Restylane - Non-Animal Stabilized Hyaluronic Acid gel; NASHA; hyaluronan; sodium glucuronate-N-acetyl-glucos-amine polymer
Status: approved; marketed
Organizations involved:
Q-Med AB – Manuf.; R&D; Tech.; Intl. mark.
Medicis Aesthetics Inc. – USA mark.
Cross ref.: See the Hyaluronic Acid Products entry (#925) and the other hyaluronic acid products entries.
Description: Restylane is an aqueous biodegradable formulation of hyaluronic acid, termed NASHA (Non-Animal Stabilized Hyaluronic Acid), produced by fermentation of equine Streptococcus bacteria, partially chemically cross-linked (about 1% of residues) with epoxide bonds, and sterilized by wet heat (steam; pasteurization). This (partially cross-linked) hyaluronic acid (HA) forms a stabilized continuous 3-dimensional gel in aqueous solution, with essentially all of the HA molecules linked to one or more other HA molecules. The individual HA molecules (ignoring cross-linkages) have a molecular weight of about 1 million (1,000 kDa). Restylane contains partially cross-linked HA at a concentration of 20 mg/mL suspended in physiologic buffer (pH = 7). Shelf life is 1.5 years after the production date (according to international product literature).
The partial cross-linking of NASHA provides Restylane and Perlane with longer-lasting effects, i.e., they are not quickly metabolized as is un-modified HA. In vivo, NASHA degrades isovole-mically, i.e., the volume of the gel network and injected material remain constant until the HA is almost fully degraded. As NASHA degrades, each resulting smaller molecule progressively binds more water (resulting from there being more free water-binding sites on each degraded molecule). Eventually, the HA is broken down enough to be transported to the liver and fully metabolized. Also, distinct from other hyaluronic acid dermal fillers, Restylane and Perlane are minimally cross-linked, making them similar to the natural hyaluronic acid found in the body.
Internationally, Q-Med manufactures and markets three Restylane products, primarily used for cosmetic purposes, e.g., filling in facial lines/folds/contours – Restylane Fine Lines; Restylane; and Restylane Perlane (Perlane). Currently, Restylane and Perlane are approved/marketed in the U.S. Each formulation contains partially cross-linked at the same 20 mg/mL concentration, but the HA in each forms gel beads or particles (massed of cross-linked molecules) of different sizes in aqueous solution. Restylane (U.S.-approved) contains gel beads/particles with a size of 250 µM with a concentration of 100, 000 Units/mL. With its intermediate particle size, Restylane is used (internationally, and often off-label in the U.S.) for treatment of moderate wrinkles and lip enhancement, besides its FDA-approved indication. Restylane Fine Lines contains gel beads with a size of 150 µm at a concentration of 200,000 Units/mL. With its smaller particle size, Restylane Fine Lines is designed primarily for correction of thin lines, across the forehead and around the eyes and mouth. Perlane contains gel beads of 1,000 µm at a concentration of 10,000 Units/mL. With its larger particle size, Restylane Perlane is intended to be implanted into the deep dermis to superficial layer of the subcutis to add volume to restore surface contour in facial wrinkles and folds.
Q-Med also manufactures and internationally markets Deflux SUI, a similar NASHA product used to augment the urethra wall at weakened sphincter muscles for treatment of vesico-ureteral reflux (VUR) and female stress urinary incontinence (SUI); and Durolane, a NASHA product for visco-supplementation of osteoarthritis of the knee.
Nomenclature: Hyaluronic acid/Q-Med [BIO]; Restylane [TR]; Non-Animal Stabilized Hyaluronic Acid gel [SY]; NASHA [SY]; HA [SY]; sodium hyaluronate [SY]; sodium glucuronate-N-acetylglucosamine polymer [SY]
Biological.: As discussed in the Hyaluronic Acid Products monograph (#925), partial covalent epoxide bond cross-linking of large HA molecules makes them substantially resistant to rapid clearance and metabolism, in addition to increasing gelling and viscoelastic properties. Without stabilization, HA would remain in human tissues for only a few days, at most, before it is degraded. Higher levels of cross-linkage adversely affect biocompatibility. After injection, the HA in Restylane generally remains where it has been injected and exerts its effects for 6-12 months. Nutritive agents, such as glucose and oxygen, as well as growth factors and hormones are able to pass freely between the gel particles in Restylane, leaving a healthy-looking skin during the entire residence period.
Companies.: Restylane was developed and is manufactured by Q-Med AB (Uppsala, Sweden). Restylane is marketed in the U.S. by Medicis Aesthetics Inc., which acquired HA North American Sales AB from Q-Med in Feb. 2003. This acquisition included rights to market Restylane (and once approved, Resty-lane Fine Lines and Restylane Perlane) in the U.S. and Canada. Restylane is marketed internationally by Q-Med (and affiliates), which retains exclusive manufacturing rights to NASHA products for the North American market for ten years with “normal profit margins.”
