Allergan Ltd

BOTOX

50 Allergan Units

Powder for Solution for Injection

Botulinum toxin^* type A, 50 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).

Posology

Refer to specific recommendations for each indication described below.

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, BOTOX 100 Allergan Units and BOTOX 200 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 50 Unit vials for Urinary incontinence due to neurogenic detrusor overactivity:

It is recommended that 100U or 200U vials are used for convenience of reconstitution.

• 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 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, 100 and 200 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.

Elderly patients

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.

Paediatric population

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).

Method of Administration

Refer to specific guidance for each indication described below.

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 (50 Units/2 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:

^a1 IM 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-evaluation 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 localised infection, pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling, erythema, and/or bleeding/bruising. Needle-related pain and/or anxiety may result in vasovagal responses, e.g. syncope, hypotension, etc. 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 4.8).

There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin. 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 additional investigations as required, should be performed to exclude potential causes of secondary hyperhidrosis (e.g. hyperthyroidism, phaeochromocytoma). This will avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of underlying disease.

Urinary incontinence due to neurogenic detrusor overactivity

Appropriate medical caution should be exercised when performing a cystoscopy.

In patients who are not catheterising, post-void residual urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks. Patients should be instructed to contact their physician if they experience difficulties in voiding as catheterisation may be required.

Autonomic dysreflexia associated with the procedure can occur. Prompt medical attention may be required.

Chronic migraine

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

Theoretically, the effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or spectinomycin, or other medicinal products that interfere with neuromuscular transmission (e.g. neuromuscular blocking agents, both depolarizing (succinylcholine) and non-depolarizing (tubocurarine derivatives), lincosamides, polymyxins, quinidine, magnesium sulphate, and anticholinesterases).

The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

No interaction studies have been performed. No interactions of clinical significance have been reported.

Pregnancy

There are no adequate data from the use of botulinum toxin type A in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. BOTOX should not be used during pregnancy and in women of childbearing potential not using contraception unless clearly necessary.

Breastfeeding

There is no information on whether BOTOX is excreted in human milk. The use of BOTOX during breastfeeding cannot be recommended.

Fertility

There are no adequate data on the effects on fertility from the use of botulinum toxin type A in women of childbearing potential. Studies in male and female rats have shown fertility reductions (see section 5.3).

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

a. General

Based on controlled clinical trial data patients would be expected to experience an adverse reaction after treatment with BOTOX at the rates of 35% of the patients with blepharospasm, 28% with cervical dystonia, 17% with paediatric cerebral palsy, 11% with primary hyperhidrosis of the axillae and 16% with focal spasticity of the upper limb associated with stroke. In clinical trials for urinary incontinence due to neurogenic detrusor overactivity, the incidence was 32% with the first treatment and declined to 18% with a second treatment. In clinical trials for chronic migraine, the incidence was 26% with the first treatment and declined to 11% with a second treatment.

In general, adverse reactions occur within the first few days following injection and, while generally transient, may have a duration of several months or, in rare cases, longer.

Local muscle weakness represents the expected pharmacological action of botulinum toxin in muscle tissue.

As is expected for any injection procedure, localised pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling/oedema, erythema, localised infection, bleeding and/or bruising have been associated with the injection. Needle-related pain and/or anxiety have resulted in vasovagal responses, including transient symptomatic hypotension and syncope. Fever and flu syndrome have also been reported after injections of botulinum toxin.

b. Adverse reactions - frequency by indication

For each indication the frequency of adverse reactions arising from clinical experience is given. The frequency is defined as follows: Very Common ( 1/10); Common ( 1/100 to <1/10); Uncommon ( 1/1,000 to <1/100); Rare ( 1/10,000 to <1/1,000); Very Rare (<1/10,000).

Some of the uncommon events may be disease related.

In the management of primary axillary hyperhidrosis, increase in non axillary sweating was reported in 4.5% of patients within 1 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.

In an uncontrolled safety study of BOTOX (50 U per axilla) in paediatric patients 12 to 17 years of age (N= 144), adverse reactions occurring in more than a single patient (2 patients each) comprised injection site pain and hyperhidrosis (non-axillary sweating).

