INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo BOTOX® vacuum-dried injection

SCHEDULING STATUS
Schedule 4

PROPRIETARY NAME
(and dosage form)

BOTOX® vacuum-dried injection

COMPOSITION
BOTOX® (
Botulinum toxin type A) is a sterile, vacuum-dried form of purified Botulinum toxin type A, produced from a culture of Clostridium botulinum. The crystalline complex is re-dissolved in a solution containing saline and albumin and sterile filtered (0,2 microns) prior to vacuum-drying.
Other ingredients
Human albumin and sodium chloride.

PHARMACOLOGICAL CLASSIFICATION
A. 30.4 Biologicals. Other.

PHARMACOLOGICAL ACTION
Pharmacodynamic properties
BOTOX® (botulinum toxin type A) blocks neuromuscular conduction by inhibiting the release of acetylcholine. When injected intramuscularly at therapeutic doses, BOTOX® produces a localised chemical denervation effect resulting in temporary muscle paralysis.
Recovery after intramuscular injection takes place usually within 12 weeks of injection. After intradermal injection, where the target is the eccrine sweat glands the effect lasted for about 4 to 7 months after the first injection in patients treated with 50 Units per axilla.
When injected into extraocular eye muscle, the medicine induces a period of paralysis lasting from 2 to 20 weeks.
Pharmacokinetic properties
The molecular weight is about 150 000 Daltons, and the molecule is constructed of a heavy chain protein, about 100 000 Daltons, and a lighter chain protein, about 50 000 Daltons, held together by one or more disulphide bonds.
Specific receptors on the terminal non-myelinated portion of the motor nerves are sites of attachment of the heavy chain. This is then internalised, and it appears that the light and heavy chain separate, the light chain acting to interfere with calcium metabolism essential to the impulse triggered release of transmitter, acetylcholine. While some minimal transport of the botulinum molecule within the nerve terminal has been shown, widespread transport of it up through the cell body and transneuronally does not occur, as with tetanus.

INDICATIONS
BOTOX® is indicated for the treatment and/or management of:
Neurologic disorders
Focal spasticity associated with dynamic equinus foot deformity due to spasticity in paediatric cerebral palsypatients, two years of age or older by specialists trained in the procedure.
Focal spasticity of the wrist and hand in adult post-stroke patients.
Selected cases of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders (hemifacial spasm), in patients 12 years of age and older.
  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. BOTOX® is ineffective in chronic paralytic strabismus.
The reduction of the signs and symptoms of cervical dystonia (spasmodic torticollis) in adults.

Bladder disorders
Idiopathic overactive bladder with symptoms of urinary incontinence (defined as three or more episodes of urinary incontinence per 3 days), urgency and urinary frequency in adult female patients who have an inadequate response to anticholinergic medicines), or who are intolerant of anticholinergic medication. Efficacy and safety have not been demonstrated for more than 2 treatment cycles. Efficacy has not been demonstrated in males with idiopathic overactive bladder (see WARNINGS AND SPECIAL PRECAUTIONS).
Urinary incontinence due to neurogenic detrusor overactivity caused by spinal cord injury (SCI) or multiple sclerosis (MS) in adult patients who are willing and able to perform clean intermittent self-catheterisation, if required.
Skin and skin appendage disorders
Persistent severe primary hyperhidrosis of the axillae, which interferes with the activities of daily living and is resistant to topical treatment.
Moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in people less than or equal to 65 years of age. Efficacy beyond 4 treatments has not been demonstrated.
Moderate to severe lateral canthal lines (crow’s feet lines) seen at maximum smile. Efficacy beyond 4 treatments has not been demonstrated.
Moderate to severe crow’s feet lines seen at maximum smile and glabellar lines seen at maximum frown when treated simultaneously. Efficacy beyond 4 treatments has not been demonstrated.

CONTRA-INDICATIONS
BOTOX® is contra-indicated:
in individuals with known hypersensitivity to botulinum toxin type A orany ingredient in the formulation;
in the presence of infection or inflammation at the proposed injection site(s); or
when excessive weakness or atrophy is present in the target muscle.
BOTOX® should not be used for treatment of patients with amyotrophic lateral sclerosis or disorders that produce peripheral neuromuscular dysfunction, or when there are neuromuscular junctional disorders e.g. myasthenia gravis or Eaton Lambert Syndrome.

BOTOX® for management of bladder disorders is contra-indicated:
in patients who have urinary tract infection at the time of treatment;
in patients with acute urinary retention at the time of treatment, who are not routinely catheterising;
in patients who are not willing or able to initiate self-catheterisation post-treatment if required.

WARNINGS AND SPECIAL PRECAUTIONS
Medical practitioners wishing to inject BOTOX®should ensure that they are adequately trained to do so and have access to adequate resuscitating facilities.

Botulinum toxin units are not interchangeable from one product to another. Doses recommended in Allergan Units are different from other botulinum toxin preparations.

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.

Post-marketing safety data from BOTOX® suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. These effects have been reported hours to weeks after injection, and may include muscular weakness, ptosis, diplopia, blurred vision, facial weakness, swallowing and speech disorders, constipation, aspiration pneumonia, difficulty in breathing and respiratory depression. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in patients who have underlying conditions and comorbidities that would predispose them to these symptoms, including children and adults treated for spasticity and other conditions.
Patients treated with BOTOX® may also experience exaggerated muscle weakness.
Older and debilitated patients should be treated with caution.
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 WARNINGS AND SPECIAL PRECAUTIONS, Cervical dystonia).
Individuals with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis or motor neuropathy) or neuromuscular junctional disorders (e.g. myasthenia gravis or Lambert-Eaton syndrome) should not receive BOTOX®. Patients with known or unrecognised neuromuscular junctional disorders areat increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of BOTOX® (see CONTRA-INDICATIONS). There have been cases of administration of botulinum toxin to patients with known or unrecognised 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 a 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.
Swallowing and breathing difficulties can be life threatening and death has been reported. Caution should be exercised when treating patients who have neurological debility or dysphagia or have a recent history of aspiration pneumonia or lung disease.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
Sedentary patients should be cautioned to resume activity slowly and carefully following administration of BOTOX®.
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.
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, oesophagus and stomach. Some patients had pre-existing dysphagia or significant debility.

Epinephrine (adrenaline) and other precautions as necessary should be available should an anaphylactic reaction occur. In the treatment of some indications with BOTOX®, there have been reports of death, sometimes associated with dysphagia, pneumonia and/or other significant debility. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
BOTOX®should be given only by medical practitioners with appropriate qualifications, and expertise in the treatment and the use of the required equipment.

Serious and/or immediate hypersensitivity reactions, such as anaphylaxis, and serum sickness have been reported, as well as other manifestations of hypersensitivity including urticaria, soft tissue oedema, and dyspnoea. If such a reaction occurs, further injection should be discontinued and appropriate medical therapy immediately instituted. Anaphylaxis and death have been reported after being injected with BOTOX® diluted with 5 mL of 1% lidocaine (lignocaine).
Localised pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling/oedema, erythema, localised infection, bleeding and/or bruising have been associated with the injection of BOTOX®. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope.
Caution should be used 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.
There have been reports of adverse events involving the cardiovascular system, including dysrhythmia and myocardial infarction, some with fatal outcomes.
New onset or recurrent seizures have been reported. The majority were in patients who are predisposed to experiencing these events. 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. The critical factors for neutralising antibody formation have not been characterised. 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 (see DOSAGE AND DIRECTIONS FOR USE).
Clinical fluctuations during the repeated use of BOTOX® (as with 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.
BOTOX® contains human albumin. In spite of effective donor screening and product manufacturing processes, this still carries a risk for transmission of viral diseases. There is also a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD). No cases of transmission of viral diseases or CJD have ever been identified for albumin.
The safe and effective use of BOTOX® depends upon proper storage of the product, selection of the correct dose and proper reconstitution and administration techniques. Medical practitioners administering BOTOX® must understand the relevant neuromuscular anatomy and any alterations to the anatomy due to prior surgical procedures and standard electromyographic techniques.

Neurologic disorders
Focal spasticity associated with paediatric cerebral palsy patients and spasticity of the hand and wrist in adult post-stroke patients
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 effective in improving range of motion at a joint affected by a fixed contracture.
There have been reports of death (sometimes associated with aspiration pneumonia) and of possible distant spread of toxin in children with comorbitities, predominantly cerebral palsy, after treatment with BOTOX® (see WARNINGS AND SPECIAL PRECAUTIONS, Paediatric Use).
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 overrecession of the antagonist has not been demonstrated.
During the administration of BOTOX® for the treatment of strabismus, retrobulbar haemorrhages sufficient to compromise retinal circulation have occurred from needle penetration 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.
Blepharospasm and hemifacial spasm
Reduced blinking from BOTOX® injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. 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 eye 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 BOTOX®, caution should be exercised when treating patients at risk for angle closure glaucoma, including patients with anatomically narrow angles.
Patients should be warned about possible disturbance of vision following injection of BOTOX®.
Cervical dystonia
Dysphagia is a commonly reported adverse event following treatment of cervical dystonia patients with BOTOX® (see SIDE EFFECTS). Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia which may be 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. 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 require bilateral injections into the sternocleidomastoid muscle, have been reported to be at greater risk of dysphagia. Dysphagia is attributable to the localised diffusion 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 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.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.

