BOTOX

100 Allergan Units

Powder for Solution for Injection

Botulinum toxin^* type A, 100 Allergan Units/vial.

^* from Clostridium botulinum

Botulinum toxin units are not interchangeable from one product to another.

For a full list of excipients, see section 6.1.

Powder for solution for injection.

White powder.

BOTOX is indicated for the management of:

Blepharospasm, hemifacial spasm and associated focal dystonias.

Cervical dystonia (spasmodic torticollis).

Focal spasticity,

- associated with dynamic equinus foot deformity due to spasticity in ambulant paediatric cerebral palsy patients, two years of age or older.

- of the wrist and hand in adult post stroke patients.

Persistent severe primary hyperhidrosis of the axillae, which interferes with the activities of daily living and is resistant to topical treatment.

Urinary incontinence in adults with neurogenic detrusor overactivity resulting from neurogenic bladder due to stable sub-cervical spinal cord injury, or multiple sclerosis.

Symptom relief in adults fulfilling criteria for chronic migraine (headaches on 15 days per month of which at least 8 days with migraine) in patients who have responded inadequately or are intolerant of prophylactic migraine medications (see section 4.4).

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

The following information is important:

If different vial sizes of BOTOX are being used as part of 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 and BOTOX 100 Allergan Units. Each syringe should be labelled accordingly.

BOTOX must only be reconstituted with sterile sodium chloride 9 mg/ml (0.9%) solution for injection. The appropriate amount of diluent (see below) should be drawn up into a syringe.

Dilution instructions for 100 Unit vials for Urinary incontinence due to neurogenic detrusor overactivity:

• 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.

This will result in three 10 ml syringes containing a total of 200 Units of reconstituted BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline.

Dilution table for BOTOX 50 and 100 Allergan Units vial size for all other indications:

This product is for single use only and any unused solution should be discarded.

For instructions on use, handling and disposal of vials please refer to section 6.6.

Adequate studies on geriatric dosing have not been performed. The lowest effective dose with the longest clinically indicated interval between injections is recommended. Elderly patients with significant medical history and concomitant medications should be treated with caution.

The safety and effectiveness of BOTOX in the treatment of blepharospasm, hemifacial spasm, or cervical dystonia in children (under 12 years) have not been demonstrated.

The safety and effectiveness of BOTOX in the treatment of urinary incontinence due to neurogenic detrusor overactivity in children (under 18 years) have not been established.

The safety and effectiveness of BOTOX in the treatment of chronic migraine have not been studied in children (under 18 years).

The safety and effectiveness of BOTOX in the treatment of primary hyperhidrosis of the axillae have not been investigated in children under 12 years. The safety and efficacy of BOTOX in children aged 12 to 17 years for the treatment of severe axillary hyperhidrosis have not been established. Currently available data are described in section 4.8 and 5.1 but no recommendation on a posology can be made (see sections 4.8 and 5.1).

BOTOX should only be given by physicians with appropriate qualifications, and expertise in the treatment and the use of the required equipment.

Generally valid optimum dose levels and number of injection sites per muscle have not been established for all indications. In these cases, individual treatment regimens should therefore be drawn up by the physician. Optimum dose levels should be determined by titration but the recommended maximum dose should not be exceeded.

Blepharospasm/hemifacial spasm

Reconstituted BOTOX is injected using a sterile, 27-30 gauge/0.40–0.30 mm needle. Electromyographic guidance is not necessary. The initial recommended dose is 1.25-2.5 Units 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. 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:

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 as needed. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient. However, there appears to be little benefit obtainable from injecting more than 5 Units per site. The initial dose should not exceed 25 Units per eye. Normally no additional benefit is conferred by treating more frequently than every three months.

In the management of blepharospasm total dosing should not exceed 100 Units every 12 weeks.

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

Reconstituted BOTOX is injected using an appropriately sized needle (usually 25-30 gauge/0.50–0.30 mm).

In clinical trials the treatment of cervical dystonia has typically included 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. In initial controlled clinical trials to establish safety and efficacy for cervical dystonia, doses of reconstituted BOTOX ranged from 140 to 280 Units. In more recent studies, the doses have ranged from 95 to 360 Units (with an approximate mean of 240 Units). As with any drug treatment, initial dosing in a naïve patient should begin at the lowest effective dose. No more than 50 Units should be given at any one site. No more than 100 Units should be given to the sternomastoid. To minimise the incidence of dysphagia, the sternomastoid should not be injected bilaterally. 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. A total dose of 300 Units at any one sitting should not be exceeded. The optimal number of injection sites is dependent upon the size of the muscle.

Clinical improvement generally occurs within the first two weeks after injection. The maximum clinical benefit generally occurs approximately six weeks-post-injection. Treatment intervals of less than 10 weeks are not recommended. The duration of beneficial effect reported in clinical trials showed substantial variation (from 2 to 33 weeks) with a typical duration of approximately 12 weeks.

Paediatric cerebral palsy

Reconstituted BOTOX is injected using a sterile 23-26 gauge/0.60–0.45 mm needle. It is administered as a divided dose through single injections into the medial and lateral heads of the affected gastrocnemius muscle. In hemiplegia, the initial recommended total dose is 4 Units/kg body weight in the affected limb. In diplegia, the initial recommended total dose is 6 Units/kg body weight divided between the affected limbs. The total dose should not exceed 200 Units.

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

Reconstituted BOTOX is injected using a sterile 25, 27 or 30 gauge needle for superficial muscles, and a longer needle for deeper musculature. 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.

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.

