Botox Special Precautions

General: Use BOTOX only as directed.
Do not use dosage recommendations and potency Units applied to other botulinum toxin products when using BOTOX.
The safe and effective use of BOTOX (Botulinum Toxin type A) depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques.
The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering BOTOX and care should be taken when injecting in or near vulnerable anatomic structures. Serious adverse events including fatal outcomes have been reported in patients who had received BOTOX injected directly into salivary glands, the oro-lingual-pharyngeal region, esophagus and stomach. Some patients had pre-existing dysphagia or significant debility. Pneumothorax associated with injection procedure has been reported following the administration of BOTOX near the thorax. Caution is warranted when injecting in proximity to the lung, particularly the apices. An understanding of standard electromyographic techniques is also required for treatment of strabismus, and may be useful for the treatment of cervical dystonia, and focal spasticity associated with paediatric cerebral palsy and spasticity.
Caution should be exercised when BOTOX is used in the presence of inflammation at the proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle. Muscle weakness remote to the site of injection and other serious adverse effects (e.g. dysphagia, aspiration pneumonia) have been rarely reported in both paediatric and adult patients, in some cases associated with a fatal outcome.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
Patients with a history of underlying neurological disorders, dysphagia and/or aspiration should be treated with extreme caution. The botulinum toxin product should be used under specialist supervision in these patients and should only be used if the benefit of treatment is considered to outweigh the risk.
Injection specific dosage and administration recommendations should be followed. In treating adult patients, including when combining indications, the maximum cumulative dose should generally not exceed 400 U, up to a maximum of 6 U/kg, in a 3 month interval. In treating paediatric patients, the maximum cumulative dose should generally not exceed 4 U/kg, up to a maximum of 200 U, in a 3 month interval.
One unit (U) of BOTOX corresponds to the calculated median intraperitoneal lethal dose (LD₅₀) in mice. The method utilized for performing the assay is specific to Allergan's product, BOTOX. Due to specific details of this assay such as the vehicle, dilution scheme and laboratory protocols for the various mouse LD₅₀ assays, Units of biological activity of BOTOX cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method. Therefore, differences in species sensitivities to different botulinum neurotoxin serotypes precludes extrapolation of animal-dose activity relationships to human dose estimates. The specific activity of BOTOX is approximately 20U/nanogram of neurotoxin protein complex.
As is expected for any injection procedure, localized pain, inflammation, paresthesia, hypoaesthesia, tenderness, swelling/edema, erythema, localized infection, bleeding and/or bruising have been associated with the injection. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope.
Human Albumin: This product contains human serum albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
Dynamic equinus foot deformity due to spasticity in paediatric cerebral palsy BOTOX is a treatment of spasticity that has only been studied in association with usual standard of care regimens, and is not intended as a replacement for these modalities. BOTOX is not likely to be effective in improving range of motion at a joint affected by a fixed contracture.
Cardiovascular System: There have been reports following administration of botulinum toxin of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including pre-existing cardiovascular disease. The exact relationship of these events to BOTOX is unknown.
Immunogenicity: 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 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. When appropriate, the potential for antibody formation may be minimized by injecting with the lowest effective dose given at the longest feasible intervals between injections.
As with all biologic products, an anaphylactic reaction may occur. Necessary precautions should be taken and epinephrine should be available.
Hypersensitivity Reactions: Serious and/or immediate hypersensitivity reactions such as anaphylactic and serum sickness have been rarely reported, as well as other manifestations of hypersensitivity including urticaria, soft tissue edema, and dyspnea. Some of these reactions have been reported following the use of BOTOX either alone or in conjunction with other products associated with similar reactions. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent for BOTOX and consequently the causal agent cannot be reliably determined. If such a reaction occurs, further injection should be discontinued and appropriate medical therapy immediately instituted.
Pre-Existing Neurologic Disorders: Extreme caution should be exercised when administering BOTOX to individuals with peripheral motor neuropathic (e.g. amyotrophic lateral sclerosis, or motor neuropathy) or neuromuscular junction disorders (e.g. myasthenia gravis or Lambert-Eaton syndrome). Patients with neuromuscular junction disorders may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of BOTOX. There have been rare cases of administration of botulinum toxin to patients with known or unrecognized neuromuscular junction disorders where the patients have shown extreme sensitivity to the systemic effects of typical clinical doses. In some of these cases, dysphagia has lasted several months and required placement of gastric feeding tube.
When exposed to very high doses, patients with neurologic disorders, e.g. paediatric cerebral palsy or adult spasticity, may also be at increased risk of clinically significant systemic effects.
Seizures: New onset or recurrent seizures have been reported, typically in patients who are predisposed to experiencing these events. The reports in children were reports predominantly from cerebral palsy patients treated for spasticity. The exact relationship of these events to the botulinum toxin injection has not been established.
