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. The exact
relationship of these events to the botulinum toxin injection has not been established. The following events have been reported with other botulinum toxin injection 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 the drug and while generally transient may have duration of several months. Local pain, tenderness and/or bruising, traction, swelling, hot feeling or hypertonia at injection site or adjacent muscles 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. When injected in patients with blepharospasm or cervical dystonia, some distant muscles from injection site can show increased electrophysiologic jitter (rapid variation in a waveform) which is not associated with clinical weakness or other types of electrophysiologic
Extraocular muscles adjacent to the injection site can be affected, causing ptosis or vertical deviations, especially with higher doses of the drug. The incidence rates of these adverse effects with other botulinum toxin injections were as follows; in 2058 adults who received a total of 3650 injections for horizontal strabismus, ptosis were observed in 15.7% of the patients and vertical deviations were in 16.9%. Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision, or past pointing. Covering the affected eye may alleviate these syndromes. 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 5587 injections of horizontal muscles in 3104 patients with other botulinum toxin injection. 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. Five eyes had pupillary change consistent with ciliary ganglion damage (Adies pupil). One patient developed anterior segment ischemia after receiving other botulinum toxin injection into the medial rectus muscle under treatment for esotropia.
In a study of blepharospasm patients who received an average dose per eye of 33 U (injected at 3-5 sites) of other botulinum toxin injections, the most frequently reported treatment-related adverse reactions were ptosis (20.8%), superficial punctuate keratitis (6.3%) and eye dryness (6.3%). All of these events were mild to moderate except of one case of ptosis which was rated severe.
Other events reported in prior clinical studies with other botulinum toxin injections in decreasing order of incidence include:
Irritation, tearing, iagophthalmos, 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 other botulinum toxin injections 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.
Frequently, anopia or conjunctivitis has been reported, which required appropriated measures be taken. In 660 patients with other botulinum toxin injections (for 6 years in Korea), a total of 41 patients (6.2%) showed adverse reactions. Adverse reactions included ptosis in 17 patients (2.6%), local swelling in 5 (0.8%), lacrimal disorders in 3 (0.5%), bulbar irritation in 3 (0.5%), logophthalmos in 3 (0.5%), muscle weakness in 3 (0.5%), eye dryness in 3. Adverse reactions obscure in causality included traction at injection site in 2 patient (0.3%), hypertonia in 2 (0.3%), conjunctival congestion in 2 (0.3%), and eye pain in 1 (0.2%).
The most frequently reported adverse events with other botulinum toxin injections in the treatment of spasmodic torticollis included pain and soreness at injection sites, local weakness, symptomatic general weakness and fatigue. However, fatigue was also reported in patients treated with placebo.
Dysphagia and local weakness may be attributable to an extension of the pharmacology of botulinum toxin resulting from the spread of the toxin from injected muscles. Since the adverse reactions associated with dosage are more frequently observed in female patients, muscle mass should be taken into consideration when selecting the appropriate dose.
Other adverse events include: Nausea, dizziness, headache, numbness, stiffness, and bruising.
Pediatric Cerebral Palsy:
Safety of Botox for the treatment of dynamic equinus foot deformity due to spasticity in pediatric cerebral palsy patients was performed.
As is expected for any intramuscular injection procedure, localized pain was associated with the injection in the patients. All treatment-related adverse events were mild-to moderate in severity. The adverse reactions most
frequently reported as related to treatment include recession, leg pain, leg (local) weakness, and general weakness. The percentage of patients who experienced these events at least once during the study are summarized in Table 2. (See Table 2.)
Click on icon to see table/diagram/image
Recession may be attributable to a change in ankle position and gait pattern and/or local weakness. Local weakness represents the expected pharmacological action of botulinum toxin. Other treatment-related adverse reactions reported in 1% of patients were: Leg cramps, fever, knee pain, ankle pain, pain at the injection site post-treatment, and lethargy.
In Korean clinical studies in subjects with moderate to severe glabellar lines and 18 years of age and ≤65 years of age, adverse reactions were observed in 28.4% of subjects who received this product. Most adverse reactions were mild to moderate and no serious adverse reaction was reported during the clinical studies. The most frequently reported adverse reactions include infections and infestations in 10 subjects (7.5%), eye disorders in 10 (7.5%), general disorders and administration site condition in 6 (4.5%), and skin and subcutaneous tissue disorders in 6 (4.5%). Adverse reactions for which causal relationship with this drug product could not be eliminated include injection site reaction in 4 subjects (3.0%) and eyelid ptosis in 6 (4.5%).