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In 2009, more than 2.5 million procedures using botulinum neurotoxin type A were performed in the United States (The American Society for Aesthetic Plastic Surgery, 2010). Despite the glabellar region being the only aesthetic indication for this neurotoxin with US Food and Drug Administration (FDA) approval, the literature is extensive with reports of successful treatments encompassing the face and neck, with and without combination therapies such as dermal fillers, laser/light-based treatments and skin care. A variety of therapeutic indications for neurotoxins also exist. The role of neurotoxins in aesthetic and therapeutic arenas has expanded along with injection approaches, facial rejuvenation modalities, and available botulinum neurtoxin type A (BoNTa) agents.
In the United States today, there are two BoNTa agents approved for aesthetic indications. Botox (Allergan, Irvine, CA) was approved in 2002. In April 2009, Dysport (Medicis, Scottsdale, AZ) received FDA approval for the same aesthetic indication of temporary improvement in the appearance of moderate to severe glabellar lines.
With the emergence of more neurotoxins on US turf, it is crucial for clinicians to understand the similarities and differences between these agents. In this inaugural issue of Plastic Surgical Nursing Journal's Aesthetic Department, a clinical update of each botulinum neurotoxin type A product currently FDA approved and those on the horizon will be presented.
In it's innate form, botulinum neurotoxin type A complexes are a combination of a 150-kDa active moiety (the neurotoxin), surrounding hemagglutinin complexing proteins, and nontoxin nonhemagglutinin proteins that are of varying size. The complexing proteins protect the neurotoxin from the acidic environment of the stomach, when ingested orally. The complexing protein's role, when injected, is said to be unknown. Each neurotoxin has a different molecular weight, which has led to discussions and debate as to diffusion; the extent of the region of muscle affected by the toxin (Pickett, 2009).
As each neurotoxin possesses unique chemical and physical properties, the FDA instituted new nonproprietary names to both available BoNTa's: BOTOX Cosmetic (onabotulinumtoxinA) and Dysport (abobotulinumtoxinA) in 2009. This reflects each products lack of interchangeability. To address the potential adverse events associated with the migration of injected BoNTa, the addition of a boxed warning and Risk Evaluation and Mitigation Strategy was instituted for all such products and will apply to any neurotoxins receiving FDA approval in the future. The goal of the REMS is to minimize risks of medication errors related to the lack of interchangeability between toxins and educate practitioners and patients about the potential for distant spread (US Food and Drug Administration, 2010).
In the United States, BOTOX Cosmetic was the only "toxin on the turf," receiving FDA approval in 2002 with its aesthetic indication for treatment of glabellar frown lines. The efficacy of BOTOX for on and off-label cosmetic indications is well documented in the literature (BOTOX[spacing macron] HEALTHCARE PROFESSIONAL SITE, n.d.).
BOTOX has a molecular weight of 900 kDa and is vacuum dried with normal saline and albumin. The pH is considered neutral. There are 100 units per vial with an on-label recommended reconstitution volume of 2.5 ml of nonpreserved normal saline. The approved total dose for the glabellar region is 20 units delivered to five injection sites with four units per site (http://www.allergan.com/assets/pdf/botox_cosmetic_pi.pdf).
With the recent FDA approval of Dysport in the United States, the "toxin turf" began expanding. Dysport has a molecular weight of 500 kDA and is freeze dried with lactose and albumin. The pH is considered neutral. There are 300 units per vial for cosmetic use and an on-label recommended recon stitution volume of 1.5 or 2.5 ml of nonpreserved normal saline (Learn more about Dysport, 2010).
The phase 2 and 3 placebo-controlled studies for treatment of glabellar lines began in the United States in 2003. Phase 2 dose-ranging studies determined that a dose range of 50-75 units was effective thus, subsequent studies used this dose range, based upon muscle mass and sex. Phase 3 trials resulted in an FDA approved dose for the glabellar region of 50 units delivered to five injection sites with 10 units per site (Clinical Courier, 2009).
Another toxin on US "turf" just receiving FDA approval in August 2010, for therapeutic indications of cervical dystonia and blepharospasm is Xeomin (Merz Pharmaceuticals, Greensboro, NC). Xeomin employs a proprietary manufacturing process that isolates the therapeutic component and eliminates the complexing proteins. It is reported to have a high biologic activity with a low protein load. It does not require refrigeration prior to reconstitution. It will be available in both 50 unit and 100 unit vials.
The FDA approval of Xeomin was based on the results of two pivotal United States clinical trials involving adult patients diagnosed with either cervical dystonia or blepharospasm. The clinical trials for Xeomin in the treatment of glabellar frown lines are completed and pending FDA approval (Merz Pharmaceuticals, 2010).
We can see from the annual statistics collected by the American Society of Aesthetic Plastic Surgeons, aesthetic injectable treatments continue to be in high demand, despite the economic state we are in. In the coming months and years, practitioners can expect to add new BoNTa agents to their aesthetic armamentarium.
