Allergan Comments On FDA Requested Class Labeling For Botulinum Toxin Treatments In Connection With Approval Of DYSPORT(R)

Main Category: Cosmetic Medicine / Plastic Surgery
Article Date: 08 May 2009 - 5:00 PST

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Allergan, Inc. (NYSE: AGN) commented on Ipsen's and Medicis's joint announcement that the U.S. Food and Drug Administration (FDA) has conditioned its approval of DYSPORT® (abobotulinumtoxinA) for the treatment of cervical dystonia and glabellar lines on their commitment to adopt a Risk Evaluation and Mitigation Strategies (REMS) program. The companies report in their news release that one of the purposes of the FDA-mandated REMS is to mitigate the significant risks such as medication errors and overdosing that may result from treating different botulinum toxins as interchangeable. For instance, DYSPORT® is not interchangeable or substitutable for BOTOX® or BOTOX® Cosmetic (collectively, BOTOX®). Additionally Ipsen has announced that the FDA has required that the DYSPORT® package insert contain a "boxed warning" regarding the potential spread of DYSPORT® distant from the site of injection, and to address this in their REMS program.

Concurrently with the approval of DYSPORT®, the FDA yesterday requested that Allergan consider certain class labeling that we assume is found in the DYSPORT® package insert, including a REMS program.

The proposed boxed warning section provides information regarding reports of spread of botulinum toxins distant from the site of injection, particularly in children treated for spasticity, an unapproved indication, who have underlying conditions that would predispose them to these symptoms. The class labeling also notes that the risk exists for adults treated for spasticity or other conditions who have an underlying disease that would predispose them to these symptoms. The proposed label update specifically notes that individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junction disorders such as myasthenia gravis or Lambert-Eaton syndrome should be monitored particularly closely when treated with a botulinum toxin product.

Additionally, the FDA has proposed language to address the safety risks associated with interchanging different botulinum toxins. BOTOX®, for instance, is a trademark for a unique biologic product manufactured and distributed by Allergan. Its molecular weight, formulation, safety margin and efficacy profile are specific to BOTOX® and no other product. In its communication to Allergan, the FDA suggested that it has received reports of overdosing associated with inappropriate interchanging of botulinum toxins. Accordingly, the FDA has proposed new language about the lack of interchangeability between botulinum toxin products and specifically that "units of biological activity of BOTOX/BOTOX Cosmetic cannot be compared to or converted into units of any other botulinum toxin products...." In connection with this, the FDA has requested a communication plan regarding "information pertaining to the lack of interchangeability of BOTOX/BOTOX Cosmetic (botulinum toxin type A) with other licensed botulinum toxins."

The FDA has also requested that Allergan accept the same boxed warning required of the DYSPORT® label. BOTOX® has been marketed in the United States for nearly 20 years, its safety and efficacy profile are well understood, and reports of suspected distant spread have been rare. Allergan, however, recognizes the increased prevalence of boxed warnings in recent years as a method of highlighting safety information. For instance, in the past 12 months the FDA required more than 50 new or revised black box warnings for marketed pharmaceuticals. Likewise, Allergan recognizes that this boxed warning is proposed as a class labeling requirement and understands that incident rates for other botulinum toxins must be considered in determining the appropriateness of a boxed warning section.

"With the approval of another botulinum toxin, the FDA's request for updated class safety labeling and the reinforcement of non-interchangeability is timely and responsible," said Dr. Sef Kurstjens, Allergan's Chief Medical Officer. "Our patients are our first priority and as the world's leader in the development of botulinum toxin we support efforts to responsibly educate patients and healthcare practitioners about important safety considerations when evaluating such treatments as no two botulinum toxins are alike. Better education enhances the risk/benefit profile of products and enhances patient outcomes and satisfaction. Accordingly, we will work with the FDA to update the safety labeling for BOTOX® and develop an appropriate REMS program."

