September 2009




Botox, others to include “black box” warnings

by Michelle Dalton EyeWorld Contributing Editor


The FDA mandates improved safety precautions

Just as Botox (botulinum toxin A, Allergan, Irvine, Calif.) was celebrating 20 years on the U.S. market, the Food and Drug Administration (FDA) burst its bubble somewhat, first by approving a direct competitor to its cosmetic franchise and second by demanding all manufacturers of the toxin include a boxed warning indicating the risk of the spread of botulinum toxin effects from the site of injection. The FDA also told the manufacturers that a Risk Evaluation and Mitigation Strategy (REMS) that must consist of a Medication Guide and Communication Plan, including a “Dear Health Care Provider” letter and a timetable for submission of assessments, is required to ensure the benefits of the injection outweigh the risks.

New Botox competitor

In late April 2009, the FDA granted regulatory approval for Dysport (abobotulinumtoxinA) to be jointly marketed by Medicis (Scottsdale, Ariz.) and Ipsen (Paris). Medicis will market the drug for the treatment of glabellar lines, while Ipsen will market the drug for the treatment of cervical dystonia. AbobotulinumtoxinA is an acetylcholine release inhibitor and neuromuscular blocking agent, the companies said, and is the same active substance found in Botox. According to Medicis, Dysport was evaluated for the treatment of glabellar lines in about 2,900 patients at more than 80 clinical study sites. Further, the drug has been used in patient care in the United Kingdom since 1991 and has marketing authorizations in 76 countries for therapeutic use and 27 countries for aesthetic use. Comparatively, Botox is approved for 20 different therapeutic indications in 80 countries worldwide, and Botox Cosmetic is approved in almost 60 countries. Medicis expects to launch the product in the U.S. in the next 30 to 60 days, while Ipsen is projecting a second half launch. Dysport has been approved outside the U.S. for the treatment of movement disorders such as cervical dystonia, blepharospasm, hemifacial spasm, and various forms of muscle spasticity, the companies said. Dysport was approved with an REMS, Medicis said.

Additional safety information

According to the American Society for Aesthetic Plastic Surgery, injections of botulinum toxin type A have been the leading nonsurgical cosmetic procedure over the past 5 years, with about 2.4 million total procedures in 2008. Allergan has stated Botox has about an 83% market share for neurotoxins that relax muscles or nerves. In early 2008, the Public Citizen Health Research Group, a consumer advocacy group, filed a petition with the FDA requesting increased safety warnings “based on rates of dysphagia and muscle weakness in preapproval clinical trials and postmarketing adverse event reports of dysphagia, aspiration, and/or pneumonia,” according to an FDA response letter. After a review of the postmarketing adverse event reports and clinical trial data and literature, the FDA concluded all three botulinum toxin products must carry a boxed warning. “The risk of symptoms is probably greatest in children treated for spasticity and other conditions,” the FDA said. Treatment of muscle spasticity is not an FDA-approved use of botulinum toxin products, the agency said.

However, in a press briefing after the announcement, the FDA said that for muscle spasticity the products are “commonly used, and we don’t mean in any way to discourage that use,” said Ellis Unger, acting deputy director, Office of Drug Evaluation, FDA. “People need to understand the risks that are involved so they can make informed risk-benefit decisions.”

The agency added the labeling for Botox, Botox Cosmetic, and Myobloc (approved for cervical dystonia only) “should be updated to include strengthened warning regarding the spread of toxin effect beyond the site of local injection and regarding dysphagia and breathing difficulties in the treatment of cervical dystonia and pre-existing neuromuscular disorders.” The FDA did note, however, that serious adverse events do not seem likely to occur with the cosmetic dosage.

Dysport was approved with a warning box and so was not included in the FDA’s directive. According to Allergan, the most common side effects following injection for the treatment of blepharospasm included ptosis (20.8%), inflammation of the cornea (6.3%), and eye dryness (6.3%). In strabismus, the company said the most common side effects after injection include ptosis (15.7%) and vertical deviation (16.9%). The most common side effects for Botox cosmetic injections included temporary eyelid droop and nausea. “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 Sef Kurstjens, M.D., chief medical officer, Allergan.

Contact information

Allergan: 714-246-4500
Medicis: 602-808-8800

Botox, others to include “black box” warnings Botox, others to include “black box” warnings
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