A brief overview and clinical update about these neurotoxins on the horizon will be presented below.
PurTox is a purified form of botulinum neurotoxin type A, named because the 150-kDa active moiety is apart from the surrounding complex proteins. As a result, patients receive only the toxin. According to the literature reviewed, how this could affect the efficacy, safety, onset of action, or duration remains to be determined. Mentor Corporation (Santa Barbara, CA) is developing this BoNTa. Clinical trials on PurTox are well underway. There is completion of the first of three Phase 3 clinical trials for the reduction of glabellar rhytids. The remaining two Phase 3 studies for this indication have completed enrollment and are currently in the follow-up stage (Mentor Corporation, 2010).
On the horizon with the potential of entering the "toxin turf" is a topical botulinum neurotoxin A. Known as RT001 (Revance Therapeudics, Palo Alto, CA), this BoNTa is combined with Cetaphil as a paste and applied to the treatment site under occlusion for 20-30 min. The vehicle (which is a protein carrier) through active transport moves the toxin through the epidermal cells and releases it into the dermis (Landau, 2009). RT001 is currently being studied for the treatment of lateral canthal lines (crow's feet) and the therapeutic indication of hyperhidrosis. Results of two Phase 2b clinical trials were presented in October 2010, at the American Society of Dermatologic Surgery conference. As more data becomes available to establish safety and efficacy of this topical BoNTa, it will be interesting to learn how and if there will be evidence to compare it's effects to injectable neurotoxins (Revance Therapeutics, 2010).
There appears to be a proliferation of counterfeit injectables (botulinum type A neurotoxins and dermal fillers) infiltrating aesthetic practices through emails, faxes, and even "representatives" knocking on doors. As educated practitioners, we need to know that it is, most importantly, illegal to order outside of the United States or from a source that does not receive product from a US pharmaceutical company. It also poses potential serious compromise to patient safety and efficacy of the treatment.
According to one source, botulinum neurotoxin type A products are being produced in India, Equador, China, and elsewhere. A sampling of these counterfeit and look-alike products was collected from these countries and toxin activity was evaluated. Findings showed that some counterfeit products have no toxin activity yet others have more toxin activity per unit than that displayed on the label. These dangers could result in patients receiving too much toxin or no toxin at all (Pickett, 2009).
A plethora of new information regarding botulinum neurotoxin type A agents is becoming more readily available through increasing clinical studies, professional society scientific meetings and product manufacturer updates. With the introduction of new BoNTa's, this current clinical data have expanded horizons in practitioners understanding and clinical applications. As we have learned in our individual aesthetic practices, competition can grow the marketplace. It will be interesting to see how these new toxin alternatives on US "turf" will impact practitioners and patients alike.
1. BOTOX[spacing macron] HEALTHCARE PROFESSIONAL SITE. (n.d.). BOTOX[spacing macron] Cosmetic Home Page | BOTOX[spacing macron] Cosmetic Website. Retrieved November 14, 2010, from http://www.botoxcosmetic.com/botox_physician_info/index.asp.
2. Clinical Courier. (2009). Current and Emerging Use of Neurotoxins: Implications for Research and Practice in the United States.., 27(5), 1-8. [Context Link]
3. Landau M. (2009, January 8-11). What's new in BTX-hyperhidrosis? Lecture presented at International Master Course on Aging Skin in France, Paris. [Context Link]
4. Learn more about Dysport. (2010). Retrieved November 14, 2010, from http://www.dysport.com/prescribinginformation.html[Context Link]
5. Mentor Corporation. (2010). Mentor Corporation Announces Completion of PurTox(R) 3A Study [Press release]. Retrieved November 14, 2010, from http://mentorcorp.com[Context Link]
6. Merz Pharmaceuticals. (2010). Xeomin FDA Approval Press Release [Press release]. Retrieved November 14, 2010, from http://www.xeomin.com[Context Link]
7. Pickett A. (2009, January 8-11). BoNT-A: myths and realities. Lecture presented at International Master Course on Aging Skin in France, Paris. [Context Link]
8. Pickett A. (2009, January 8-11). Counterfeit botulinum toxins: a serious risk to patient health. Lecture presented at International Master Course on Aging Skin in France, Paris.
9. Revance Therapeutics. (2010, October 22). Press Releases [Press release]. Retrieved November 20, 2010, from http://www.revance.com/news.html[Context Link]
10. The American Society for Aesthetic Plastic Surgery. (2010). The American Society for Aesthetic Plastic Surgery: The Mark of Distinction in Cosmetic Plastic Surgery. Retrieved November 14, 2010, from http://www.surgery.org/
11. US Food and Drug Administration. (2010). Retrieved November 20, 2010, from http://www.fda.gov/'[Context Link]
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