Colorado Springs Dermatology

 
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.