General: There have been rare spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility oranaphylaxis, 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 products 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 nay have a 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 electrophysiological normalitics.
Strabismus: Extraocular muscle near the injection site can be affected causing eyelid drooping or vertical deviation, especially when a high dose is administered. The incidence rate of adverse events when 2,058 adult patients were treated with other botulinum toxin product for horizontal strabismus with 3,650 injections is as follows: Eyelid drooping: 15.7%; vertical deviation: 16.9%.
Spatial disorientation, double field of vision, and past-pointing can be developed by inducing paralysis in one or more of extraocular muscles. These symptoms can be reduced by covering up the affected eye. The incidence rate of eyelid ptosis was 0.9% for inferior rectus injection and 37.7% for superior recurs. The incidence rate of adverse menu that lasted for 6 months after 3.104 patients received series of 5,587 injections in the horizontal muscle is as follows: Eyelid drooping: 0.3%; vertical deviation of greater than 2 prism diopters: 2.1%.
From those patients, 9 cases developed sclera perforation due to the injection process itself. One case developed vitreous hemorrhage but improved afterward. There were no cases of retinal detachment or loss of vision. There were 16 cases of retrobulbar hemorrhage. After 5 minutes, the eye socket was decompressed in order to recover the retinal circulation. There was no loss of vision due to posterior eyelid hemorrhage. A pupil change that comes with ciliary ganglion damage occurred in 5 cases. There was reported a case of anterior segment ischemia after administering other botulinum toxin product in the medical rectus muscle 4 to treat estropia (Adies pupil).
Blepharospasm: In a study of blepharospasm patients who received an avenge dose per eye of 33 U (injected at 3 to 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 for 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. 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 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.
In a study of blepharospasm patients with other botulinum toxin product. one case of acute closed angle glaucoma has been reported one day after the injection. The patient was treated with laser itidotomy and trabeculetomy and recovered in four months. After a treatment for blepharospasm, worsening myasthenia, local facial paralysis, and fainting cases were reported. In case of cloudy vision and conjunctivitis, appropriate treatment should be initiated. Through the post marketing surveillance study of other botulinum toxin products for the last 6 years, 41 cases (6.2%) of adverse events were reported out of 660 total cases. Major adverse events were 17 cases of ptosis (2.6%), 5 cases of local swelling (0.8%), 3 cases of illacrimation (0.5%). 3 can of eye irritation (0.5%), 3 cases of lagophthalmos (0.5%), 3 cases of muscle weakness (0.5%), and 3 cases of ophthalmoxerosis (0.5%). The following are adverse events have been reported, 2 cases of pulling at the injection site (0.3%). 2 cases of conjunctival hyperaemia (0.3%), 2 cases of hypertonia (0.3%), and lease of ophthalmalgia (0.2%).
Cervical Dystonia: The most common adverse events associated with spasmodic torticollis in other botulinum toxin product are as follows: Dysphasia, soreness at injection site, localized lassitude and symptomatic, systemic lassitude and malaise. However, malaise was also reported in patients with placebo. Dysphasia 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. These dose-related adverse events are more common among women. Therefore, the dose must be adjusted appropriately as the muscle size is smaller. Other adverse events are reported nausea, drowsiness, headache, numbness, spasticity, and bruising.
Pediatric cerebral palsy: Safety of NEURONOX for the treatment of equinus foot deformity due to spasticity in pediatric cerebral palsy patients was evaluated in a clinical trial in Korea. In this clinical trial, 60 patients who injected NEURONOX showed common adverse reactions (>1%) such as nasopharyngitis (5%), upper respiratory tract infection (1.67%), pyrexia (3.3%), gait disturbance (1.67%), pain in extremity (1.67%), musculoskeletal and connective tissue disorders (1.67%), febrile convulsion (1.67%), constipation (1.67%), and lower limb fracture (1.67%). Additionally the common adverse reactions (> I%) which are shown from 59 patients who injected the control medicine at the comparison clinical trials are as follows; nasopharyngitis (5.08%), haemophilia infection (1.69%), pneumonia (1.69%), pyrexa (5.08%), asthenia (1.69%), joint contracture(1.69%), muscular weakness (1.69%), unequal limb length (1.69%), conjunctivitis (1.69%), headache (1.69%), and anaemia (1.69%). These kinds of adverse reactions may be occurred depending on the patients characteristics. In the literatures about other botulinum toxin products, similar adverse reactions which are related to the use of botulinum toxin are mentioned such as respiratory infection, brochitis, nasopharyngitis, asthma, muscular weakness, urinary incontinence, falling down, convulsion, pyrexia, pain and others.