Bladder Dysfunction: Appropriate medical caution should be exercised for performing a cystoscopy.
In patients who are not catheterizing, post-void residual urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks. Patients should be instructed to contact their physician if they experience difficulties in voiding as catheterization may be required.
Due to the risk of urinary retention, only patients who are willing and/or able to initiate catheterization post-treatment, if required, should be considered for treatment.
For the management of urinary incontinence, BOTOX should be administered by physicians who are experienced in the assessment and treatment of bladder dysfunction (eg, urologists and urogynaecologists).
Overactive Bladder: Urinary Retention: In double-blind, placebo-controlled trials in patients with OAB, the proportion of subjects who initiated clean intermittent catheterisation (CIC) for urinary retention following treatment with BOTOX or placebo is shown in the Table as follows. The duration of post-injection catheterisation for those who developed urinary retention is also shown. (See Table 19.)

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Patients with diabetes mellitus treated with BOTOX were more likely to develop urinary retention than those without diabetes, as shown in the Table as follows. (See Table 20.)

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Urinary Tract Infection: BOTOX increases the incidence of urinary tract infection (see Adverse Reactions). Clinical trials for overactive bladder excluded patients with more than 2 UTIs in the past 6 months and those taking antibiotics chronically due to recurrent UTIs. Use of BOTOX for the treatment of overactive bladder in such patients and in patients with multiple recurrent UTIs during treatment should only be considered when the benefit is likely to outweigh the potential risk.
Use in Males: The pivotal studies in overactive bladder were not powered for a subgroup analysis based on gender, however a statistically significant treatment-by-gender interaction was demonstrated. No statistically significant benefit was demonstrated in males for incontinence frequency or on the Treatment Benefit Scale (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions). In men, 12.2% of the overall study population, mean incontinence was decreased by 0.42 episodes per day (by LS mean difference) relative to placebo (p=0.612) from a baseline of 5.6 episodes per day, whereas in women it was reduced by 2.0 episodes (p<0.001). The proportion of men who felt that treatment had led to improvement on the Treatment Benefit Scale was ~40% (p=0.060), with the attributable proportion being 15% (after subtracting the placebo response of 25%). Approximately 60% of men given BOTOX for overactive bladder felt that their condition was unchanged or worsened after treatment. Men considering BOTOX for overactive bladder should be made aware of the gender specific results, including potential risk of urinary tract infections (BOTOX 9.5% vs placebo 2.6%) and urinary retention (BOTOX 7.9% vs placebo 1.3%).
Neurogenic Detrusor Overactivity: In these patients, autonomic dysreflexia associated with the procedure could occur, which may require prompt medical therapy.
Patients with spinal cord injury above T1 were excluded from BOTOX clinical trials.
Other Warnings: Blepharospasm/Hemifacial Spasm: Reduced blinking following BOTOX injection into the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. One case of corneal perforation in an aphakic eye requiring corneal grafting has occurred because of this effect. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means.
Because of the anticholinergic activity of botulinum toxin, caution should be exercised when treating patients at risk for angle closure glaucoma, including patients with anatomically narrow angles. Acute angle closure glaucoma has been reported very rarely following periorbital injections of botulinum toxin.
Strabismus: BOTOX is ineffective in chronic paralytic strabismus except to reduce antagonist contracture in conjunction with surgical repair. The efficacy of BOTOX in deviations over 50 prism diopters, in restrictive strabismus, in Duane's syndrome with lateral rectus weakness, and in secondary strabismus caused by prior surgical over-recession of the antagonist is doubtful. In order to enhance efficacy, multiple injections over time may be required.
During the administration of BOTOX for the treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred from needle penetrations into the orbit. It is recommended that appropriate instruments to decompress the orbit be accessible. Ocular (globe) penetrations by needles have also occurred. An ophthalmoscope to diagnose this condition should be available.
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.
Cervical Dystonia: Dysphagia is a commonly reported adverse event following treatment of cervical dystonia patients with all types of botulinum toxins. Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia which may be mild, but could be severe. Consequent to the dysphagia there is the potential for aspiration, dyspnea and occasionally the need for tube feeding. In rare cases, dysphagia followed by aspiration pneumonia and death has been reported.
Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia.
Dysphagia has contributed to decreased food and water intake resulting in weight loss and dehydration. Patients with subclinical dysphagia may be at increased risk of experiencing more severe dysphagia following a BOTOX injection.
