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.
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.
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.
Extraocular muscles adjacent to the injection site can be affected, causing ptosis or vertical deviation, especially with higher doses of BOTOX®. The incidence rates of these adverse effects in 2058 adults who received a total of 3650 injections for horizontal strabismus are 15.7% and 16.9%, respectively. 4
Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision, or past-pointing. Covering the affected eye may alleviate these symptoms.
The incidence of ptosis was 0.9% after inferior rectus injection and 37.7% after superior rectus injection.
Ptosis (0.3%) and vertical deviation greater than two prism diopters (2.1%) were reported to persist for over six months in a larger series of 5587 injections of horizontal muscles in 3104 patients.
In these patients, the injection procedure itself caused nine scleral perforations. A vitreous hemorrhage occurred in one case and later cleared. No retinal detachment or visual loss occurred in any case. Sixteen retrobulbar hemorrhages occurred without visual loss. Decompression of the orbit after five minutes was done to restore retinal circulation in one case. Five eyes had pupillary change consistent with ciliary ganglion damage (Adie's pupil).
One patient developed anterior segment ischemia after receiving BOTOX® injection into the medial rectus muscle under direct visualization for esotropia.
Formation of neutralizing antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX® treatment by inactivating the biological activity of the toxin. The rate of formation of neutralizing antibodies in patients receiving BOTOX® has not been well studied.
In the phase 3 cervical dystonia study1 that enrolled only patients with a history of receiving BOTOX® for multiple treatment sessions, at study entry there were 192 patients with antibody assay results, of whom 33 (17%) had a positive assay for neutralizing activity. There were 96 patients in the randomized period of the phase 3 study with valid assays at both study entry and end and who were neutralizing activity negative at entry. Of these 96, 2 patients (2%) converted to positive for neutralizing activity. Both of these converting patients were among the 52 who had received two BOTOX® treatments between the two assays; none were in the group randomized to placebo in the controlled comparison period of the study.
In the randomized period of the cervical dystonia study, patients in the BOTOX® group whose baseline assays were neutralizing antibody negative showed improvements on CDSS (n=64, mean CDSS change -2.1) while patients whose baseline assays were neutralizing antibody positive did not (n=14, mean CDSS change +1.1).
However, in uncontrolled studies there are also individual patients who are perceived as continuing to respond to treatments despite the presence of neutralizing activity. Not all patients who become non-responsive to BOTOX® after an initial period of clinical response have demonstrable levels of neutralizing activity.
One patient among the 445 hyperhidrosis patients with analyzed specimens showed the presence of neutralizing antibodies.
The data reflect the patients whose test results were considered positive or negative for neutralizing activity to BOTOX® in a mouse protection assay. The results of these tests are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample handling, concomitant medications and underlying disease. For these reasons, comparison of the incidence of neutralizing activity to BOTOX® with the incidence reported to other products may be misleading.
The critical factors for neutralizing antibody formation have not been well characterized. The results from some studies suggest that BOTOX® injections at more frequent intervals or at higher doses may lead to greater incidence of antibody formation. The potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections.