FDA issues boxed warning for Botox and botulinum toxin products

The Food and Drug Administration (FDA), as part of an ongoing safety review, has notified manufacturers of licensed botulinum toxin products – also known as Botox and Botox Cosmetic and Myobloc – of the need to strengthen warnings in product labeling and add a boxed warning of the risk of adverse events when the effects of the toxin spread beyond the site where it was injected.

FDA has ordered manufacturers to develop and implement a Risk Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of the product outweigh the risks. The REMS will include a plan to communicate information regarding the risk for distant spread of botulinum toxin effects after local injection as well as information to explain that botulinum toxin products cannot be interchanged. The strategy also will include a Medication Guide that explains risks to patients, their families, and caregivers.

Botulinum toxin products have been approved by FDA for one or more of the following uses: temporary improvement in the appearance of glabellar lines (frown lines between the eyebrows), treatment of strabismus (crossed eyes), blepharospasm (abnormal tics and twitches of the eyelids), cervical dystonia (involuntary sustained or repetitive contraction of the neck muscles), and primary axillary hyperhidrosis (severe underarm sweating). For these uses, botulinum toxin is injected into the skin or into muscle tissue.

In pediatric post-marketing adverse events reports, botulinum toxins were mostly used to treat muscle spasticity in patients with cerebral palsy, a use not approved by the FDA. Reported adverse events reported following such use included difficulty breathing, difficulty swallowing, muscular weakness, drooping eyelids, constipation, aspiration pneumonia, speech disorder, facial drooping, double vision or respiratory depression. Serious case reports described hospitalizations involving ventilatory support and reports of death.

The majority of adult post-marketing reports of distant spread of toxin events occurred following use of the product for treatment of spasticity, which is not an FDA-approved use, and cervical dystonia. Some cases resulted in hospitalization, including several cases that required placement of a gastric tube or mechanical ventilation. Several deaths have been reported though the FDA says it is not possible to attribute them to botulinum toxin because the patients also suffered from complications from pre-existing conditions. Some reports are from dermatologic use however no definitive serious adverse events of distant spread of toxin effects with dermatologic use of Botox at the labeled dose of 20 units (for glabellar lines) or 100 units (for severe primary axillary hyperhidrosis) have been identified.

Adverse events have been reported as early as several hours and as late as several weeks after treatment.

The FDA recommends that healthcare professionals who use botulinum toxin products understand that the dosage strength are different among the botulinum toxin products; be alert to and education patients and caregivers about potential adverse events due to distant spread; and to advise patients to seek medical attention if they develop any symptoms following treatment.