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
Nasolabial Folds
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.
FDA ISSUES/CONCERNS
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
the study.
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
indications.
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