Bladder disorders
Due to the risk of urinary retention, only patients who are willing and able to initiate catheterisation post-treatment, if required, should be considered for treatment. 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 medical practitioner if they experience difficulties in voiding as catheterisation may be required.
Overactive bladder
Only a limited number of males were studied in the two phase 3 clinical studies and the results were not statistically significant for patients administered with BOTOX® compared to placebo. Men with signs and symptoms of urinary obstruction should not be treated with BOTOX®.
Urinary incontinence due to neurogenic detrusor overactivity
In patients with neurogenic detrusor overactivity, autonomic dysreflexia associated with cystoscopy could occur, which may require prompt medical therapy.

Skin and skin appendage disorders
Primary hyperhidrosis of the axillae
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.
Glabellar lines and crow’s feet 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 VII nerve disorders. Caution should be used when BOTOX® treatment is used in patients who have an inflammatory skin problem at the injection site, marked facial asymmetry, ptosis, excessive dermatochalasis (excess skin in the upper and lower eyelids), deep dermal scarring, thick sebaceous skin, or the inability to substantially lessen glabellar lines by physically spreading them apart. Injection intervals of BOTOX® should be no more frequent than every three months and should be performed using the lowest effective dose.
Care should be taken to ensure that BOTOX® is not injected into a blood vessel when it is injected in the glabellar lines or in the crow’s feet lines (see DOSAGE AND DIRECTIONS FOR USE).
There is a risk of eyelid ptosis following treatment (see SIDE EFFECTS). Refer to DOSAGE AND DIRECTIONS FOR USE for administration instructions on how to minimise the risk.

Paediatric use
The safety and efficacy of BOTOX® in the treatment of individual indications have not been established in children and adolescents under the ages listed in Table 1. No data are available.
Table 1: Paediatric use
Focal spasticity associated with paediatric cerebral palsy 2 years
Upper limb spasticity associated with stroke 18 years
Strabismus, blepharospasm and hemifacial spasm 12 years
Cervical dystonia 16 years
Overactive bladder and neurogenic detrusor overactivity 18 years
Primary hyperhidrosis of the axillae 18 years
Glabellar lines and crow’s feet lines 18 years

The safety and efficacy of BOTOX® in indications other than those described for the paediatric population in Table 1 have not been established. Post-marketing reports of distant spread of toxin have been reported in paediatric patients with comorbidities, predominantly with cerebral palsy (see SIDE EFFECTS).
There have been spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with BOTOX®, 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. BOTOX® should not be used in patients with poor underlying health status.

Elderly
With the exception of overactive bladder, clinical studies of BOTOX® did not include sufficient numbers of subjects aged 65 years and over to determine safety and efficacy. The lowest effective dose with the longest clinically indicated interval between injections is recommended. Older people with significant medical history and concomitant medications should not be treated (for overactive bladder, see PHARMACOLOGICAL ACTION, Pharmacodynamic properties and SIDE EFFECTS).

Effects on the ability to drive and use machines
BOTOX® may cause asthenia, muscle weakness, dizziness and visual disturbance, which could make driving or using machines dangerous.

INTERACTIONS
The effect of botulinum toxin type A may be potentiated by aminoglycoside antibiotics or any other medicinal products that interfere with neuromuscular transmission (e.g. neuromuscular blocking agents). Caution should be exercised when BOTOX® is used in patients receiving aminoglycosides (e.g. streptomycin, tobramycin, neomycin, gentamycin, netilmycin, kanamycin, amikacin), tetracyclines, lincomycin, or any other medicine that interferes with neuromuscular transmission (e.g. neuromuscular blocking agents, both depolarising and non-depolarising, lincosamides, polymyxins, quinidine, magnesium sulfate, and anticholinesterases). (See SIDE EFFECTS.)
No tests have been carried out to establish the possibility of clinical interaction with other medicinal product.
The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive weakness may be exacerbated by administration of another dose of BOTOX® prior to the resolution of the effects of a previously administered BOTOX®.

PREGNANCY AND LACTATION
BOTOX® should not be used during pregnancy and lactation.
Safety of BOTOX® when administered during pregnancy or lactation has not been established. No information is available on the passage of the toxin into breast milk.

DOSAGE AND DIRECTIONS FOR USE
Please note that dosage and directions for use is specific to each individual indication.
BOTOX® should be administered only by a suitably qualified and registered medical practitioner.
BOTOX® is for single patient use only.

FOR INTRADERMAL, INTRADETRUSOR OR INTRAMUSCULAR USE
Once opened and reconstituted in the vial, use within twenty four hours and discard remaining solution, as the product and diluent do not contain a preservative. Reconstituted BOTOX® should not be frozen. When BOTOX® is diluted for urinary incontinence in a syringe, it should be used immediately.
Optimum dose levels and number of injection sites per muscle have not been established. Individual treatment regimens should therefore be drawn up by the medical practitioner. Optimum dose levels should be determined by titration.

Dilution technique
The following information is important:
If different vial sizes of BOTOX® are being used as one injection procedure, care should be taken to use the correct amount of diluent when reconstituting a particular number of Units per 0,1 mL. The amount of diluent varies between BOTOX® 50 Allergan Units, BOTOX® 100 Allergan Units and BOTOX® 200 Allergan Units. Each syringe should be labelled accordingly.
BOTOX® must only be reconstituted with sterile non-preserved sodium chloride 9 mg/mL (0,9%) solution for injection. The appropriate amount of diluent (see Table 2) should be drawn up into a syringe.
Since BOTOX® is denatured by bubbling or similar violent agitation; inject the diluent into the vial gently. Discard the vial if a vacuum does not pull the diluent into the vial. Record the date and the time of reconstitution on the space on the label. BOTOX® should be administered within 24 hours after reconstitution. During this time period, reconstituted BOTOX® should be stored in a refrigerator (2° to 8°C). Reconstituted BOTOX® should be clear, colourless and free of particulate matter. Parenteral products should be inspected visually for particulate matter and discolouration prior to administration and whenever the solution and the container permit.

Table 2: Dilution table for BOTOX® 50, 100 and 200 Unit vials for all indications except bladder disorders
Resulting dose
(Units per 0,1 mL)
50 Unit vial 100 Unit vial 200 Unit vial
  Amount of diluent (sodium chloride 9 mg/mL (0,9%) solution for injection) added in a 50 Unit vial Amount of diluent (sodium chloride 9 mg/mL (0,9%) solution for injection) added in a 100 Unit vial Amount of diluent (sodium chloride 9 mg/mL (0,9%) solution for injection) added in a 200 Unit vial
20 Units 0,25 mL 0,5 mL 1 mL
10 Units 0,5 mL 1 mL 2 mL
5 Units 1 mL 2 mL 4 mL
4 Units 1,25 mL 2,5 mL 5 mL
2,5 Units 2 mL 4 mL 8 mL
1,25 Units 4 mL 8 mL N/A
Note: These dilutions are calculated for an injection volume of 0,1 mL. A decrease or increase in the BOTOX® dose is also possible by administering a smaller or larger injection volume - from 0,05 mL (50% decrease in dose) to 0,15 mL (50% increase in dose).
An injection of BOTOX® is prepared by drawing into a sterile 1,0 mL syringe an amount of the properly diluted toxin (see Table 2) slightly greater than the intended dose. Air bubbles in the syringe barrel are expelled and the syringe is attached to the electro-myographic injection needle, preferably a 27 gauge needle. Injection volume in excess of the intended dose is expelled through the needle into an appropriate waste container to assure patency of the needle and to confirm that there is no syringe-needle leakage. A new, sterile needle and syringe should be used to enter the vial on each occasion for dilution or removal of BOTOX®.

Overactive bladder - dilution instructions
It is recommended that one 100 Unit or two 50 Unit vials are used for convenience of reconstitution.
Dilution instructions using a 100 Unit vial
Reconstitute a 100 Unit vial of BOTOX® with 10 mL of 0,9% non-preserved saline solution and mix gently.
Draw the 10 mL from the vial into a 10 mL syringe.
Dilution instructions using two 50 Unit vials
Reconstitute two 50 Unit vials of BOTOX® each with 5 mL of 0,9% non-preserved saline solution and mix the vials gently.
Draw the 5 mL from each of the vials into a single 10 mL syringe.
This will result in a 10 mL syringe containing a total of 100 Units of reconstituted BOTOX®. Use immediately after reconstitution in the syringe. Dispose of any unused saline.