Manufacture: Streptococcus bacteria selected for high yield of HA production are cultured in the presence of sugars. HA is excreted into media, and is ethanol precipitated, filtered and dried. The amount of bacterial molecules (contamination) in the product is minimized by maintaining cellular integrity during fermentation, e.g., minimizing sheer forces. This HA has a molecular weight of about 1 million (1,000 kDa). Purification concentrates on reducing impurities, rather than maintaining molecular weight. Then about 1% of the HA (i.e., ~1% of saccharide residues) is cross-linked using 1,4-butandiol digly-cidylether (BDDE) to form permanent epoxidic links. This cross-linking of the large HA molecules with epoxide bonds stabilizes them against rapid metabolism and increases gel-forming properties. The cross-linked HA is suspended in physiologic buffer (pH = 7) at a concentration of 20 mg/mL. Aspects of NASHA manufacture, particularly cross-linking, are further discussed in the “Tech. transfer” section below.
The gel is filled into syringes and sterilized by moist heat (steam). Restylane has a sterility assurance level (SAL) of < 106, a level of sterility above that of aseptic manufacturing methods (and results in a product in which the probability of finding a syringe containing a detectable microorganism is less than one in one million units).
Quality control analyses performed on the final product include: concentration of hyaluronic acid; sterility; endotoxin level; pH; tests for impurities; and visual inspection The production process complies with ISO 9001/EN46001 standards, current FDA GMP regulations, and requirements for the various countries in which Restylane is registered.
FDA class: Medical device PMA
Approvals: Date = 20031212; first approval (Restylane), PMA
Date = 20070502; PMA supplement; Indication = approval of Perlane for implantation into the deep dermis to superficial subcutis for the correction of moderate to severe facial folds and wrinkles, such as nasolabial folds
Indications: [full text of the “Indication” section of product insert/labeling for Restylane]:
RESTYLANE is indicated for mid-to-deep dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds.
Status: The Premarket Application (PMA) for Restylane was submitted in June 2002 and approved on Dec. 12, 2003 (approval time = ~19 months). The clinical trials supporting FDA approval involved limited data on the safety of Restylane in non-Caucasians. Q-Med agreed to conduct a post-approval (Phase IV) U.S. study in non-Caucasians to determine the product’s safety in these groups. The firm will also provide training to physicians on the correct use of the device.
Restylane Fine Lines and SubQ have not been approved by the FDA for use in the U.S.
Restylane is currently registered in about 40 countries. All three Restylane products (Restylane Fine Lines; Restylane; and Restylane Perlane) and Deflux SUI have received CE Mark (European Union) medical device approval. Restylane was first approved for sale within Europe and obtained European Union approval (CE mark) in 1996. Restylane Fine Lines (for fine lines) and Restylane Perlane (for deep folds) were introduced in 2000. Deflux Gel was approved in Europe in 1998 for vesicoureteral reflux (VUR) in children, and for treatment of stress urinary incontinence (SUI) in women in 1999. The NASHA in Deflux gel acts as a vehicle for dextranomer, the active component. Durolane or NASHA for visco-supple-mentation injection treatment of knee osteoarthritis received European approval in spring 2001. In various foreign countries, besides facial wrinkles/folds, Restylane is also approved to enhance the appearance and fullness of lips. However, the safety and efficacy of Restylane for this indication has not been established in controlled studies submitted to the FDA.
Tech. transfer: U.S. patents covering aspects of Resytlane include 5,827,937, assigned to Q-Med, with Dr. B. Ågerup as sole inventor. These patents cover HA and other polysaccharide cross-linking methods, with epoxidation performed in two steps/stages. As described in 5,827,937, this involves cross-linking HA dissolved in sodium hydroxide solution (e.g., 1% NaOH pH > 9) under sterically hindering conditions, resulting in the production of activated polysaccharide, stopping the reaction before gelation is initiated (e.g., evaporating water to increase HA concentration), and resuming cross-linking under sterically unhindered conditions (e.g., by dialysing the aqueous medium or allowing diffusion of water into the solution at alkaline pH) The cross-linking agent is 1,4-butandiol digly-cidylether (BDDE), e.g., at 0.2% concentration. U.S. 5,633,001, with Dr. Ågerup as sole inventor, assigned to Med-invent (apparently, now Q-Med or licensed by Q-Med), primarily covers uses of partially-crosslinked HA for tissue augmentation.
