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

Follow-up on announcement of 7 August 2007.

In cooperation with the European Pharmacovigilance Working Party, the Danish Medicines Agency has studied adverse reactions to medicinal products containing Clostridium botulinum toxin (A and B). Four products are marketed in the EU: Botox®, Dysport®, Vistabel® and Neurobloc®. The most frequently used products in EU are Botox® and Vistabel®; in Denmark Botox® and Dysport®. Consumption is increasing, cf. the table below.

Number of packs of Botox® and Dysport®, respectively, sold in Denmark in the period 2002-2006

It is not possible to tell from the sales figures what the medicinal products have been used for. In particular, it is highly uncertain to what extent the medicinal products are used 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. However, no other medicinal products containing botulinum toxin are licensed for cosmetic treatments. However, several of them are used for off label cosmetic indications.

Assessment of adverse reactions

The assessment of adverse reactions cover the total 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. Since the entry of the product on the market, more than 600 reports of this type have been registered. Approx. half of all serious adverse reactions were caused by spread of toxin. 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, there are several examples of deaths arising from respiratory complications.

On a global basis, a total of 28 deaths have been recorded in connection with treatment with botulinum toxin. 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.

In Denmark, the Danish Medicines Agency has received nine reports about adverse reactions as a result of spread of toxin (four women, four men, one non-disclosed gender; aged between 36 and 63):

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

Next steps

As it appears from our announcement dated 7 August 2007, a letter was recently sent to doctors using medicinal products containing botulinum toxin, i.e. doctors specialised in skin disorders, neurological disorders, eye diseases and plastic surgery.

The monitoring of adverse reactions continues according to routine. Companies marketing products containing botulinum toxin must currently 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, Consumer Safety Division, telephone +45 44 88 92 47.

The Danish Medicines Agency, 9 August 2007