FDA Requires Boxed Warning for All Botulinum Toxin Products

Prompted by reports of serious adverse events, the U.S. Food and Drug Administration today announced that safety label changes, including a boxed warning, and a Risk Evaluation and Mitigation Strategy (REMS), are necessary for all botulinum toxin products.

The agency said it took the action because of reports that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism, including unexpected loss of strength or muscle weakness, hoarseness or trouble talking, trouble saying words clearly, loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids.

These symptoms have mostly been reported in children with cerebral palsy being treated with the products for muscle spasticity, an unapproved use of the drugs. Symptoms have also been reported in adults treated both for approved and unapproved uses.

The agency also took the action because of the potential for serious risks associated with the lack of interchangeability among the three licensed botulinum toxin products.

“Updated labels for this class of products will help health care professionals and patients better understand the risks and benefits,” said Russell Katz, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Botulinum toxin products have benefits but can cause serious health problems and it is important that anyone who administers or uses these products understands these risks.”

Product Names

The products required to add the new label and a REMS are Botox and Botox Cosmetic (botulinum toxin type A), marketed by Allergan; Myobloc (botulinum toxin type B), marketed by Solstice Neurosciences; and a new FDA-approved product, Dysport (abobotulinumtoxinA), marketed by Ipsen Biopharm Ltd.

Botox, Myobloc, and Dysport are approved by the FDA for the treatment of a condition marked by repetitive contraction of the neck muscles (cervical dystonia). Botox Cosmetic and Dysport are approved by the FDA for dermatologic use in the temporary improvement in the appearance of frown lines between the eyebrows called glabellar lines. In addition, Botox is approved for the treatment of severe underarm sweating (primary axillary hyperhidrosis), crossed eyes (strabismus), and abnormal tics and twitches of the eyelids (blepharospasm).

Recommendations for Health Care Professionals

The FDA has notified the manufacturers of Botox and Myobloc that label changes and a REMS are necessary to ensure that the benefits of the product outweigh the risks. The FDA approved a REMS for Dysport as part of the product approval. The REMS for each of these products will include a Medication Guide and a Communication Plan. Medication Guides are FDA-approved handouts given to patients, or their families and caregivers, when a medicine is dispensed. The Medication Guides will contain information about the risks associated with botulinum toxin products. The FDA is also requiring the manufacturers to collect safety data in children and adults with muscle spasticity to assess the signal of risk regarding distant spread of toxin effects.

Treatment of muscle spasticity is not an FDA-approved use of botulism toxin products. The doses used in treatment of muscle spasticity are often much higher than the doses for uses described in FDA-approved product label. Symptoms consistent with spread of toxin effects have been reported at doses comparable to or lower than doses used to treat cervical dystonia.

For the FDA-approved dermatologic use of temporary improvement in the appearance of glabellar lines, the agency has not identified any definitive serious adverse event reports of a distant spread of toxin effect producing symptoms consistent with botulism when the botulinum toxin products are used in accordance with the approved label.

The companies that make Botox and Myobloc are required to submit the requested safety label changes, including the boxed warning and the Medication Guide, to the FDA within 30 days, or to provide a reason why they do not believe such changes are necessary. If they do not submit new language, or the FDA disagrees with the language the companies propose, the Food, Drug, and Cosmetic Act provides strict timelines for discussions regarding the changes. At the end of these discussions the agency is allowed to issue an order directing the label change as deemed appropriate to address the new safety information.

Health care professionals who use botulinum toxins should do the following:

Understand that dosage strength (potency) expressed in “Units” is different among the botulinum toxin products; clinical doses expressed in units are not interchangeable from one product to another.

Be alert to and educate patients and caregivers about the potential for effects following administration of botulinum toxins such as: unexpected loss of strength or muscle weakness, hoarseness or trouble talking, trouble saying words clearly, loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids.
Understand that these effects have been reported as early as several hours and as late as several weeks after treatment.

Advise patients to seek immediate medical attention if they develop any of these symptoms.
Health care professionals and consumers may report serious adverse events (side effects) or product quality problems with the use of this product to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail, fax or phone.--Online --Regular Mail: use postage-paid FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787--Fax: 800-FDA-0178--Phone: 800-FDA-1088

Today’s action updates a February 2008 announcement that the FDA was conducting an ongoing safety review of botulinum toxin products.The FDA also issued a response to a citizen petition related to the risk of spread of botulinum toxin effects from the site of injection. This response provides additional detail regarding the FDA’s analysis of this safety issue. The FDA’s response to the Citizen Petition can be found at http://www.fda.gov/cder/drug/early_comm/botulinum_CP_response.pdf
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