Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

The recommended dosages and frequencies of administration of BOTOX should not be exceeded due to the potential for overdose, exaggerated muscle weakness, distant spread of toxin and the formation of neutralising antibodies. Initial dosing in treatment naïve patients should begin with the lowest recommended dose for the specific indication. Prescribers and patients should be aware that side effects can occur despite previous injections being well tolerated. Caution should therefore be exercised on the occasion of each administration.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially “sodium free”.

BOT API MAR23 CL-2                                17/44
Side effects related to spread of toxin distant from the site of administration have been reported (see section 4.8), sometimes resulting in death, which in some cases was associated with dysphagia, pneumonia and/or significant debility. The symptoms are consistent with the mechanism of action of botulinum toxin and have been reported hours to weeks after injection. The risk of symptoms is probably greatest in patients who have underlying conditions and comorbidities that would predispose them to these symptoms, including children and adults treated for spasticity, and are treated with high doses.
Patients treated with therapeutic doses may also experience exaggerated muscle weakness.

Consideration should be given to the risk-benefit implications for the individual patient before embarking on treatment with BOTOX.

Dysphagia has also been reported following injection to sites other than the cervical musculature (see section 4.4 ‘cervical dystonia’).

BOTOX should only be used with extreme caution and under close supervision in patients with subclinical or clinical evidence of defective neuromuscular transmission e.g. myasthenia gravis or Lambert-Eaton Syndrome in patients with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis or motor neuropathy) and in patients with underlying neurological disorders. Such patients may have an increased sensitivity to agents such as BOTOX, even at therapeutic doses, which may result in excessive muscle weakness and an increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise. 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. Patients with a history of dysphagia and aspiration should be treated with extreme caution.

Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.

As with any treatment with the potential to allow previously-sedentary patients to resume activities, the sedentary patient should be cautioned to resume activity gradually.

The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering BOTOX and injection into vulnerable anatomic structures must be avoided.

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) or other vulnerable anatomic structures.

Serious adverse events including fatal outcomes have been reported in patients who had received off- label injections of BOTOX directly into salivary glands, the oro-lingual-pharyngeal region, oesophagus and stomach. Some patients had pre-existing dysphagia or significant debility.

Serious and/or immediate hypersensitivity reactions have been rarely reported including anaphylaxis, serum sickness, urticaria, soft tissue oedema and dyspnoea. Some of these reactions have been reported following the use of BOTOX either alone or in conjunction with other products associated with similar reactions. If such a reaction occurs, further injection of BOTOX should be discontinued and appropriate medical therapy, such as epinephrine, immediately instituted. One case of anaphylaxis has been reported in which the patient died after being injected with BOTOX inappropriately diluted with 5 ml of 1% lidocaine.
Epinephrine (adrenaline) or any other anti-anaphylactic measures should therefore be available.


BOT API MAR23 CL-2                              18/44
As with any injection, procedure-related injury could occur. An injection could result in localised infection, pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling, erythema, and/or bleeding/bruising. Needle-related pain and/or anxiety may result in vasovagal responses, e.g. syncope, hypotension, etc.

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. Caution should also be exercised when BOTOX is used for treatment of patients with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis or motor neuropathy).

There have also been reports of adverse events following administration of BOTOX involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes.
Some of these patients had risk factors including cardiovascular disease.

New onset or recurrent seizures have been reported, typically in adult and paediatric patients, who are predisposed to experiencing these events. The exact relationship of these events to the botulinum toxin injection has not been established. The reports in children were predominantly from cerebral palsy patients treated for spasticity.

Formation of neutralising antibodies to botulinum toxin type A may reduce the effectiveness of BOTOX treatment by inactivating the biological activity of the toxin. 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 minimised by injecting with the lowest effective dose given at the longest clinically indicated intervals between injections.

Clinical fluctuations during the repeated use of BOTOX (as with all botulinum toxins) may be a result of different vial reconstitution procedures, injection intervals, muscles injected and slightly differing potency values given by the biological test method used.


Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.


