BehindTheMedspeak: Death by Botox

Last Wednesday, January 23, 2008, Public Citizen petitioned the FDA to add a "Black Box" warning — its strongest — to Botox and Myobloc.

The request was supported by extensive documentation, including the graphic up top; excerpts follow.

Petition to the FDA requesting regulatory action concerning the possible spread of botulinum toxin (Botox, Myobloc) from the site of injection to other parts of the body

This letter would alert physicians to serious problems, including hospitalizations and deaths, resulting from the spread of the toxin from the site of injection to other parts of the body.

The European Union (EU) has posted a series of warnings concerning botulinum toxin on its web site, the latest in March 2007, alerting physicians in its 27 member states about the need to monitor for signs of botulinum toxin adverse events. The U.K. and Germany amplified the EU warning with “Dear Doctor Letters,” but no similar official warnings have been forthcoming from the FDA.

The spread of toxin has been implicated in serious adverse events including muscle weakness, dysphagia (difficulty swallowing), and aspiration pneumonia, the latter sometimes resulting in death. Public Citizen has done its own analysis of the FDA Adverse Event database (AERS) for Botox and Myobloc (excluding foreign reports) and found 180 adverse event cases submitted by drug manufacturers relating to these conditions, including 16 deaths. Four of these deaths occurred in children less than 18 years of age.


Description, indications, and mechanism of action

Botulinum toxins are proteins produced by a bacterium, Clostridium botulinum. Botulinum toxin acts by blocking the transmission of nerve impulses to muscles, causing those muscles to relax and resulting in a loss of muscle control. In the case of food poisoning from botulinum toxin, in which the toxin spreads widely around the body, early symptoms include dry mouth, difficulty swallowing, slurred speech, drooping eyelids, and muscle weakness. Subsequent paralysis of respiratory muscles can lead to death.

In the case of injected therapeutic or cosmetic use of botulinum toxin, if the product spreads from the injection site to another area of the body, this loss of muscle control can be similarly harmful. For example, when muscle control to the esophagus is lost, one loses the ability to control swallowing; food and drink can then accidentally reflux and be aspirated into the respiratory tract and lungs, causing a serious complication, aspiration pneumonia, and occasionally lead to death.

Botox has one approved cosmetic use (Myobloc has none) and that is for temporary improvement of glabellar lines (wrinkles between the eyebrows). Most cosmetic use of botulinum toxin is unapproved by the FDA and is therefore considered off-label.


Chronology of European cautions

March 2005: Of 552 total reported adverse event cases, 165 (30%) were serious and 66 (12% of the total) were serious cases with possible systemic effects, i.e., the toxin had moved from the injection site to other areas of the body producing dry mouth, dysphagia, and/or blurred vision.

November 2005: Of the cumulative 693 total adverse event cases, there were 17 deaths with 6 (35%) of these due to aspiration pneumonia.


Public Citizen analysis of adverse events

We found 658 cases of adverse events..., of which 180 (27%) were associated with aspiration, dysphagia, or pneumonia. Of these 180, 106 had an indication listed: 18 cosmetic only and 87 non-cosmetic only. Eighty-seven of the cases... were hospitalized and 16 died (including 4 children less than 18 years of age).

It should be noted that these data come from voluntary reports submitted to the FDA which have been estimated to represent approximately 10% of the actual occurrences.

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I find it surprising that, apart from five sentences in the January 25, 2008 Washington Post and four in the Wall Street Journal about this development, nothing more has appeared in the news about it.