In controlled clinical trials the following doses were administered:

In controlled and open non-controlled clinical trials doses between 200 and 240 Units divided among selected muscles have been used at a given treatment session.

In controlled clinical trials patients were followed for 12 weeks after single treatment. Improvement in muscle tone occurred within two weeks with the peak effect generally seen within four to six weeks. In an open, non-controlled continuation study, most of the patients were re-injected after an interval of 12 to 16 weeks, when the effect on muscle tone had diminished. These patients received up to four injections with a maximal cumulative dose of 960 Units over 54 weeks. If it is deemed appropriate by the treating physician, repeat doses may be administered, when the effect of a previous injection has diminished. Re-injections should not occur before 12 weeks. 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.

Primary hyperhidrosis of the axillae

Reconstituted BOTOX (100 Units/4 ml) is injected using a 30 gauge needle. 50 Units of BOTOX is injected intradermally, evenly distributed in multiple sites approximately 1-2 cm apart within the hyperhidrotic area of each axilla. The hyperhidrotic area may be defined by using standard staining techniques, e.g. Minor´s iodine-starch test. Doses other than 50 Units per axilla have not been studied and therefore cannot be recommended.

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 physician deems it necessary. Injections should not be repeated more frequently than every 16 weeks (see section 5.1).

Urinary incontinence due to neurogenic detrusor overactivity

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.

Prior to injection, either an intravesical instillation of diluted 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 the next steps of the injection procedure.

The recommended dose is 200 Units of BOTOX, as 1 ml (~6.7 Units) injections across 30 sites in the detrusor.

Reconstituted BOTOX (200 Units/30 ml) is injected into the detrusor muscle via a flexible or rigid cystoscope, avoiding the trigone. The bladder should be instilled with enough saline to achieve adequate visualisation for the injections, but over-distension should be avoided.

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.

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 diagram). 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.

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 for BOTOX 200 Units), but no sooner than 3 months from the prior bladder injection.

Chronic Migraine

Chronic migraine should be diagnosed by, and BOTOX should be exclusively administered under the supervision of neurologists who are experts in the treatment of chronic migraine.

The recommended reconstituted BOTOX dose for treating chronic migraine is 155 Units to 195 Units administered intramuscularly (IM) using a 30-gauge, 0.5 inch needle as 0.1 ml (5 Units) injections to 31 and up to 39 sites. Injections should be divided across 7 specific head/neck muscle areas as specified in the table below. A 1-inch needle may be needed in the neck region for patients with extremely thick neck muscles. With the exception of the procerus muscle, which should be injected at 1 site (midline), all muscles should be injected bilaterally with half the number of injections sites administered to the left, and half to the right side of the head and neck. If there is a predominant pain location(s), additional injections to one or both sides may be administered in up to 3 specific muscle groups (occipitalis, temporalis, and trapezius), up to the maximum dose per muscle as indicated in the table below.

The following diagrams indicate the injection sites:

The recommended retreatment schedule is every 12 weeks.

BOTOX Dosing By Muscle for Chronic Migraine:

^a1IM injection site = 0.1 mL = 5 Units BOTOX

^bDose distributed bilaterally

All indications

In case of treatment failure after the first treatment session, i.e. absence, at one month after injection, of significant clinical improvement from baseline, the following actions should be taken:

- Clinical verification, which may include electromyographic examination in a specialist setting, of the action of the toxin on the injected muscle(s);

- Analysis of the causes of failure, e.g. bad selection of muscles to be injected, insufficient dose, poor injection technique, appearance of fixed contracture, antagonist muscles too weak, formation of toxin-neutralising antibodies;

- Re-eva luation of the appropriateness of treatment with botulinum toxin type A;

- In the absence of any undesirable effects secondary to the first treatment session, instigate a second treatment session as following: i) adjust the dose, taking into account the analysis of the earlier treatment failure; ii) use EMG; and iii) maintain a three-month interval between the two treatment sessions.

In the event of treatment failure or diminished effect following repeat injections alternative treatment methods should be employed.

BOTOX is contraindicated:

- in individuals with a known hypersensitivity to botulinum toxin type A or to any of the excipients;

- in the presence of infection at the proposed injection site(s).

BOTOX for management of urinary incontinence due to neurogenic detrusor overactivity is also contraindicated:

- 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 and/or able to initiate catheterisation post-treatment if required.

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. The recommended dosages and frequencies of administration of BOTOX should not be exceeded.

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 (see section 4.8c for additional information).

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.

Patients treated with therapeutic doses may experience exaggerated muscle weakness. Patients with underlying neurological disorders including swallowing difficulties are at increased risk of these side effects. 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.

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

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.

Formation of neutralizing 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 minimized by injecting with the lowest effective dose given at the longest clinically indicated intervals between injections.

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.

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. 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).

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 Eaton Lambert Syndrome; such patients may have an increased sensitivity to agents such as BOTOX, which may result in excessive muscle weakness. Patients with neuromuscular disorders may be at an increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of BOTOX.

As with any injection, procedure-related injury could occur. An injection could result in localized 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. Care should be taken when injecting near vulnerable anatomic structures.

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.

Cervical dystonia

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.

Focal spasticity associated with paediatric cerebral palsy 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 likely to be effective in improving range of motion at a joint affected by a fixed contracture.

Post-marketing reports of possible distant spread of toxin have been very rarely reported in paediatric patients with co-morbidities, predominately with cerebral palsy. In general the dose used in these cases was in excess of that recommended (see section 4.2).

There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin. Caution should be exercised when treating paediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease.

Primary hyperhidrosis of the axillae

Medical history and physical examination, along with specific