From the FMS Global News Desk of Jeanne Hambleton (UK)
Courtesy of FDA/Center for Drug Evaluation and Research
FDA notified healthcare professionals that after an ongoing safety review initiated in February 2008, the manufacturers of licensed botulinum toxin products will be required by FDA to strengthen warnings in product labeling and add a boxed warning regarding the risk of adverse events when the effects of the toxin spread beyond the site where it was injected.
FDA will also require that manufacturers develop and implement a Risk Evaluation and Mitigation Strategy [REMS], including a communication plan to provide more 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 REMS would also include a Medication Guide that explains the risks to patients, their families, and caregivers. FDA is requiring the manufacturers to submit safety data after multiple administrations of the product in a specified number of children and adults with spasticity to assess the signal of serious risk regarding distant spread of toxin effects.
FDA’s evaluation of the data continues to support the recommendations made in the 2008 Early Communication.
Follow-up to the February 8, 2008, Early Communication about an Ongoing Safety Review of Botox and Botox Cosmetic (Botulinum toxin Type A) and Myobloc (Botulinum toxin Type B)
This information reflects FDA’s current analysis of available data concerning these drugs.
As the result of an ongoing safety review, FDA has notified the manufacturers of licensed botulinum toxin products of the need to strengthen warnings in product labeling, and add a boxed warning, regarding the risk of adverse events when the effects of the toxin spread beyond the site where it was injected.
FDA also has notified the manufacturers that development and implementation of a Risk Evaluation and Mitigation Strategy (REMS) is necessary to ensure that the benefits of the product outweigh the risks. The REMS would include a Communication Plan to provide more 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 REMS would also include a Medication Guide that explains the risks to patients, their families, and caregivers.
In addition, FDA is requiring the manufacturers to submit safety data after multiple administrations of the product in a specified number of children and adults with spasticity to assess the signal of serious risk regarding distant spread of toxin effects.
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.
The following information summarizes FDA’s review of postmarketing safety data obtained from the manufacturers of botulinum toxin products, and all existing data within the Agency regarding these adverse events:
In pediatric postmarketing adverse event case reports, botulinum toxin products were mostly used to treat muscle spasticity in cerebral palsy, a use that has not been approved by the FDA. The reported cases of spread of botulinum toxin effect beyond the site of injection were described as botulism, or involved symptoms including 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 the adult postmarketing case reports of distant spread of toxin effects occurred following use of botulinum toxin for the treatment of spasticity (an unapproved use) or cervical dystonia. Some cases resulted in hospitalization, including several cases that required placement of a gastric tube or mechanical ventilation. Although there were several deaths in adults, it is not possible to attribute them to the botulinum toxin because the patients also suffered from complications of their pre-existing conditions. In addition, there have been reports where some symptoms could be consistent with distant spread of toxin effect following dermatologic use. However, no definitive serious adverse event reports of distant spread of toxin effect associated 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.
FDA’s evaluation of the data continues to support the recommendations made in the 2008 Early Communication; that healthcare professionals who use botulinum toxin products should:
Understand that dosage strength (potency) expressed in “Units” or “U” are different among the botulinum toxin products; clinical doses expressed in units are not interchangeable from one botulinum toxin product to another.
Be alert to and educate patients and caregivers about potential adverse events due to distant spread of botulinum toxin effects following local injections including: unexpected loss of strength or muscle weakness, hoarseness or trouble talking (dysphonia), trouble saying words clearly (dysarthria), loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooping eyelids.
Understand that these adverse events 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.
FDA urges both healthcare professionals and patients to report side effects from the use of Botox and Botox Cosmetic (Botulinum toxin Type A), Myobloc (Botulinum toxin Type B), and Dysport (abobotulinumtoxinA) to the FDA’s MedWatch Adverse Event Reporting program through:
Online at http://www.fda.gov/medwatch/report.htm
By returning the postage-paid FDA form 3500 available in PDF format at http://www.fda.gov/medwatch/getforms.htm to 5600 Fishers Lane, Rockville, MD 20852-9787
Faxing the form to 1-800-FDA-0178
By phone at 1-800-332-1088
EDITOR’S NOTE: In January 2008 the Public Citizen Health Research Group presented a citizens petition led by Elizabeth Barbehenn, Ph.D. Peter Lurie, M.D., M.P.H. Shiloh Stark, B.A. Sidney Wolfe, M.D. that requested the Food and Drug Administration (FDA or Agency) immediately to require the Biologics License Application (BLA) holders of all formulations of botulinum toxin to issue a ‘Dear Health Care Professional’ (DHCP) letter to “alert physicians to serious problems, including hospitalizations and deaths, resulting from the spread ofthe toxin from the site of injection to other parts ofthe body” (Petition at 1).
The Petition also requested that FDA require BLA holders of botulinum toxin products to provide “additional warnings in the form of a black box” to product labeling regarding the risk of distant spread of the toxin effects from the site of injection and provide an FDA-approved Medication Guide for patients, to be dispensed by physicians at the time of injection. The request was based on rates of dysphagia and muscle weakness in preapproval clinical trials and postmarketing adverse event reports of dysphagia, aspiration, and/or pneumonia.
In April 2009 the Department of Health and Human Services Food and Drug Administration in Rockville MD 20857, replied. To read the full text log on to:
The FDA reply includes the following information:
Spread of Botulinum Toxin Effects
Botulism is a serious bacterial toxin-mediated neuroparalytic illness whose onset is typically marked by cranial nerve dysfunction (resulting in double vision (diplopia), inability to control or coordinate the muscles used in speaking (dysarthria), and/or difficulty swallowing (dysphagia)), followed by progressive descending muscle weakness or paralysis that can lead to respiratory failure and death.6 Thebotulism syndromes may result from absorption of botulinum toxin through a mucosal membrane (intestine or lungs) or from a wound.7 The clinical use of licensed botulinum toxin products presents the potential for iatrogenic botulism, which may be described as the appearance of one or more clinical manifestations of botulism that has the potential to be clinically serious.8
Local extension of effect of the botulinum toxin to anatomical structures (nerves and muscles) adjacent (contiguous) to the site of injection may occur and is described in product labeling.9 For example, dysphagia (difficulty swallowing) is described in product labeling as a “commonly reported adverse event following treatment with all botulinum toxins in cervical dystonia patients.”l0 However, dysphagia may also be a sign of distant spread of botulinum toxin effects when the botulinum toxin is administered at a site other than the neck.
Details of references can be found on the website link.
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