Urinary incontinence due to neurogenic detrusor overactivity - dilution instructions
It is recommended that a 200 Unit vial or two 100 Unit vials are used for convenience of reconstitution.

Dilution instructions using two 100 Unit vials
Reconstitute two 100 Unit vials of BOTOX®, each with 6 mL of 0,9% non-preserved saline solution and mix the vials gently.
Draw 4 mL from each vial into each of two 10 mL syringes. Draw the remaining 2 mL from each vial into a third 10 mL syringe.
Complete the reconstitution by adding 6 mL of 0,9% non-preserved saline solution into each of the 10 mL syringes, and mix gently.

Dilution instructions using a 200 Unit vial
Reconstitute a 200 Unit vial of BOTOX® with 6 mL of 0,9% non-preserved saline solution and mix the vial gently.
Draw 2 mL from the vial into each of three 10 mL syringes.
Complete the reconstitution by adding 8 mL of 0,9% non-preserved saline solution into each of the 10 mL syringes, and mix gently.

Dilution instructions using four 50 Unit vials
Reconstitute four 50 Unit vials of BOTOX, each with 3 mL of 0,9% non-preserved saline solution and mix the vials gently.
Draw 3 mL from the first vial and 1 mL from the second vial into one 10 mL syringe.
Draw 3 mL from the third vial and 1 mL from the fourth vial into a second 10 mL syringe.
Draw the remaining 2 mL from the second and fourth vials into a third 10 mL syringe.
Complete the reconstitution by adding 6 mL of 0,9% non-preserved saline solution into each of the three 10 mL syringes, and mix gently.
This will result in three 10 mL syringes each containing 10 mL (~67 Units in each), for a total of 200 Units of reconstituted BOTOX®. Use immediately after reconstitution in the syringe. Dispose of any unused saline.

Method of administration
Neurologic disorders
Focal spasticity associated with paediatric cerebral palsy
Recommended needle: Sterile 23 - 26 gauge / 0,60 - 0,45 mm needle
Administration guidance: To be administered as a divided dose through single injections into the medial and lateral heads of the affected gastrocnemius muscle.
Recommended dose: Hemiplegia: The initial recommended dose is 4 Units/kg body weight in the affected limb.
  Diplegia: The initial recommended dose is 6 Units/kg body weight divided between the affected limbs.
Maximum total dose: 200 Units
Additional information: Clinical improvement generally occurs within the first two weeks after injection. Repeat doses should be administered when the clinical effect of a previous injection diminishes but not more frequently than every three months. It may be possible to adapt the dosage regimen to obtain an interval of at least six months between treatment sessions.

Focal upper limb spasticity associated with stroke
Recommended needle: Sterile 25, 27 or 30 gauge needle. Needle length should be determined based on muscle location and depth.
Administration guidance: Localisation of the involved muscles with electromyographic guidance or nerve stimulation techniques may be useful. Multiple injection sites may allow BOTOX® to have more uniform contact with the innervation areas of the muscle and are especially useful in larger muscles.
Recommended dose: The exact dosage and number of injection sites should be tailored to the individual based on the size, number and location of muscles involved, the severity of spasticity, presence of local muscle weakness, and the patient response to previous treatment.

Table 3: In controlled clinical trials the following doses were administered
Muscle Total Dose
Flexor digitorum profundus         50 Units
Flexor digitorum sublimis         50 Units
Flexor carpi radialis         50 Units
Flexor carpi ulnaris         50 Units
Adductor pollicis         20 Units
Flexor pollicis longus         20 Units

Maximum total dose: It is recommended that the dose at any treatment session does not exceed 240 Units divided among selected muscles. Re-injections should not occur before 12 weeks.
Additional information: Improvement in muscle tone occurs within two weeks with the peak effect generally seen within four to six weeks. If it is deemed appropriate by the treating practitioner, repeat doses may be administered, when the effect of a previous injection has diminished. Consistent response to re-injection has been observed with up to 5 successive treatments. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of BOTOX® and muscles to be injected. The lowest effective dose should be used.

Strabismus
BOTOX® is intended for injection into extraocular muscles utilising the electrical activity recorded from the tip of the injection needle as a guide to placement within the target muscle. Injection without surgical exposure of the muscle to be treated or electromyographic guidance should not be attempted. Medical practitioners should be familiar with electromyographic technique.
Administration guidance: To prepare the eye for BOTOX® injection, it is recommended that several drops of a local anaesthetic and an ocular decongestant be given several minutes prior to injection.
Recommended dose: The volume of BOTOX® injected for treatment of strabismus should be between 0,05 mL to 0,15 mL per muscle.
  Initial doses: (Use the lower listed doses for treatment of small deviations. Use the larger doses only for large deviations.)
For vertical muscles, and for horizontal strabismus of less than 20 prism diopters: 1,25 Units to 2,5 Units in any one muscle.
For horizontal strabismus of 20 prism diopters to 50 prism diopters: 2,5 Units to 5,0 Units in any one muscle.
For persistent VI nerve palsy of one month or longer duration: 1,25 Units to 2,5 Units in the medial rectus muscle.
  Subsequent doses for residual or recurrent strabismus:
It is recommended that patients be re-examined 7 to 14 days after each injection to assess the effect of that dose.
Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose.
Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to twice the size of the previously administered dose.
Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles.

Maximum total dose: The maximum recommended dose as a single injection for any one muscle is 25 Units. The cumulative dose of BOTOX® for treatment of strabismus in a two month period should generally not exceed 200 Units.
Additional information: The initial listed doses of the diluted BOTOX® typically create paralysis of injected muscles beginning one to two days after injection and increasing in intensity during the first week. The paralysis lasts for 2 to 6 weeks and gradually resolves over a similar time period. Overcorrections lasting over 6 months have been rare. About one half of patients will require subsequent doses because of inadequate paralytic response of the muscle to the initial dose or because of mechanical factors such as large deviations or restrictions, or because of the lack of binocular motor fusion to stabilise the alignment.

Blepharospasm and hemifacial spasm
Recommended needle: Sterile, 27 - 30 gauge / 0,40 - 0,30 mm needle
Administration guidance: Electromyographic guidance is not necessary
Recommended dose: For blepharospasm, the initial recommended dose is 1,25 to 2,5 Units (0,05 mL to 0,1 mL volume at each site) injected into the medial and lateral orbicularis oculi of the upper lid and the lateral orbicularis oculi of the lower lid. Additional sites in the brow area, the lateral orbicularis and in the upper facial area may also be injected if spasms here interfere with vision.
Maximum total dose: The initial dose should not exceed 25 Units per eye. In the management of blepharospasm total dosage should not exceed 100 Units every 12 weeks.
Additional information: Avoiding injection near levator palpebrae superioris may reduce the complication of ptosis. Avoiding medial lower lid injections, and thereby reducing diffusion into the inferior oblique, may reduce the complication of diplopia.
The following diagrams indicate the possible injection sites:

[Figure 1 Illustrated here, please refer to original package insert]

In general, the initial effect of the injections is seen within three days and reaches a peak at one to two weeks post-treatment. Each treatment lasts approximately three months, following which the procedure can be repeated at not less than three month intervals. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient - usually defined as an effect that does not last longer than two months. However, there appears to be little benefit obtainable from injecting more than 5 Units per site. No additional benefit is conferred by treating more frequently than every three months.

Patients with hemifacial spasm or VIIth nerve disorders should be treated as for unilateral blepharospasm, with other affected facial muscles being injected as needed.