For nearly 20 years, physicians and patients have come to rely on the well understood and trusted risk-benefit profile of BOTOX®, which has been established in approximately 50 randomized, placebo-controlled clinical trialsi and in approximately 11,000 patients treated with BOTOX® and BOTOX® Cosmetic in Allergan's clinical trials.ii BOTOX® is the only neurotoxin worldwide approved for 21 different indications across approximately 80 countries. BOTOX® Cosmetic, first approved in the United States in 2002, has been the most popular physician-administered aesthetic injectable treatment for the past seven years and has since received approvals in more than 60 countries worldwide, marketed under different trade names. Approximately 22 million vials of BOTOX® and BOTOX® Cosmetic have been distributed worldwide since the product was first approved and nearly 17 million treatment sessions have been recorded with BOTOX® and BOTOX® Cosmetic in the United States alone over the past 14 years (1994-2008).iii With approximately 2,000 articles on BOTOX® and BOTOX® Cosmetic in peer-reviewed publications,iv the product is one of the most widely researched medicines in the world.

Important BOTOX® and BOTOX® Cosmetic (Botulinum Toxin Type A) Information

BOTOX® is indicated for the treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia.

BOTOX® is also indicated for the treatment of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders in patients 12 years of age and above.

The efficacy of BOTOX® treatment in deviations over 50 prism diopters, in restrictive strabismus, in Duane's syndrome with lateral rectus weakness, and in secondary strabismus caused by prior surgical over-recession of the antagonist has not been established. BOTOX® is ineffective in chronic paralytic strabismus except when used in conjunction with surgical repair to reduce antagonist contracture.

And BOTOX® is indicated for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents.

BOTOX® Cosmetic is approved for the temporary treatment of moderate to severe frown lines between the brows in people ages 18-65.

Important BOTOX® and BOTOX® Cosmetic (Botulinum Toxin Type A) Safety Information

BOTOX® and BOTOX® Cosmetic treatment should not be injected in the presence of infection at the proposed injection site(s) and in individuals with known hypersensitivity to any ingredient in the formulation.

Serious heart problems and serious allergic reactions have been reported rarely. If you think you're having an allergic reaction or other unusual symptoms, such as difficulty swallowing, speaking or breathing, call your doctor immediately. Individuals with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis, or motor neuropathy) or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should only receive BOTOX® or BOTOX® Cosmetic with caution. Patients with neuromuscular disorders may be at increased risk of clinically significant systemic side effects with BOTOX® or BOTOX® Cosmetic. For full prescribing information, please visit http://www.botox.com and http://www.botoxcosmetic.com.

BOTOX® for Blepharospasm in Patients ≥ 12 Years of Age: Reduced blinking from BOTOX® injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal perforation. The most frequently reported treatment-related adverse reactions in these patients are ptosis (20.8%), superficial punctate keratitis (6.3%) and eye dryness (6.3%).

BOTOX® for Strabismus in Patients ≥ 12 Years of Age: Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision or past pointing. The most commonly reported adverse effects are ptosis (16%) and vertical deviation (17%).

BOTOX® for Cervical Dystonia in Adults: There have been rare cases of dysphagia severe enough to warrant the insertion of a gastric feeding tube. The most frequently reported adverse reactions in patients with cervical dystonia are dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%).

BOTOX® for Severe Primary Axillary Hyperhidrosis Inadequately Managed with Topical Agents: The most frequently reported adverse events (3 - 10%) are injection site pain and hemorrhage, non-axillary sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, and anxiety.

BOTOX® Cosmetic for Temporary Improvement in the Appearance of Moderate to Severe Frown Lines Between the Brows in Adults 18-65: The most common side effects following injection include temporary eyelid droop and nausea. Localized pain, infection, inflammation, tenderness, swelling, redness and/or bleeding/bruising may be associated with the injection.

i Allergan data on file, Medical Affairs
ii Allergan data on file, Medical Affairs
iii Allergan data on file; global Regulatory Affairs
iv Allergan data on file; global Literature & Information Services

Source
Allergan, Inc