Paediatric Use
The safety and efficacy of BOTOX in indications other than those described for the paediatric population in section 4.1 has not been established. Post-marketing reports of possible distant spread of toxin have been very rarely reported in paediatric patients with comorbidities, predominantly with cerebral palsy. In general the dose used in these cases was in excess of that recommended (see section 4.8).
There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin, including following off-label use (e.g. neck area). Extreme caution should be exercised when treating paediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease. Treatment in patients with poor underlying health status should be administered only if the potential benefit to the individual patient is considered to outweigh the risks.

NEUROLOGIC DISORDERS:

Focal spasticity associated with paediatric cerebral palsy and focal spasticity of the lower and upper limb, in adult


BOT API MAR23 CL-2                               19/44
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 walking), or improved symptoms (e.g. reduction in pain), or to faciliate care. In addition, improvement in active function may be limited if BOTOX treatment is initiated longer than 2 years post-stroke or in patients with less severe ankle spasticity (Modified Ashworth Scale (MAS) < 3).

Caution should be exercised when treating adult patients with 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.
• BOTOX should only be used for the treatment of post-stroke lower limb spasticity following evaluation by health care professionals experienced in the management of the rehabilitation of post-stroke patients.

There have been post-marketing reports of death (sometimes associated with aspiration pneumonia) and of possible distant spread of toxin in children with co-morbidities, predominantly cerebral palsy following treatment with botulinum toxin. See warnings under section 4.4, “Paediatric use”.

Blepharospasm
Reduced blinking following botulinum toxin injection into the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. 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.

Ecchymosis occurs easily in the soft eyelid tissues. This can be minimised by applying gentle pressure at the injection site immediately after injection.

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.

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 haemorrhages sufficient to compromise retinal circulation have occurred from needle penetrations into the orbit. It is recommended that appropriate instruments to examine and 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

BOT API MAR23 CL-2                               20/44
Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia which may be very mild, but could be severe. Dysphagia may persist for two to three weeks after injection, but has been reported to last up to five months post-injection. Consequent to the dysphagia there is the potential for aspiration, dyspnoea and occasionally the need for tube feeding. In rare cases dysphagia followed by aspiration pneumonia and death has been reported.

Limiting the dose injected into the sternocleidomastoid muscle 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 spread of the toxin to the oesophageal musculature. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia.

Dysphagia may contribute 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.

Chronic migraine
Safety and efficacy have not been established in prophylaxis of headaches in patients with episodic migraine (headaches on < 15 days per month) or chronic tension type headache. Safety and efficacy of BOTOX in patients with medication overuse headache (secondary headache disorder) has not been studied.

BLADDER DISORDERS:
Appropriate medical caution should be exercised when performing a cystoscopy.

In patients who are not catheterising, 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 catheterisation may be required.

Overactive bladder
Men with overactive bladder and signs or symptoms of urinary obstruction should not be treated with BOTOX.

Urinary incontinence due to neurogenic detrusor overactivity
Autonomic dysreflexia associated with the procedure can occur. Prompt medical attention may be required.

SKIN AND SKIN APPENDAGE DISORDER:

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, phaeochromocytoma). This will avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of underlying disease.

Vertical lines between the eyebrows seen at maximum frown (glabellar lines), lateral canthal lines seen at maximum smile (crow’s feet lines) and forehead lines seen at maximum eyebrow elevation 
Care should be taken to ensure that BOTOX is not injected into a blood vessel (see section 4.2).
There is a risk of eyelid ptosis following treatment, refer to Section 4.2 for administration instructions on how to minimize this risk.
It is mandatory that BOTOX is used for one single patient treatment only during a single session.


BOT API MAR23 CL-2                                21/44
Patients with unrecognised neuromuscular disorders may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of botulinum toxin type A. In some of these cases, dysphagia has lasted several months and required placement of a gastric feeding tube (see section 4.3).


The use of BOTOX is not recommended in individuals under 18 years. There is limited phase 3 clinical data with BOTOX in patients older than 65 years.

Effects on Driving

4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. However, BOTOX may cause asthenia, muscle weakness, dizziness and visual disturbance, which could affect driving and using machines.