Cervical dystonia
Recommended needle: Appropriately sized needle (usually 25 - 30 gauge / 0,50 - 0,30 mm)
Administration guidance: The treatment of cervical dystonia may include, but is not limited to, injection of BOTOX® into the sternocleidomastoid, levator scapulae, scalene, splenius capitis, semispinalis, longissimus and/or the trapezius muscle(s). This list is not exhaustive as any of the muscles responsible for controlling head position may be involved and therefore require treatment.
  The muscle mass and the degree of hypertrophy or atrophy are factors to be taken into consideration when selecting the appropriate dose. Muscle activation patterns can change spontaneously in cervical dystonia without a change in the clinical presentation of dystonia.
  In case of any difficulty in isolating the individual muscles, injections should be made under electromyographic assistance by an experienced medical practitioner.
Recommended dose: No more than 200 Units total should be injected for the first course of therapy, with adjustments made in subsequent courses dependent on the initial response.
  In controlled clinical trials, doses have ranged from 95 to 360 Units (with an approximate mean of 240 Units). Initial dosing in a treatment-naïve patient should begin at the lowest recommended dose.No more than 50 Units should be given at any one site. Limiting the total dose injected into the sternocleidomastoid muscles to 100 Units or less may decrease the occurrence of dysphagia. To minimise the incidence of dysphagia, the sternomastoid should not be injected bilaterally.
Maximum total dose: A total dose of 300 Units at any one sitting should not be exceeded. The maximum cumulative dose for cervical dystonia should not generally exceed 360 Units in a 3 month interval. The optimal number of injection sites is dependent upon the size of the muscle. Treatment intervals of less than 10 weeks are not recommended.
Additional information: Clinical improvement generally occurs within the first two weeks after injection. The maximum clinical benefit generally occurs approximately six weeks post-injection. The duration of beneficial effect reported in clinical trials showed substantial variation (from 2 to 32 weeks) with a typical duration of approximately 12 to 16 weeks.

Bladder disorders
Patients should not have a urinary tract infection at the time of treatment.
Prophylactic antibiotics should be administered 1-3 days pre-treatment, on the treatment day, and 1-3 days post-treatment.
It is recommended that patients discontinue anti-platelet therapy at least 3 days before the injection procedure. Patients on anti-coagulant therapy need to be managed appropriately to decrease the risk of bleeding.
For the management of urinary incontinence, BOTOX® should be administered by medical practitioners who are experienced in the assessment and treatment of bladder dysfunction (e.g., urologists and urogynaecologists).

Overactive bladder
Recommended needle: A flexible or rigid cystoscope can be used. The injection needle should be filled (primed) with approximately 1 mL of the reconstituted BOTOX® prior to the start of the injections (depending on the needle length) to remove any air.
Administration guidance: Prior to injection an intravesical instillation of diluted local anaesthetic, with or without sedation, may be used, per local site practice. If a local anaesthetic instillation is performed, the bladder should be drained and irrigated with sterile saline before the next steps of the procedure.
  Reconstituted BOTOX® (100 Units / 10 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone and base. The bladder should be instilled with enough saline to achieve adequate visualisation for the injections, but over-distension should be avoided.
  The needle should be inserted approximately 2 mm into the detrusor, and 20 injections of 0,5 mL each (total volume 10 mL) should be spaced approximately 1 cm apart (see Figure 2). For the final injection, approximately 1 mL of sterile normal saline should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualisation should not be drained so that patients can demonstrate their ability to void prior to leaving the clinic. The patient should be observed for at least 30 minutes post-injection and until a spontaneous void has occurred.

[Figure 2Illustrated here, please refer to original package insert]

Recommended dose: The recommended dose is 100 Units of BOTOX®, as 0,5 mL (5 Units) injections across 20 sites in the detrusor.
Additional information: Clinical improvement may occur within 2 weeks. Patients should be considered for reinjection when the clinical effect of the previous injection has diminished (median duration in phase 3 clinical studies was 166 days [~24 weeks]), but no sooner than 3 months from the prior bladder injection.
  For geriatric use, the lowest effective dose with the longest clinically indicated interval between injections is recommended. Older people with significant medical history and concomitant medications should be treated with caution.

Urinary incontinence due to neurogenic detrusor overactivity
Recommended needle: A flexible or rigid cystoscope can be used. The injection needle should be filled (primed) with approximately 1 mL prior to the start of the injections (depending on the needle length) to remove any air.
Administration guidance: Prior to injection, either an intravesical instillation of diluted local anaesthetic (with or without sedation) or general anaesthesia may be used, per local site practice. If a local anaesthetic instillation is performed, the bladder should be drained and rinsed with sterile saline before injection.
  Reconstituted BOTOX® (200 Units / 30 mL) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone and base. The bladder should be instilled with enough saline to achieve adequate visualisation for the injections, but over-distension should be avoided.
  The needle should be inserted approximately 2 mm into the detrusor, and 30 injections of 1 mL each (total volume 30 mL) should be spaced approximately 1 cm apart (see Figure 2). For the final injection, approximately 1 mL of sterile normal saline should be injected so the full dose is delivered. After the injections are given, the saline used for bladder wall visualisation should be drained. The patient should be observed for at least 30 minutes post-injection.
Recommended dose: The recommended total dose is 200 Units of BOTOX®, as 1 mL (~6,7 Units) injections across 30 sites in the detrusor.
Additional information: Clinical improvement generally occurs within 2 weeks. Patients should be considered for reinjection when the clinical effect of the previous injection has diminished (median duration in phase 3 clinical studies was 256 - 295 days (36 - 42 weeks) for BOTOX® 200 Units), but no sooner than 3 months from the prior bladder injection.

Skin and skin appendage disorders
Primary hyperhidrosis of the axillae
Recommended needle: Sterile 30-gauge needle
Administration guidance: The hyperhidrotic area may be defined by using standard staining techniques, e.g. Minor´s iodine-starch test.
Recommended dose: 50 Units of BOTOX® are injected intradermally, evenly distributed in multiple sites approximately 1 to 2 cm apart within the hyperhidrotic area of each axilla.
Maximum total dose: Doses other than 50 Units per axilla cannot be recommended. Injections should not be repeated more frequently than every 16 weeks.
Additional information: Clinical improvement generally occurs within the first week after injection. Repeat injection of BOTOX® can be administered when the clinical effect of a previous injection diminishes and the treating practitioner deems it necessary.

Glabellar lines (50 Units per vial)
Recommended needle: 30 gauge / 0,30 mm needle
Recommended dose: 0,1 mL (4 Units) should be administered in each of five sites, two in each corrugator muscle and one in the procerus muscle for a total dose of 20 Units. Efficacy for more than 4 treatments has not been demonstrated.
[Figure 3Illustrated here, please refer to original package insert]

Additional information: The needle should be oriented superiorly and medially during the injection. In order to reduce the risk of eyelid ptosis, the maximum dose of 4 Units for each injection site as well as the number of injection sites should not be exceeded. In addition, injection near the levator palpebrae superioris should be avoided, particularly in patients with larger brow-depressor complexes. Medial corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.

Crow’s feet lines
Recommended needle: Sterile 30 gauge needle
Recommended dose: 0,1 mL (4 Units) is administered in each of the 3 injection sites per side (total of 6 injection sites) in the lateral orbicularis oculi muscle, for a total dose of 24 Units in a total volume of 0,6 mL (12 Units per side). Efficacy for more than 4 treatments has not been established.
  Injections should be given with the needle tip bevel up and oriented away from the eye. The first injection (A) should be made approximately 1,5 to 2,0 cm temporal to the lateral canthus and just temporal to the orbital rim. If the lines in the crow’s feet region are above and below the lateral canthus, inject as shown in Figure 4. Alternatively, if the lines in the crow’s feet region are primarily below the lateral canthus, inject as shown in Figure 5.

[Figures 4&5 Illustrated here, please refer to original package insert]

  For simultaneous treatment with glabellar lines seen at maximum frown, the dose is 24 Units for crow’s feet lines seen at maximum smile and 20 Units for glabellar lines (see Method of Administration for Glabellar lines, and Figure 3), for a total dose of 44 Units in a total volume of 1,1 mL.
Additional information: In order to reduce the risk of eyelid ptosis, the maximum dose of 4 Units for each injection site as well as the number of injection sites should not be exceeded. In addition, injections should be made temporal to the orbital rim, thereby maintaining a safe distance from the muscle controlling eyelid elevation.
  Improvement of severity of crow’s feet lines seen at maximum smile, when assessed by the investigator, occurred within one week of treatment. The effect was demonstrated for a median of 4 months after injection.
  Treatment intervals should not be more frequent than every 3 months.

All indications
In the absence of the desired effect after the first treatment session, i.e. no significant clinical improvement from baseline by one month after injection, the following actions should be considered:
Clinical verification of the action of the toxin in the injected muscle(s), which may include electromyographic examination by an experienced electromyographer;
Analysis of the potential causes of lack of effect, e.g. inappropriate selection of muscles to be injected, insufficient dose, poor injection technique, fixed contracture, relative weakness of antagonist muscles, and/or formation of toxin-neutralising antibodies;
Re-evaluation of the appropriateness of treatment with botulinum toxin type A.
For the second treatment session, in the absence of any undesirable effects after the first treatment session, the medical practitioner should consider the following:
Adjust the dose, taking into account the analysis of the earlier treatment failure;
Use of EMG guidance as appropriate; and
Maintain a three-month interval between the two treatment sessions.
In the event of treatment failure or diminished effect following repeat injections, taking into account dosage adjustments and targeting of injections, alternative treatment methods should be considered.