Glabellar Wrinkles: In multicenter, double-blind, active-controlled, parallel study of the same protocol, the efficacy and safety for those patients, who are in the age 18 to 65 years old with serious glabellar wrinkles were evaluated (n=313, NEURONOX treatment group 156 patients, BOTOX placebo group 157 patients). Adverse events were reported from 26.92% of the treatment group and 22.29% of the control group. Most frequently reported adverse events associated with the treatment were eyelid drooping from 3.21% of the treatment group (5/156) and 1.91% of the control group (3/157). The 8 cases of eyelid drooping reported in both groups were all mild and temporary. To list the adverse events reported in more than 1% of NEURONOX treatment group in the order of highest to lowest incidence frequency, it is as follows: nasopharyngitis (4.49%), eyelid drooping (3.21%), headache (1.92%), hyperglycemia (1.28%), and articulation sprain (1.28%), pyuria (1.28%), eyelids disease (1.28%). Most of reported adverse events were mild to moderate and temporary.
Muscle Spasticity: The use of NEURONOX in treatment for 196 patients (NEURONOX group: 98 patients, BOTOX group: 98 patients) with upper extremity spasticity related to stroke was evaluated for safety. In general, most of the reported adverse events were mild or moderate. The adverse events in the clinical trial were reported total 174 cases and were reported in 39 of 98 patents of treatment group (39.80%, 93 cases) and 41 of 98
patients of control group (41.84%, 87 cases). The adverse events reported by ≥2% of NEURONOX treated patients are listed in the order of frequency: nasopharyngitis (4.08%), pain in extremity (4.08%), cough (4.08%), diarrhea (3.06%), vomiting (3.06%), backache (3.06%), peripheral edema (3.06%), abdominal distension (2.04%), dyspepsia (2.04%), nausea (2.04%), Upper Respiratory Tract Infections (214%), musculoskeletal pain (2.04%), hematoma of injection site (2.04%), pyrexia (2.04%), acute cholecystitis (2.04%). Most of reported adverse events were mild to moderate and temporary.
Post-Marketing Experience: There have been the post marketing surveillance and phase IV trials in 641 patients with Benign Essential Blepharospasm for 6 years in Korea. It has been reported that rate of adverse reaction was 12.5% (80/541, 116 cases), in which 7.8% (50/641 57 cases) cases could not be excluded by causality with the drug and ptosis was reported 3.9% (25 cases, 25 of 641 patients). Other treatment-related adverse events reported by ≤ 1% were as follows: facial swelling (6 cases). ocular abnormality (4 cases), rash (3 cases), itching, paresthesia, lid leg, abnormal tear secretion, ophthalmalgia (2 cases), corneal ulcer, diplopia, arrhythmia, periorbital swelling, oculomotor nerve palsy, headache, paralysis, dizziness, and purpura (I case). The rate of serious adverse events was reported 3 of 641 patients (0.5%, 5 cases): spinal stenosis (2 cases), melosalgia (1 case), myocardial infarction case), and arrhythmia (1 case).
Unexpected adverse drug reactions were reported in 11 of 641 patients (1.7%), but there was no unexpected serious adverse event among them. The unexpected and non serious adverse drug reactions were reported as follows: facial swelling (6 cases), ocular abnormality (2 cases), headache, paresthesia. dizziness (1 case).
In PMS (Post Marketing Surveillance) study in 210 patients with equinus foot deformity due to cerebral palsy in Korea, it has been reported that the rate of adverse event was 21.4% (45/210, 84 cases). Among them, the rate of adverse drug reaction which could not be excluded by causality was 1.4% (3/210 patients, 3 cases) and the rate of inflammation of injection site was 1% (2/210 patients, 2 cases). Another adverse drug reaction, myalgia was reported ≤ 1%. The rate of serious adverse event was reported 14% (3/210 patients, 3 cases) by 2 cases of pneumonia and 1 case of urinary tract infection. However, there was no reported unexpected serious adverse event among them.