* procedure-related adverse reactions

In clinical trials urinary tract infection was reported in 49.2% of patients treated with 200 U BOTOX and in 35.7% of patients treated with placebo (53.0% of multiple sclerosis patients treated with 200 U vs. 29.3% with placebo; 45.4% of spinal cord injury patients treated with 200 U vs. 41.7% with placebo). Urinary retention was reported in 17.2% of patients treated with 200 U BOTOX and in 2.9% of patients treated with placebo (28.8% of multiple sclerosis patients treated with 200 U vs. 4.5% with placebo; 5.4% of spinal cord injury patients treated with 200 U vs. 1.4% with placebo).

No change in the type of adverse reactions was observed 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.

Among patients who were not catheterising at baseline prior to treatment, catheterisation was initiated in 38.9% following treatment with BOTOX 200 Units versus 17.3% on placebo.

The discontinuation rate due to adverse events in these phase 3 trials was 3.8% for BOTOX vs. 1.2% for placebo.

c. Additional information

Dysphagia ranges in severity from mild to severe, with potential for aspiration, which occasionally may require medical intervention (see section 4.4).

Side effects related to spread of toxin distant from the site of administration have been reported very rarely (exaggerated muscle weakness, dysphagia, aspiration/aspiration pneumonia, with fatal outcome in some cases) (see section 4.4).

The following other adverse events have been reported since the drug has been marketed: dysarthria, abdominal pain; vision blurred; visual disturbance; pyrexia; facial palsy, facial paresis; hypoaesthesia; malaise; myalgia; pruritus; hyperhidrosis; alopecia (including madarosis); diarrhoea; anorexia; hypoacusis; tinnitus; vertigo; radiculopathy; syncope; myasthenia gravis; paraesthesia; erythema multiforme; dermatitis psoriasiform; vomiting and brachial plexopathy.

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

Serious and/or immediate hypersensitivity reactions such as anaphylaxis and serum sickness have been rarely reported, as well as other manifestations of hypersensitivity including 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 agents known to cause similar reactions.

A case of peripheral neuropathy has been reported in a large adult male after receiving four sets of BOTOX injections, totalling 1800 Units (for neck and back spasm, and severe pain) over an 11 week period.

Angle closure glaucoma has been reported very rarely following botulinum toxin treatment for blepharospasm.

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

Needle-related pain and/or anxiety may result in vasovagal responses.

Overdose of BOTOX is a relative term and depends upon dose, site of injection, and underlying tissue properties. No cases of systemic toxicity resulting from accidental injection of BOTOX have been observed. No cases of ingestion of BOTOX have been reported. Signs and symptoms of overdose are not apparent immediately post-injection. Should accidental injection or ingestion occur, the patient should be medically monitored for up to several weeks for progressive signs and symptoms of muscular weakness distant from the site of injection that may include ptosis, diplopia, swallowing and speech disorders, generalized weakness or respiratory failure. These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalization.

With increasing dosage, generalised and profound muscular paralysis occurs. When the musculature of the oropharynx and oesophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralysed, intubation and assisted respiration will be required until recovery takes place.

Pharmacotherapeutic group: Other Muscle relaxants, peripherally acting agents

ATC code: M03A X01

Botulinum toxin type A blocks peripheral acetylcholine release at presynaptic cholinergic nerve terminals by cleaving SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within the nerve endings.

After injection, there is an initial rapid high-affinity binding of toxin to specific cell surface receptors. This is followed by transfer of the toxin across the plasma membrane by receptor-mediated endocytosis. Finally, the toxin is released into the cytosol. This latter process is accompanied by progressive inhibition of acetylcholine release, clinical signs are manifest within 2-3 days, with peak effect seen within 5-6 weeks of injection.

Recovery after intramuscular injection takes place normally within 12 weeks of injection as nerve terminals sprout and reconnect with the endplates. After intradermal injection, where the target is the eccrine sweat glands the effect lasted an average of 7.5 months after the first injection in patients treated with 50 Units per axilla. However, in 27.5 % of patients the duration of effect was 1 year or greater. Recovery of sympathetic nerve endings that innervate sweat glands after intradermal injection with BOTOX has not been studied.

Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity via inhibition of acetylcholine release. In addition BOTOX may inhibit afferent neurotransmitters and sensory pathways.

