General

There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility or anaphylaxis, after treatment with botulinum toxin.

There have also been rare reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease. The exact relationship of these events to the botulinum toxin injection has not been established.

The following events have been reported since the drug has been marketed and a causal relationship to the botulinum toxin injected is unknown: skin rash (including erythema multiforme, urticaria and psoriasiform eruption), pruritus, and allergic reaction.

In general, adverse events occur within the first week following injection of BOTOX® and while generally transient may have a duration of several months. Localized pain, tenderness and/or bruising may be associated with the injection. Local weakness of the injected muscle(s) represents the expected pharmacological action of botulinum toxin. However, weakness of adjacent muscles may also occur due to spread of toxin.

Cervical Dystonia

In cervical dystonia patients evaluated for safety in double-blind and open-label studies following injection of BOTOX®, the most frequently reported adverse reactions were dysphagia (19%), upper respiratory infection (12%), neck pain (11%), and headache (11%).7

Other events reported in 2-10% of patients in any one study in decreasing order of incidence include: increased cough, flu syndrome, back pain, rhinitis, dizziness, hypertonia, soreness at injection site, asthenia, oral dryness, speech disorder, fever, nausea, and drowsiness. Stiffness, numbness, diplopia, ptosis, and dyspnea have been reported rarely.

Dysphagia and symptomatic general weakness may be attributable to an extension of the pharmacology of BOTOX® resulting from the spread of the toxin outside the injected muscles.

The most common severe adverse event associated with the use of BOTOX® injection in patients with cervical dystonia is dysphagia with about 20% of these cases also reporting dyspnea. (See Warnings). Most dysphagia is reported as mild or moderate in severity. However, it may rarely be associated with more severe signs and symptoms (See Warnings).

Additionally, reports in the literature include a case of a female patient who developed brachial plexopathy two days after injection of 120 Units of BOTOX® for the treatment of cervical dystonia, and reports of dysphonia in patients who have been treated for cervical dystonia.

Primary Axillary Hyperhidrosis

The most frequently reported adverse events (3 - 10% of patients) following injection of BOTOX® in double-blind studies included injection site pain and hemorrhage, non-axillary sweating, infection, pharyngitis, flu syndrome, headache, fever, neck or back pain, pruritus, and anxiety.

The data reflect 346 patients exposed to BOTOX® 50 Units and 110 patients exposed to BOTOX® 75 Units in each axilla.

Because clinical trials are conducted under widely varying conditions, adverse events observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not be predictive of rates observed in practice.

Blepharospasm

In a study of blepharospasm patients who received an average dose per eye of 33 Units (injected at 3 to 5 sites) of the currently manufactured BOTOX®, the most frequently reported treatment-related adverse reactions were ptosis (20.8%), superficial punctate keratitis (6.3%) and eye dryness (6.3%).8

In this study, the rate for ptosis in the current BOTOX® treated group (20.8% of patients) was significantly higher than the original BOTOX® treated group (4.0% of patients) (p=0.014%). All of these events were mild or moderate except for one case of ptosis which was rated severe.

Other events reported in prior clinical studies in decreasing order of incidence include: irritation, tearing, lagophthalmos, photophobia, ectropion, keratitis, diplopia and entropion, diffuse skin rash and local swelling of the eyelid skin lasting for several days following eyelid injection.

In two cases of VII nerve disorder (one case of an aphakic eye), reduced blinking from BOTOX® injection of the orbicularis muscle led to serious corneal exposure, persistent epithelial defect, and corneal ulceration. Perforation occurred in the aphakic eye and required corneal grafting.

A report of acute angle closure glaucoma one day after receiving an injection of botulinum toxin for blepharospasm was received, with recovery four months later after laser iridotomy and trabeculectomy. Focal facial paralysis, syncope and exacerbation of myasthenia gravis have also been reported after treatment of blepharospasm.

REFERENCE

7. Data on file, Allergan, Inc. 1999.

8. Data on file, Allergan, Inc. Arandomized, multicenter, double-blind, parallel clinical trial to compare the safety and efficacy of BOTOX® (botulinum toxin type A) purified neurotoxin complex manufactured from neurotoxin complex batch BCB2024 to that manufactured from neurotoxin complex batch 79-11 in blepharospasm patients. 1997.