SIDE EFFECTS
General
Patients can be expected to experience an adverse reaction after treatment with BOTOX® at the rates of 35% for blepharospasm, 28% with cervical dystonia, 17% for paediatric cerebral palsy, 11% for hyperhidrosis of the axillae, 16% with focal spasticity of the upper limb associated with stroke. In clinical trials for overactive bladder the incidence was 26% with the first treatment and 22% with the second treatment. In clinical trials for urinary incontinence due to neurogenic detrusor overactivity, the incidence of adverse reactions was 32% with the first treatment and declined to 18% with a second treatment.
In controlled clinical trials for glabellar lines, adverse events considered by the investigators to be related to BOTOX® were reported in 23,5% (placebo: 19,2%) of patients. In treatment cycle 1 of the pivotal controlled clinical trials for crow’s feet lines seen at maximum smile, such events were reported in 7,6% (24 Units for crow’s feet lines alone) and 6,2% (44 Units : 24 Units for crow’s feet lines administered simultaneously with 20 Units for glabellar lines) of patients compared to 4,5% for placebo. Adverse reactions may be related to the treatment, injection technique or both.
Adverse reactions usually occur within the first few days following injection and may have duration of several months or, in some cases, longer.
Local muscle weakness represents the expected pharmacological action of botulinum toxin in muscle tissue. However, weakness of adjacent and/or distant muscles has also occurred due to spread of toxin.
Localised pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling/oedema, erythema, localised infection, bleeding and/or bruising may be associated with the injection. Fever and flu-like symptoms have also been reported after injections with botulinum toxin. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope.

Adverse reactions –frequency by indication
For each indication the frequency of adverse reactions arising from clinical experience is given as follows: Very common (>1/10); Common (>1/100, < 1/10); Uncommon (>1/1 000, < 1/100); Rare (>1/10 000, < 1/1 000); Very rare (< 1/10 000).
Below are lists of side effects which vary depending on the part of the body where BOTOX® is injected.
Neurologic disorders
Focal spasticity associated with paediatric cerebral palsy
System Organ Class Preferred Term Frequency
Infections and infestations Viral infection, ear infection Very common
Nervous system disorders Somnolence, gait disturbance, paraesthesia Common
Skin and subcutaneous tissue disorders Rash Common
Musculoskeletal and connective tissue disorders Myalgia, muscular weakness, pain in extremity Common
Renal and urinary disorders Urinary incontinence Common
Injury, poisoning and procedural complications Fall Common
General disorders and administration site conditions Malaise, injection site pain, asthenia Common

Focal upper limb spasticity associated with stroke
System Organ Class Preferred Term Frequency
Psychiatric disorders Depression, insomnia Uncommon
Nervous system disorders Hypertonia Common
  Hypoaesthesia, headache, paraesthesia, incoordination, amnesia Uncommon
Ear and labyrinth disorders Vertigo Uncommon
Vascular disorders Orthostatic hypotension Uncommon
Gastrointestinal disorders Nausea, oral paraesthesia Uncommon
Skin and subcutaneous tissue disorders Ecchymosis, purpura Common
  Dermatitis, pruritus, rash Uncommon
Musculoskeletal and connective tissue disorders Pain in extremity, muscle weakness Common
  Arthralgia, bursitis Uncommon
General disorders and administration site conditions Injection site pain, pyrexia, influenza-like illness, injection site haemorrhage, injection site irritation Common
  Asthenia, pain, injection site hypersensitivity, malaise, peripheral oedema Uncommon

Strabismus
System Organ Class Preferred Term Frequency
Eye disorders Eyelid ptosis, eye movement disorder Very common
  Ocular retrobulbar haemorrhages, eye penetration, Holmes-Adie pupil Uncommon
  Vitreous haemorrhage Rare

Blepharospasm and hemifacial spasm
System Organ Class Preferred Term Frequency
Nervous system disorders Dizziness, facial paresis, facial palsy Uncommon
Eye disorders Eyelid ptosis Very common
  Punctuate keratitis, lagophthalmos, dry eye, photophobia, eye irritation, increased lacrimation Common
  Keratitis, ectropion, diplopia, entropion, visual disturbance, blurred vision Uncommon
  Eyelid oedema Rare
  Ulcerative keratitis, corneal epithelium defect, corneal perforation Very rare
Skin and subcutaneous tissue disorder Ecchymosis Common
  Rash/dermatitis Uncommon
General disorders and administration site conditions Irritation, face oedema Common
  Fatigue Uncommon

Cervical dystonia
Safety data were compiled from placebo controlled, double-blind trials involving 231 patients treated with BOTOX®. The following adverse reactions were reported:
System Organ Class Preferred Term Frequency
Infections and infestations Rhinitis, upper respiratory tract infection Common
Nervous system disorders Dizziness, hypertonia, hypoaesthesia, somnolence, headache Common
Eye disorders Diplopia, eyelid ptosis Uncommon
Respiratory, thoracic and mediastinal disorders Dyspnoea, dysphonia Uncommon
Gastrointestinal disorders Dysphagia Very common
  Dry mouth, nausea Common
Musculoskeletal and connective tissue disorders Muscular weakness Very common
  Musculoskeletal stiffness, soreness Common
General disorders and administration site conditions Pain Very common
  Asthenia, influenza-like illness, malaise Common
  Pyrexia Uncommon

Bladder disorders
Overactive bladder
System Organ Class Preferred Term Frequency
Infections and infestations Urinary tract infection Very common
  Bacteriuria Common
Renal and urinary disorders Dysuria Very common
  Urinary retention, pollakiuria, leukocyturia Common
Investigations Residual urine volume* Common
* Elevated post-void residual urine volume (PVR) not requiring catheterisation

Procedure-related adverse reactions that occurred with a common frequency were dysuria and haematuria. During the complete treatment cycle, urinary tract infections and urinary retention were reported in 25,5% and 5,8%, respectively, for patients treated with BOTOX®.
Clean intermittent catheterisation was initiated in 6,5% of patients following treatment with BOTOX® 100 Units versus 0,4% in the placebo group.
Of 1242 patients in the placebo-controlled clinical studies, 41,4% of patients (n = 514) were >65 years of age and 14,7% (n = 182) were >75 years of age. No overall difference in the safety profile following BOTOX® treatment was observed between patients >65 years compared to patients <65 years in these studies, with the exception of urinary tract infection where the incidence was higher in older people in both the placebo and BOTOX® groups compared to the younger patients.
In patients 65 years and older, urinary tract infection was reported in 33,1% and 15,2% in patients treated with BOTOX® and placebo respectively. In patients less than 65 years of age, urinary tract infection was reported in 21,2% and 6,6% in patients treated with BOTOX® and placebo respectively. In patients 65 years and older, urinary retention was reported in 8,4% and 0,4% in patients treated with BOTOX® and placebo respectively. In patients less than 65 years of age, urinary retention was reported in 6,1% and 0,6% in patients treated with BOTOX® and placebo respectively.
No change was observed in the overall safety profile with onerepeat dosing.

Urinary incontinence due to neurogenic detrusor overactivity
The following rates in double-blind studies with BOTOX® 200 Units were reported during the complete treatment cycle (median duration of 44 weeks of exposure):
System Organ Class Preferred Term Frequency
Infections and infestations Urinary tract infection Very common
Psychiatric disorders Insomnia Common
Gastrointestinal disorders Constipation Common
Musculoskeletal and connective tissue disorders Muscular weakness, muscle spasm Common
Renal and urinary disorders Urinary retention Very common
  Haematuria*, dysuria*, bladder diverticulum Common
General disorders and administration site conditions Fatigue, gait disturbance Common
Injury, poisoning and procedural complications Autonomic dysreflexia*, fall Common
* Procedure-related adverse reactions
In clinical trials urinary tract infection was reported in 49,2% of patients treated with 200 Units of BOTOX® and in 35,7% of patients treated with placebo (53,0% of multiple sclerosis patients treated with 200 Units vs. 29,3% with placebo; 45,4% of spinal cord injury patients treated with 200 Units vs. 41,7% with placebo). Urinary retention was reported in 17,2% of patients treated with 200 Units of BOTOX® and in 2,9% of patients treated with placebo (28,8% of multiple sclerosis patients treated with 200 Units vs. 4,5% with placebo; 5,4% of spinal cord injury patients treated with 200 Units vs. 1,4% with placebo).

No change was observed in the overall safety profile with repeat dosing.
No difference on the multiple sclerosis (MS) exacerbation annualised rate (i.e. number of MS exacerbation events per patient-year) was observed (BOTOX® = 0,23; placebo = 0,20) in the MS patients enrolled in the pivotal studies.

Skin and skin appendage disorders
Primary hyperhidrosis of the axillae
System Organ Class Preferred Term Frequency
Nervous system disorders Headache, paraesthesia Common
Vascular disorders Hot flushes Common
Gastrointestinal disorders Nausea Common
Skin and subcutaneous tissue disorders Hyperhidrosis (non-axillary sweating), abnormal skin odour, pruritus, subcutaneous nodule, alopecia Common
Musculoskeletal and connective tissue disorders Pain in extremity Common
  Muscular weakness, myalgia, arthropathy Uncommon
General disorders and administration site conditions Injection site pain Very common
  Pain, injection site oedema, injection site haemorrhage, injection site hypersensitivity, injection site irritation, asthenia, injection site reactions Common
Note: Increase in non-axillary sweating was reported in 4,5% of patients within one month after injection and showed no pattern with respect to anatomical sites affected. Resolution was seen in approximately 30% of the patients within four months.
Weakness of the arm has been also reported uncommonly (0,7%) and was mild, transient, did not require treatment and recovered without sequelae. This adverse event may be related to treatment, injection technique, or both. In the uncommon event of muscle weakness being reported a neurological examination may be considered. In addition, a re-evaluation of injection technique prior to subsequent injection is advisable to ensure intradermal placement of injections.

Glabellar lines
System Organ Class Preferred Term Frequency
Infections and infestations Infection Uncommon
Psychiatric disorders Anxiety Uncommon
Nervous system disorders Headache, paraesthesia Common
  Dizziness Uncommon
Eye disorders Eyelid ptosis Common
  Blepharitis, eye pain, visual disturbance (includes blurred vision) Uncommon
Gastrointestinal disorders Nausea Common
  Oral dryness Uncommon
Skin and subcutaneous tissue disorders Erythema, skin tightness Common
  Oedema (face, eyelid, periorbital), photosensitivity reaction, pruritus, dry skin Uncommon
Musculoskeletal and connective tissue disorders Localised muscle weakness Common
  Muscle twitching Uncommon
General disorders and administration site conditions Facial pain, injection site oedema, ecchymosis, injection site pain, injection site irritation Common
  Flu syndrome, asthenia, fever Uncommon

Crow’s feet lines
The following adverse reactions were reported in the double-blind, placebo-controlled clinical studies following injection of BOTOX® 24 Units for crow’s feet lines alone:
System Organ Class Preferred Term Frequency
Eye disorders Eyelid oedema Common
General disorders and administration site conditions Injection site haemorrhage*, injection site haematoma* Common
  Injection site pain*, injection site paraesthesia Uncommon
* Procedure-related adverse reactions

Crow’s feet lines and glabellar lines
The following adverse reactions were reported in double-blind, placebo-controlled clinical studies following injection of BOTOX® 44 Units (simultaneous treatment of crow’s feet lines and glabellar lines):
System Organ Class Preferred Term Frequency
General disorders and administration site conditions Injection site haematoma* Common
  Injection site haemorrhage*, injection site pain* Uncommon
*Procedure-related adverse reactions
No change was observed in the overall safety profile following repeat dosing.

Post-marketing experience
There have been spontaneous reports of death, sometimes associated with dysphagia, pneumonia, and/or other significant debility, after treatment with BOTOX®.
Serious and/or immediate hypersensitivity reactions such as anaphylaxis and serum sickness have been reported, as well as other manifestations of hypersensitivity including urticaria, soft tissue oedema, and dyspnoea. One fatal case of anaphylaxis has been reported in which the patient died after being injected with BOTOX® diluted with 5 mL of 1% lidocaine (lignocaine). The causal role of BOTOX®, lidocaine, or both cannot be reliably determined.
There have also been reports of adverse events involving the cardiovascular system, including dysrythmia and myocardial infarction, some with fatal outcomes following BOTOX® treatment. Some of these patients had risk factors including cardiovascular disease.
A case of peripheral neuropathy has been reported in a large adult male after receivingfour setsof BOTOX® injections, totalling 1 800 Units (for neck and back spasm, and severe pain) over an 11 week period.
Lagophthalmos has been reported following BOTOX® injection into the glabellar lines or crow’s feet lines.
The following list includes adverse reactions or other medically relevant adverse events that have been reported since BOTOX® has been marketed, regardless of indication:

System Organ Class Preferred Term
Cardiac disorders Dysrythmia, myocardial infarction
Ear and labyrinth disorders Hypoacusis, tinnitus, vertigo
Eye disorders Angle-closure glaucoma (for treatment of blepharospasm), strabismus (including overcorrection for childhood esotropia), blurred vision, visual disturbance
Gastrointestinal disorders Abdominal pain, diarrhoea, constipation, dry mouth, dysphagia, nausea, vomiting
General disorders and administration site conditions Denervation atrophy, malaise, pyrexia
Immune system disorders Anaphylaxis, angioedema, serum sickness, urticaria
Metabolism and nutrition disorders Anorexia
Musculoskeletal and connective tissue disorders Muscle atrophy, myalgia
Nervous system disorders Brachial plexopathy, dysphonia, dysarthria, facial paresis, hypoaesthesia, muscle weakness, myasthenia gravis, peripheral neuropathy, paraesthesia, radiculopathy, seizures (new onset or recurrent), syncope, facial palsy
Respiratory, thoracic and mediastinal disorders Aspiration pneumonia (some with fatal outcome), dyspnoea, bronchospasm, respiratory depression, respiratory failure
Skin and subcutaneous tissue disorders Alopecia, psoriasiform dermatitis, erythema multiforme, hyperhidrosis, madarosis, pruritus, rash

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Signs and symptoms of overdose are likely not to be apparent immediately post-injection. Overdose may produce local, or distant, generalised and profound neuromuscular paralysis.
Should accidental injection or oral ingestion occur or overdose be suspected, the patient should be medically monitored for up to several weeks for progressive signs or symptoms of systemic muscular weakness which could be local, or distant from the site of injection which may include ptosis, diplopia, dysphagia, dysarthria, generalised weakness or respiratory failure. These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalisation.
If the musculature of the oropharynx and esophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralysed or sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes place, and may involve the need for a tracheostomy and prolonged mechanical ventilation, in addition to other general supportive care.

IDENTIFICATION
Clear glass vial containing a small white vacuum-dried powder cake.
Reconstituted BOTOX® should be clear, colourless and free of particulate matter.

PRESENTATION
BOTOX® (botulinum toxin type A) is available in three vial sizes: 50 Units, 100 Units or 200 Units. The clear glass vials are sealed with rubber closures and aluminium seals.
In order to verify receipt of actual BOTOX® product from Allergan, look for a tamper-evident seal that contains a translucent silver Allergan logo on the top and bottom flaps of the BOTOX® cartons, and a holographic film on the vial label. In order to see this film, examine the vial under a desk lamp or fluorescent light source. Rotating the vial back and forth between your fingers, look for horizontal lines of rainbow colour on the label and confirm that the name “Allergan” appears within the rainbow lines.
Do not use the product and contact your local Allergan office for additional information if:
The horizontal lines of rainbow colour or the word “Allergan” are not present on the vial label
The tamper-evident seal is not intact and present on both ends of the carton
The translucent silver Allergan logo on the seal is not clearly visible or has a black circle with a diagonal line through it (i.e., prohibition sign)
Additionally, Allergan has created detachable stickers on the BOTOX® vial label, which include the lot number and expiry date of the product you have received. These stickers can be peeled off and placed in your patient’s clinical file for traceability purposes. Note that once you remove the sticker off the BOTOX® vial label, the word “USED” will show, which is to provide you with further assurance that you are using an authentic BOTOX® product manufactured by Allergan.

STORAGE INSTRUCTIONS
Store the vacuum-dried product in a refrigerator between 2°C to 8°C, or in a freezer at or below -5°C. Administer BOTOX® within twenty-four (24) hours after the vial is removed from the freezer and reconstituted. During these twenty-four (24) hours, reconstituted BOTOX® should be stored in a refrigerator (2°C to 8°C). Reconstituted BOTOX® should be clear, colourless and free of particulate matter.
Since the product does not contain a preservative, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at +2°C to +8°C. Do not freeze the reconstituted vial.
All vials, including expired vials, or equipment used with the medicine should be disposed of carefully as is done with all medical waste.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
27/30.4/0164

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE
Allergan Pharmaceuticals (Pty) Ltd
30 New Road (entrance off Bavaria Road)
Randjespark Ext 11, Midrand, 1682
Johannesburg, Gauteng
SOUTH AFRICA

DATE OF PUBLICATION OF PACKAGE INSERT
Date of registration: 5 February 1993
Date of the most recently revised Package Insert as approved by Council: 25 November 2016


PATIENT INFORMATION LEAFLET

SCHEDULING STATUS
Schedule 4

PROPRIETARY NAME, STRENGTH AND PHARMACEUTICAL FORM
BOTOX®
vacuum-dried injection

Read all of this leaflet carefully before you are given BOTOX®
Keep this leaflet. You may need to read it again.
If you have further questions, please ask your doctor or pharmacist.
BOTOX® has been prescribed for you personally and you should not share your medicine with other people. It may harm them, even if their symptoms are the same as yours.

BOTOX®is not for self medication and must be administered only by a medical practitioner and who is qualified for its use.

1. WHAT BOTOX® CONTAINS
The active substance is botulinum toxin type A from Clostridium botulinum.
The other ingredients are human albumin and sodium chloride.

2. WHAT BOTOX® IS USED FOR
BOTOX® can be injected directly into the muscles, and can be used to control the following conditions:

  In children aged two years or older with cerebral palsy, who can walk, BOTOX® is used to control foot deformity.
  In adults:

    Persistent muscle spasms in the wrist and hand of patients who have suffered a stroke;
    Persistent muscle spasms in the eyelid and face;
    Persistent muscle spasms in the neck and shoulders.

When injected into the bladder wall, BOTOX® works on the bladder muscle to reduce leakage of urine (urinary incontinence) and control the following conditions in adults:

  Overactive bladder in females with leakage of urine, the sudden urge to empty your bladder and needing to go to the toilet more than usual when another medicine (called an anticholinergic) did not help;
  Leakage of urine due to bladder problems associated with spinal cord injury or multiple sclerosis.

In adults, BOTOX® can be injected deep into the skin and can work on sweat glands to reduce excessive sweating of the armpits, which affects the activities of daily living when other local treatments do not help.
In adults, BOTOX® is used temporarily for the temporary improvement in the appearance of:

  Vertical lines between the eyebrows seen at maximum frown in adults;
  Fan-shaped lines from the corner of the eyes (crow’s feet lines) seen at maximum smile;
  Fan-shaped lines from the corner of the eyes seen at maximum smile, when treated at the same time as vertical lines between the eyebrows seen at maximum frown.

3 BEFORE YOU ARE GIVEN BOTOX®
You should not be given BOTOX®:
If you are hypersensitive (allergic) to botulinum toxin type A or any of the other ingredients of BOTOX®;
If you have an infection at the proposed site of injection;
If you have significant weakness or wasting of the muscles which your doctor plans to inject;
If you have any muscle disorders in other parts of your body or chronic disease affecting your muscles, such as myasthenia gravis, or Eaton Lambert Syndrome;
If you suffer from certain diseases affecting your nervous system (such as amyotrophic lateral sclerosis or motor neuropathy);
If you are being treated for leakage of urine and have either a urinary tract infection or a sudden inability to empty your bladder (and are not regularly using a catheter);
If you are being treated for leakage of urine and are not willing to begin using a catheter if required.

Take special care with BOTOX®
Tell your doctor or healthcare professional before being given BOTOX®:
If you have ever had problems with swallowing of food or liquid accidentally going into your lungs, especially if you will be treated for persistent muscle spasms in the neck and shoulder(s);
If you are over 65 years of age and have other serious illness;
If you have had any problems with injections (such as fainting) in the past;
If you have inflammation in the muscles or skin area where your doctor plans to inject;
If you have significant weakness or wasting of the muscles which your doctor plans to inject;
If you suffer from any other muscle problems or chronic diseases affecting your muscles (such as myasthenia gravis or Eaton Lambert Syndrome);
If you suffer from certain diseases affecting your nervous system (such as amyotrophic lateral sclerosis or motor neuropathy);
If you suffer from cardiovascular disease (disease of the heart or blood vessels);
If you suffer or have suffered from seizures;
If you have an eye disease called glaucoma (high pressure in the eye) or were told you are at risk for developing glaucoma;
If you have had any surgery or injury that may have in some way changed the muscle to be injected;
If you are about to be treated for overactive bladder with leakage of urine and you are a male with signs and symptoms of urinary obstruction, such as difficulty in passing urine or a weak or interrupted stream.

The safety and effectiveness of BOTOX® have not been established in children or adolescents under the following ages:
Persistent muscle spasms in the legs of children who have cerebral palsy 2 years
Persistent muscle spasms in the wrist and hand of patients who have suffered a stroke         18 years
Persistent muscle spasms of the eyelid, face         12 years
Neck and shoulder         16 years
Leakage of urine         18 years
Excessive sweating of the armpits         18 years
Lines between the eyebrows and crow’s feet lines         18 years

With the exception of overactive bladder, the safety and effectiveness of BOTOX® have not been established in adults over the age of 65.

After you have been given BOTOX®
You or your caregiver should
contact your doctor and seek medical attention immediately if you experience any of the following:
•        Difficulty in breathing, swallowing, or speaking;
•        Hives, swelling including swelling of the face or throat, wheezing, feeling faint and shortness of breath (possible symptoms of severe allergic reaction).

It is possible for the procedure to result in infection, pain, swelling, burning and stinging, increased sensitivity, tenderness, redness, and/or bleeding/bruising at the site of injection.
Side effects, possibly related to the spread of toxin away from the injection site, may occur with BOTOX® (e.g. muscle weakness, difficulty swallowing or unwanted food or liquid in the airways). This is a particular risk for patients with an underlying illness that makes them susceptible to these symptoms.
If you are given BOTOX® too often or the dose is too high, you may experience muscle weakness and side effects related to the spread of toxin or your body may start producing some antibodies, which can reduce the effect of BOTOX®.
If you have not done much exercise for a long time before receiving BOTOX® treatment, then after your injections you should start any activity gradually.
It is unlikely that BOTOX® will improve the range of motion of joints where the surrounding muscle has lost its ability to stretch.
When BOTOX® is used in the treatment of persistent muscle spasms in the eyelid, it could make your eyes blink less often, which may harm the surface of your eyes. In order to prevent this, you may need treatment with eye drops, ointments, soft contact lenses or even protective covering which closes the eye. Your doctor will tell you if this is required.
When BOTOX® is used to control the leakage of urine, your doctor will give you antibiotics before and after the treatment to help prevent urinary tract infection. You will be seen by your doctor approximately two weeks after the injection, if you were not using a catheter before the injection. You will be asked to pass urine and will then have the volume of urine left in your bladder measured using ultrasound. Your doctor will decide if you need to return for the same test during the next 12 weeks. You must contact your doctor if at any time you are unable to pass urine because it is possible that you may need to start using a catheter.

Pregnancy and breast-feeding
The use of BOTOX® is not recommended during pregnancy and in women of childbearing potential not using contraception. BOTOX® is not recommended in breast-feeding women.
If you are pregnant or breast-feeding your baby, please consult your doctor, pharmacist or other health care professional for advice before receiving BOTOX®.

Driving and using machinery
BOTOX® may cause dizziness, sleepiness, tiredness or problems with your vision. If you experience any of these effects, do not drive or use any machines. If you are not sure, ask your doctor for advice.

Important information about some of the ingredients of BOTOX®
BOTOX® contains human albumin which comes from human blood. There is a possibility of passing on infections. To reduce this risk, blood donors are chosen very carefully. Furthermore, BOTOX® is made in a way that should remove or destroy viruses.

Taking other medicines with BOTOX®
Always tell your healthcare professional if you are taking any other medicine. (This includes complementary or traditional medicines.)

Tell your doctor or pharmacist if:
You are using any antibiotics (used to treat infections) or muscle relaxants. Some of these medicines may increase the effect of BOTOX®;
You have recently been injected with a medicine containing a botulinum toxin (the active substance of BOTOX®), as this may increase the effect of BOTOX® too much;
You are using any anti-platelet (asprin-like products) and/or anti-coagulants (blood thinners).

4. HOW TO RECEIVE BOTOX®
Do not share medicines prescribed for you with any other person.
You will not be expected to give yourself BOTOX®. It will be given to you by a person who is qualified to do so. BOTOX® must only be injected by a medical doctor with specific skills on how to use the medicine.

Method and route of administration
BOTOX® is injected into your muscles (intramuscularly), into the bladder wall via a specific instrument (cytoscope) to inject into the bladder or into the skin (intradermally). It is injected directly into the affected area of your body; your doctor will usually inject BOTOX® into several sites within each affected area.

General information about dosage
Your medical practitioner will decide how much, how often, and in which muscle(s) BOTOX® will be given to you.

If you have received more BOTOX® than you should
The signs of too much BOTOX® may not appear for several days after the injection. Should you swallow BOTOX® or have it accidentally injected, you should see your doctor who might keep you under observation for several weeks.
If you have received too much BOTOX®, you may have any of the following symptoms and you must contact your doctor immediately. He/she will decide if you have to go to hospital:
Muscle weakness which could be local or distant from the site of injection;
Difficulty in breathing, swallowing or speaking due to muscle paralysis;
Food or liquid accidentally going into your lungs which might cause pneumonia (infection of the lungs) due to muscle paralysis;
Drooping of the eyelids, double vision;
Generalised weakness.
If you have any further questions on the use of BOTOX®, ask your doctor or pharmacist.
In the event of overdosage, consult your doctor or pharmacist. If neither is available, contact the nearest poison control centre.

5. POSSIBLE SIDE EFFECTS
BOTOX® can have side effects.
If any of the following happens after receiving BOTOX®, tell your doctor immediately or go to the casualty department at your nearest hospital:
If you have any difficulty in breathing, swallowing or speaking;
If you experience hives, swelling including swelling of the face or throat, wheezing, feeling faint and shortness of breath.
These are all very serious side effects. If you have them, you may have had a serious allergic reaction to BOTOX®. You may need urgent medical attention or hospitalisation.

Side effects usually occur within the first few days following injection and may last for several months or, in some cases, longer.
Below are lists of side effects which vary depending on the part of the body where BOTOX® is injected.
Injections in the legs of children with cerebral palsy
Frequent Viral infection, ear infection, sleepiness, problems with walking, numbness, rash, muscle pain, muscle weakness, pain in the extremities such as the hands and fingers, urinary incontinence (leakage of urine), fall, feeling generally unwell, pain where the injection was given, feeling of weakness
There have been reports of death in children with severe cerebral palsy after treatment with BOTOX®.

Injections in the wrist and hand of patients who have had a stroke
Frequent Increased muscle tension, bruising and bleeding under the skin causing red patches (ecchymosis or purpura), pain in the extremities such as the hands and fingers, muscle weakness, pain where the injection was given, fever, flu syndrome, bleeding or irritation where the injection was given
Less frequent Depression, difficulty in sleeping (insomnia), decreased skin sensation, headache, numbness, lack of coordination of movements, loss of memory, feeling of dizziness or “spinning” (vertigo), fall in blood pressure on standing up which causes dizziness, light headedness or fainting; nausea, numbness around the mouth, inflammation of the skin (dermatitis), itching, rash, joint pain or inflammation, general weakness, pain, increased sensitivity where the injection was given, feeling generally unwell, swelling of the extremities such as the hands and feet

Injections in the eye muscles
Frequent Drooping of the eyelid, problems with eye movement
Less frequent Bleeding behind the eyeball, penetration of the needle into the eye, pupil defects, bleeding in the vitreous (jellylike substance that fills the back of the eyeball)

Injections in the eyelid and face
Frequent Drooping of the eyelid, pinpoint damage of the cornea (transparent surface covering the front of the eye), difficulty in completely closing the eye, dry eyes, sensitivity to light, eye irritation, overflow of tears, bruising under the skin, skin irritation, swelling of the face
Less frequent Dizziness, weakness of the face muscles, drooping of the muscles on one side of the face, inflammation of the cornea (transparent surface covering the front of the eye), abnormal turning of the eyelids (outwards or inwards), double vision, difficulties in seeing clearly, blurred vision, rash, tiredness, swelling of the eyelid, ulcer, damage to the cornea (transparent surface covering the front of the eye)

Injections in the neck and shoulder
Frequent Swelling and irritation inside the nose (rhinitis), blocked or runny nose, cough, sore throat, tickle or irritation in the throat, dizziness, increased muscle tension (cramps), decreased skin sensation, sleepiness, headache, difficulty in swallowing, dry mouth, nausea, muscle weakness, stiff or sore muscles, pain, feeling of weakness, flu syndrome, feeling generally unwell
Less frequent Double vision, drooping of the eyelid, shortness of breath, changes in your voice, fever

Injections in the bladder wall for leakage of urine due to overactive bladder
Frequent Urinary tract infection, painful urination after the injection*, bacteria in the urine, inability to empty your bladder (urinary retention), incomplete emptying of the bladder, frequent daytime urination, white blood cells in the urine, blood in urine after injection**
* This side effect may also be related to the injection procedure
** This side effect is only related to the injection procedure

Injections in the bladder wall for leakage of urine due to bladder problems associated with spinal cord injury or multiple sclerosis
Frequent Urinary tract infection, inability to empty your bladder (urinary retention), difficulty in sleeping (insomnia), constipation, muscle weakness, muscle spasm, blood in the urine after the injection*, painful urination after the injection*, bulge in the bladder wall (bladder diverticulum), tiredness, problems with walking (gait disturbance), possible uncontrolled reflex reaction of your body (e.g. profuse sweating, throbbing headache or increase in pulse rate) around the time of the injection (autonomic dysreflexia)*, fall
* Some of these common side effects may also be related to the injection procedure
Injections for excessive sweating of the armpits
Frequent Pain where the injection was given, headache, numbness, hot flushes, nausea, increased sweating at sites other than the armpit, abnormal skin odour, itching, lump under the skin, hair loss, pain in the extremities such as the hands and fingers, pain, swelling, bleeding, increased sensitivity, irritation or reactions where the injection was given, general weakness
Less frequent Muscle weakness, feeling of weakness, muscle pain, problem with the joints

Injections for the temporary improvement in the fan-shaped lines from the corner of the eyes
Frequent Swelling of the eyelid, injection site bleeding, injection site bruising
Less frequent Injection site pain, injection site tingling or numbness

Injections for the temporary improvement in the fan-shaped lines from the corner of the eyes, when treated at the same time as vertical lines between the eyebrows seen at frown
Frequent Injection site bruising
Less frequent Injection site bleeding, injection site pain

The following list describes additional side effects reported for BOTOX® since it has been marketed: heart problems, decreased hearing, noises in the ear, feeling of dizziness or “spinning” (vertigo), increase in eye pressure, strabismus (crossed-eyes), blurred vision, difficulties in seeing clearly, abdominal pain, diarrhoea, constipation, dry mouth, difficulty swallowing, nausea, vomiting, loss of nerve supply to injected muscle, feeling generally unwell (malaise), fever, allergic reaction, including reactions to injected proteins or serum, swelling of the deeper layers of the skin, hives, eating disorders, loss of appetite, shrinkage of injected muscle, muscle pain, nerve damage (brachial plexopathy), voice and speech problems, weakness of the face muscles, decreased skin sensation, muscle weakness, chronic disease affecting the muscles (myasthenia gravis), difficulty moving the arm and shoulder, numbness, pain, numbness or weakness starting from the spine, seizures, fainting, droop of muscles on one side of the face, aspiration pneumonia (lung inflammation caused by accidentally breathing in food, drink, saliva or vomit), breathing problems, respiratory depression, respiratory failure, hair loss, psoriasis-like skin patches, different types of red blotchy skin rashes, excessive sweating, loss of eyelashes or eyebrows, itching, rash, difficulty in completely closing the eye.

Not all side effects reported for BOTOX® are included in this leaflet. Should your general health worsen or you experience any untoward effects while using BOTOX®, please consult your doctor, pharmacist or other healthcare professional for advice. If you notice any side effects not mentioned in this leaflet, please inform your doctor or pharmacist.

6. STORING AND DISPOSING OF BOTOX®
Store all medicines out of the reach of children.
Store in a refrigerator (2°C –8°C), or store in a freezer (at or below - 5°C).
After the solution is made up, immediate use of the solution is recommended; however it can be stored for up to 24 hours in a refrigerator (2°C –8°C).
Your doctor should not use BOTOX® after the expiry date which is stated on the label after ‘EXP’. The expiry date refers to the last day of that month.
Return all unused medicine to your pharmacist.
Do not dispose of unused medicine in drains or sewerage systems (e.g. toilets).

7. PRESENTATION OF BOTOX®
BOTOX® vacuum dried injection is supplied in a transparent glass vial containing 50 Units, 100 Units or 200 Units of botulinum toxin type A. Each vial is packed in an outer carton.

8. IDENTIFICATION OF BOTOX®
BOTOX® is a white powder. Prior to injection, the product must be dissolved in a sterile saline solution. Dissolved BOTOX® is a clear colourless to slightly yellow solution free of any particles.

9. REGISTRATION NUMBER
27/30.4/0164

10. NAME AND ADDRESS OF REGISTRATION HOLDER
Allergan Pharmaceuticals (Pty) Ltd
30 New Road (entrance off Bavaria Road)
Randjespark Ext. 11, Midrand, 1682
Johannesburg, Gauteng
SOUTH AFRICA
Tel. 011 545 6600

11. DATE OF PUBLICATION OF THIS PATIENT INFORMATION LEAFLET
Date of registration: 5 February 1993
Date of the most recently revised Patient Information Leaflet as approved by Council: 25 November 2016

Updated on this site: September 2017
Source: Pharmaceutical Industry

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