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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.

*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:

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.

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.

Science Meets Beauty: Using Medicine to Improve Appearances

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 approve.

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.

diagram showing formation of wrinkle in the skin

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 consequences."

Facing Facts

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 the market.

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 benefit-to-risk ratio.

"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 says.

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 plastic surgery.
Begin with a consultation to find the right doctor, and select one who is qualified to do the procedure you want.
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 elective procedures.

Saving Face

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."

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."

Buyer Beware

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."