Trials: Q-Med filed an IND in 2000, and started Restylane’s first (and pivotal) U.S. trial in Jan. 2001. This 6-month randomized, multi-center, double-blinded study evaluated 138 patients seeking correction of bilateral nasolabial folds. Patients received Restylane in one nasolabial fold and Zyplast (cross-linked bovine collagen from Inamed Corp.), the market-leading dermal collagen product in the U.S., in the opposite nasolabial fold. Total follow-up period was 12 months, with clinical efficacy assessments conducted at 2, 4 and 6 months using the Wrinkle Severity Rating Scale (WSRS) and Global Aesthetic Improvement Scale (GAIS). Restylane showed a statistically significant difference over Zyplast with respect to the change (from pre-treatment) in WSRS score at all post-baseline time points (p <0.0001). At six months post-baseline, Restylane was better than Zyplast in 56.9% of patients, while Zyplast was better than Restylane in 9.5% of patients (p <0.0001). Also at six months, 67.2% of Zyplast-treated folds returned to pre-treatment condition, compared to only 29.9% of Restylane-treated folds. The total injection volume needed to produce an “optimal cosmetic result” was lower for Restylane (mean 1.0 mL) than Zyplast (mean 1.6 mL). The most commonly reported adverse events were redness and swelling, which typically occurred at the injection site and were transient and mild to moderate in intensity.
Medical: Generally, most patients need one Restylane injection (per line., fold, contour, etc., being filled in from below the skin surface), requiring only about 30 minutes, while one third of patients need more than one. The effect of Restylane generally lasts about six months (with non-U.S. product literature reporting a duration of effect for up to one year). For comparison, non-stabilized HA can last only days to weeks at most.
There are no contraindications: to the use of Restylane products and the precautions are mainly those that should be observed for any intradermal injection. Local tolerance of Restylane is excellent, as the material integrates with local tissues. Degraded material is metabolized and excreted by the same pathways as natural HA. Adverse events are very rare. Transient reactions, which are thought to be of a hypersensitivity nature, have been reported in about one in every 2,000 patients. Other types of reactions are even more rare. [from international, not U.S.-specific product information].
Internationally (ex-U.S.), Restylane is used for smoothing out folds and wrinkles, lip enhancements and shaping facial contours (indications: beyond those currently FDA-approved). Presumably, now that it is approved and available in the U.S., Restylane will also be used for these indications: off-label. The most common areas of use are the glabellar lines (between the eyebrows), the nasolabial folds (from the root of the nose to the angle of the mouth; an FDA-approved indication), and the lips, but other sites can also be treated. Very superficial or very deep wrinkles may be difficult to correct with Restylane (vs. the other particle size formulation not yet approved in the U.S).
Market: Q-MED reported 2003 total sales of SEK 517 million (~ $50 million), with nearly all sales from its NASHA products. With the plastic surgery and cosmetic filler market rapidly expanding, the authors crude/rough guess for 2006 sales is in the range of $100 million or more.
Almost half a million people had received Restylane treatments and other soft tissue filler products during 2004. Since first launched in 1996, well over one million Restylane treatments have been successfully carried out worldwide. Since initial launch in Europe in 1996, sales have almost doubled every year. Restylane is now sold in more than 60 countries.
The Average Wholesale Price (AWP) is not available (product not in 2007 or 2004 Red Book). Restylane is reported to cost between $500-$750 per treatment.
Competition: In the U.S., Restylane competes against injectable collagen products, which are well-established for filling-in facial folds, furrows, creases, plumping of lips, etc. However, these older products are tending to fall out of favor with physicians. Another HA product, Hylaform (derived from rooster combs; see related entry below), is also marketed in the U.S. and Europe, where it is used for some of the same cosmetic indications: as Restylane. Hylaform has a higher molecular weight and lower concentration (6 mg/mL), and has more elastic tendencies (while Restylane is more viscous).
Restylane also competes, including for its approved indications: (moderate to severe facial wrinkles and folds), with Botox Cosmetic or injected botulinum toxin from Allergan (see entry #601). Although presumably not approved by FDA, many plastic surgeons and the popular press make claims such as, “Restylane provides a safe alternative for people who are hesitant to try Botox.” Restylane treatment costs about the same as Botox Cosmetic treatment and lasts about just as long, with the active component being inherently inocuous, compared to botulinum toxin, and nearly no potentially serious adverse effects, as may occur if excessive toxin is injected.
Ref.: NASHA: The Monograph, by B. Ågerup, O. Wik, Q-Med AB, Uppsala, Sweden, 2001.
Companies involvement:
Full monograph
929 Hyaluronic acid/Q-Med
Nomenclature:
Hyaluronic acid/Q-Med [BIO]
Restylane [TR]
Hyaluronan injection [FDA]
HA [SY]
hyaluronic acid [SA]
NASHA [SY]
Natrii Hyaluronas [SY Latin]
Non-Animal Stabilized Hyaluronic Acid [SY]
sodium glucuronate-N-acetylglucosamine polymer [SY]
sodium hyaluronate [SY]
FDA Class: PMA Med. Dev.
Year of approval (FDA) = 2003
Date of 1st FDA approval = 20031212
(in format YYYYMMDD)
Index Terms:
bacterial culture <!-- bacterialculture -->
biopharmaceutical products
glycosaminoglycans
implants
polysaccharides
bacterial culture <!-- bacterialculture -->
Streptocccus pneumoniae
1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
ethanol
heat treatment (pasteurization)
sodium hydroxide
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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