Limiting the dose injected into both sternocleidomastoid muscles to less than 100 units may decrease the occurrence of dysphagia. Patients with smaller neck muscle mass, or patients who receive bilateral injections into the sternocleidomastoid muscle, have been reported to be at greater risk of dysphagia. Dysphagia is attributable to the localized diffusion of the toxin to the oesophageal musculature.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
Focal Spasticity associated with Pediatric Cerebral Palsy and Focal Spasticity associated with Stroke in Adults: BOTOX is a treatment of focal spasticity that has only been studied in association with usual standard of care regimens, and is not intended as a replacement for these treatment modalities. BOTOX is not likely to be effective in improving range of motion at a joint affected by a fixed contracture.
BOTOX should not be used for the treatment of focal lower limb spasticity in adult post-stroke patients if muscle tone reduction is not expected to result in improved function (e.g., improvement in gait), or improved symptoms (e.g. reduction in pain), or to facilitate care.
Caution should be exercised when treating adult patients with post-stroke spasticity who may be at increased risk of fall.
BOTOX should be used with caution for the treatment of focal lower limb spasticity in elderly post-stroke patients with significant co-morbidity and treatment should only be initiated if the benefit of treatment is considered to outweigh the potential risk.
There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin. Caution should be exercised when treating pediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease.
Primary hyperhidrosis of the axillae: Medical history and physical examination, along with specific additional investigations as required, should be performed to exclude potential causes of secondary hyperhidrosis (e.g. hyperthyroidism or phaeochromocytoma). This will avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of underlying disease.
Upper Facial Lines: Reduced blinking from BOTOX injection of the orbicularis oculi muscle can lead to corneal exposure, persistent epithelial defects and corneal ulceration, especially in patients with cranial nerve VII disorders. Caution should be used when BOTOX treatment is used in patients who have an inflammation at the injection site, marked facial asymmetry, ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin or the inability to substantially lessen glabellar lines by physically spreading them apart.
In order to reduce the complications of ptosis, avoid injection near the levator palpebrae superioris, particularly in patients with larger brow-depressor complexes. Medial corrugator injections should be placed at least 1 cm above the bony supraorbital ridge. To reduce the occurrence of diplopia, injections of the lateral canthal lines should be outside the bony orbit, not medial to the vertical line through the lateral canthus. To reduce the occurrence of lip ptosis, injections should be above the insertion of the zygomaticus muscles.
Chronic Migraine: Refer to previously mentioned for head and neck injections, due to similar injection sites.
Carcinogenesis and Mutagenesis: Studies in animals have not been performed to evaluate the carcinogenic potential of BOTOX. BOTOX was not mutagenic in in vitro and in vivo mutagenicity studies.
Effects on the Ability to Drive and Use Machines: Asthenia, muscle weakness, dizziness and visual disturbance have been reported after treatment of BOTOX and could make driving or using machines dangerous.
Use in Children (2-18 years of age): There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin. A causal association to BOTOX has not been established in these cases. Post-marketing reports of possible distant effects from the site of injection of toxin have been very rarely reported in pediatric patients with co-morbidities, predominantly with cerebral palsy, who received > 8 U/kg. Extreme caution should be exercised when treating pediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease.
The safety and effectiveness of BOTOX in the prophylaxis of headaches in chronic migraine has not been investigated in children and adolescents under 18 years of age.
The safety and effectiveness of BOTOX in the treatment of blepharospasm or strabismus have not been investigated in children under 12 years of age.
The safety and effectiveness of BOTOX in the treatment of cervical dystonia has not been investigated in children under 16 years of age.
The safety and effectiveness of BOTOX in the management of focal spasticity, of the upper limbs associated with stroke and severe, primary hyperhidrosis of the axillae, has not been investigated in children and adolescents under 18 years of age.
The safety and effectiveness of BOTOX in the treatment of dynamic equinus foot deformity due to spasticity in pediatric cerebral palsy patients has not been investigated in children under two years of age.
The safety and effectiveness of BOTOX in the treatment of overactive bladder, and urinary incontinence due to neurogenic detrusor overactivity have not been established in children and adolescents under 18 years of age.
Use in Elderly (>65 years of age): The reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range. The safety and effectiveness of BOTOX in the prophylaxis of headaches in chronic migraine has not been investigated in subjects over 65 years of age.
Overactive Bladder: Of 1242 patients in placebo-controlled clinical studies of BOTOX, 41.4% (n=514) were 65 years of age or older, and 14.7% (n=182) were 75 years of age or older. No overall difference in the safety profile following BOTOX treatment was observed between patients aged 65 years and older compared to younger patients in these studies, with the exception of urinary tract infection. In the placebo group, the incidence of urinary tract infection was higher in patients 65 years of age or older compared to younger patients (15.2% vs. 6.6%, respectively). The incidence was also higher in patients 65 years and older who were given BOTOX compared to younger patients (33.1% vs. 21.2 %, respectively). No overall difference in effectiveness was observed between these age groups in placebo-controlled pivotal clinical studies. (See Table 21.)

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