Research opens up questions about Botulinumtoxin A

Adverse reactions to botulinum toxin (Botox®, Dysport®, Vistabel®, Neurobloc®)

In a new study in rats, scientists from the Italian Instituto di Neuroscienze in Pisa have discovered that Botulinumtoxin A injected into the jaw muscle of rats had found its way to the rats' brains three days after and that it was still present in the rats’ brains after six months. In cooperation with the European Medicines Agency, (EMEA), the Danish Medicines Agency intends to investigate this further.

In Denmark, the most frequently used products are Botox®, Dysport® and Xeomin®.

Number of packs sold in Denmark in the period 2002–2008, distributed on Botox®, Dysport® and Xeomin®

The sales figures do not indicate what the products have actually been used for. In particular, there is great uncertainty about the products' extent of use in cosmetic treatments.

Spectrum of usage of medicinal products containing botulinum toxin
Medicinal products that contain botulinum toxin are primarily licensed for the treatment of abnormal muscle contraction (dystonia, spasticity) in different regions of the body, e.g. the head and neck region. By injecting botulinum toxin into the muscle, the muscle is relaxed. The effect lasts for a certain period of time (and reverses), and the treatment must be repeated regularly.

Another licensed indication is unwanted excessive sweating (axillary hyperhidrosis). Finally, one single product, Vistabel®, is licensed for the treatment of wrinkles between the brows. Otherwise, no other botulinum toxin-containing medicinal products are licensed for cosmetic treatments. However, several of them are used off label to treat cosmetic indications.

Assessment of adverse reactions
The assessment of adverse reactions covers the aggregate international experience from the four products marketed in the EU, with special focus on adverse reactions arising as a result of unintended spread of toxin to adjacent tissue. Adverse reactions of this type are estimated to appear in less than ten out of 10,000 treated patients (<10/10.000). In other words, such adverse reactions are very rare.

Distant spread of botulinum toxin may lead to muscle weakness and paralysis of one or several muscle groups other than the target muscle group. In case of spread to the neck muscles, the patient may experience difficulties in speaking and swallowing. In the worst case, difficulties in swallowing (dysphagia) increases the risk of food entering the respiratory tract and lungs. This is a serious complication in that aspiration may cause acute respiratory distress and pneumonia. Worldwide, several deaths are caused by respiratory complications.

Worldwide, deaths have been recorded in connection with treatment with botulinum toxin. However, it must be emphasised that in the majority of these deaths there were significant contributing factors that may explain the fatal outcome. For example, several of the patients suffered from a serious neurological disorder and had previously experienced episodes of dysphagia and aspiration. In Denmark, there has been one recorded death related to a patient suffering from a known mental disorder requiring treatment.

The muscle weakness may be explicit and long-lasting and could impact the mobility of the patient. Also, it should be emphasised that particularly children, elderly weakened patients as well as patients suffering from a serious neurological disorder are at an increased risk of experiencing serious adverse reactions. Furthermore, there is an increased risk of distant toxin spread if the dose given is too high and if the recommended injection technique is not followed.

Serious adverse reactions arising from the distant spread of toxin have in particular been seen in chronically ill patients suffering dystonia and spasticity. The most frequent adverse reaction is dysphagia. However, we must also emphasise that serious adverse reactions arising from spread of toxin have also been seen in connection with the treatment of hyperhidrosis and in connection with cosmetic treatments.

There are no known Danish incidents of serious adverse reactions related to cosmetic uses. However, it should be borne in mind that adverse reactions are substantially under-reported in general.

Since 1993, the Danish Medicines Agency has received a total of 23 adverse reactions reports of which 11 describe adverse reactions that may be caused by spread of toxin (five women, five men, one non-disclosed gender; aged between 9 and 63): These adverse reactions appear from the table below:

1 presumed indication as the route of administration is infravesical
2 route of administration intradermal; hyperhidrosis?
3 cervical dystonia: Tensed neck muscles

Next steps
The monitoring of adverse reactions continues according to routine. Companies marketing products containing botulinum toxin must continuously report any observed adverse reactions to the authorities.

The Danish Medicines Agency advises patients and doctors to report adverse reactions – even a suspicion is enough to file a report.

For further information, please contact Chief Medical Officer Doris Irene Stenver, tel. +45 4488 9247.

Danish Medicines Agency, 7 May 2009 (last updated 30 July 2009)