February 8, 2008 — As a result of an ongoing safety review, the US Food and Drug Administration (FDA) has issued an early communication regarding botulinum toxin type A (Botox, Botox Cosmetic; Allergan), and botulinum toxin type B (Myobloc; Solstice Neurosciences, Inc). These drugs have been associated with systemic adverse reactions, including respiratory compromise and death resembling that seen with botulism, in which botulinum toxin spreads in the body beyond the injection site.
In the most serious cases, reported mostly in children treated for limb spasticity associated with cerebral palsy, outcomes included hospitalization and death. However, respiratory compromise and death were reported after the use of botulinum toxin types A and B for treatment of a variety of conditions, using a wide range of botulinum toxin doses, for both FDA-approved and FDA-unapproved uses.
Despite the literature describing use of botulinum toxin to treat limb spasticity, use of botulinum toxin for treatment of limb spasticity is not an FDA-approved use, either in children or adults. The safety, efficacy, and dose of botulinum toxin have not been established for this indication or for any indication in children younger than 12 years.
"Posting this information does not mean that FDA has concluded there is a causal relationship between the drug products and the emerging safety issue," the early communication states. "Nor does it mean that FDA is advising healthcare professionals to discontinue prescribing these products. FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action."
The FDA is now reviewing safety data from clinical studies provided by the drug manufacturers, postmarketing adverse event reports from its Adverse Event Reporting System database, and the medical literature concerning children and adults diagnosed with botulism after a local injection with a marketed botulinum toxin product. Their communication will be updated as new information becomes available.
Pending the results from this review, the FDA makes the following recommendations for clinicians who administer medicinal botulinum toxin:
Realize that potency determinations (units) vary among the botulinum toxin products and that clinical doses expressed in units are not comparable from one botulinum product to the next.
Remain vigilant for systemic effects that may follow administration of botulinum toxins, including dysphagia, dysphonia, weakness, dyspnea, or respiratory distress. These symptoms, which are suggestive of botulism, have been reported from 1 day to several weeks after treatment.
Inform patients and caregivers regarding how to recognize the signs and symptoms of systemic effects after being injected with a botulinum toxin. Advise patients to seek immediate medical attention for worsening or unexpected difficulty swallowing or talking, trouble breathing, or muscle weakness.
Botulism cases in children younger than 16 years, most of whom received botulinum toxin for treatment of limb muscle spasticity associated with cerebral palsy, were associated with adverse events including dysphagia, respiratory insufficiency requiring use of gastric feeding tubes and ventilatory support, hospitalization, and death. Doses in these cases ranged from 6.25 to 32 U/kg for botulinum toxin type A and from 388 to 625 U/kg for botulinum toxin type B.
Adverse events associated with adult botulism cases included neck weakness, dysphagia, ptosis, and lower extremity weakness and numbness. Some serious cases in adults required hospitalization, but none required intubation or ventilatory support, and there were no reported deaths. Doses in these cases ranged from 100 to 700 U for botulinum toxin type A and from 10,000 to 20,000 U for botulinum toxin type B.
FDA-approved indications for Botox are blepharospasm, cervical dystonia, and severe primary axillary hyperhydrosis; Botox Cosmetic is approved for temporary treatment of moderate to severe facial frown lines; and Myobloc is cervical dystonia in adults.
Current labeling for these products describes adverse reactions near the injection site, including dysphagia after injections for cervical dystonia or ptosis after injections for glabellar frown lines or for strabismus and blepharospasm.
Current warnings note that important systemic adverse effects, including severe dysphagia and difficulty breathing, may occur in patients with neuromuscular disorders after local injection of usual doses of botulinum toxin. As described above, the FDA now has evidence of similar, potentially life-threatening systemic toxicity in patients with other underlying conditions, such as those with cerebral palsy, and in children.
"This early communication is in keeping with FDA's commitment to inform the public about its ongoing safety reviews of drugs," the statement concludes. "FDA will communicate to the public its conclusions, resulting recommendations, and any regulatory actions after the review of the data are completed."
Serious adverse events should be reported to FDA's MedWatch by telephone at 1-800-FDA-1088, by fax to 1-800-FDA-0178, online at https://www.fda.gov/medwatch/report/hcp.htm, or by mail to 5600 Fishers Lane, Rockville, MD 20853-9787.
Medscape Medical News © 2008 Medscape
Cite this: Laurie Barclay. Respiratory Compromise, Death May Be Linked to Botulinum Toxin - Medscape - Feb 08, 2008.