CLINICAL STUDIES

Primary hyperhidrosis of the axillae

A double-blind, multi-centre clinical study was conducted in patients presenting with persistent bilateral primary axillary hyperhidrosis defined as baseline gravimetric measurement of at least 50 mg spontaneous sweat production in each axilla over 5 minutes at room temperature, at rest. Three hundred and twenty patients were randomized to receive either 50 Units of BOTOX (N=242) or placebo (N=78). Treatment responders were defined as subjects showing at least a 50% reduction from baseline in axillary sweating. At the primary endpoint, week 4 post-injection, the response rate in the BOTOX group was 93.8% compared with 35.9% in the placebo group (p< 0.001). The incidence of responders among BOTOX treated patients continued to be significantly higher (p<0.001) than placebo treated patients at all post-treatment time points for up to 16 weeks.

A follow up open-label study enrolled 207 eligible patients who received up to 3 BOTOX treatments. Overall, 174 patients completed the full 16-month duration of the 2 studies combined (4 month double-blind and 12 month open-label continuation). Incidence of clinical response at week 16 following the first (n=287), second (n=123) and third (n=30) treatments was 85.0%, 86.2% and 80% respectively. The mean duration of effect based on the combined single-dose and open-label continuation trial was 7.5 months following the first treatment, however for 27.5% of patients the duration of effect was 1 year or greater.

There is limited clinical trial experience of the use of BOTOX in primary axillary hyperhidrosis in children between the ages of 12 and 18. A single, year long, uncontrolled, repeat dose, safety study was conducted in US paediatric patients 12 to 17 years of age (N=144) with severe primary hyperhidrosis of the axillae. Participants were primarily female (86.1%) and Caucasian (82.6%). Participants were treated with a dose of 50 U per axilla for a total dose of 100 U per patient per treatment. However no dose finding studies have been conducted in adolescents so no recommendation on posology can be made. Efficacy and safety of BOTOX in this group have not been conclusively established.

Urinary incontinence due to neurogenic detrusor overactivity

Two double-blind, placebo-controlled, randomised, multi-centre Phase 3 clinical studies were conducted in patients with urinary incontinence due to neurogenic detrusor overactivity who were either spontaneously voiding or using catheterisation. A total of 691 spinal cord injury or multiple sclerosis patients, not adequately managed with at least one anticholinergic agent, were enrolled. These patients were randomised to receive either 200 Units of BOTOX (n=227), 300 Units of BOTOX (n=223), or placebo (n=241).

In both phase 3 studies, significant improvements compared to placebo in the primary efficacy variable of change from baseline in weekly frequency of incontinence episodes were observed favouring BOTOX (200 Units and 300 Units) at the primary efficacy time point at week 6, including the percentage of dry patients. Significant improvements in urodynamic parameters including increase in maximum cystometric capacity and decreases in peak detrusor pressure during the first involuntary detrusor contraction were observed. Significant improvements, compared with placebo, in patient reported incontinence specific health-related quality of life scores as measured by the Incontinence Quality of Life questionnaire (I-QOL) (including avoidance limiting behaviour, psychosocial impact and social embarrassment) were also observed. No additional benefit of BOTOX 300 Units over 200 Units was demonstrated and a more favourable safety profile was observed with BOTOX 200 Units.

Results from the pooled pivotal studies are presented below:

Primary and Secondary Endpoints at Baseline and Change from Baseline in Pooled Pivotal Studies:

* Percentage of dry patients (without incontinence) throughout week 6 was 37% for the 200 Unit BOTOX group and 9% for placebo. The proportions achieving a 75% reduction from baseline, in incontinence episodes, were 63% and 24% respectively. The proportions achieving a 50% reduction from baseline were 76% and 39% respectively.

^a Primary endpoint

^b Secondary endpoints

^c I-QOL total score scale ranges from 0 (maximum problem) to 100 (no problem at all).

^d In the pivotal studies, the pre-specified minimally important difference (MID) for I-QOL total score was 8 points based on MID estimates of 4-11 points reported in neurogenic detrusor overactivity patients.

The median duration of response in the two pivotal studies, based on patient request for re-treatment, was 256-295 days (36-42 weeks) for the 200 Unit dose group compared to 92 days (13 weeks) with placebo.

For all efficacy endpoints, patients experienced consistent response with re-treatment.

In the pivotal studies, none of the 475 neurogenic detrusor overactivity patients with analysed specimens developed neutralising antibodies.

Chronic migraine

BOTOX blocks the release of neurotransmitters associated with the genesis of pain. The mechanism of action of BOTOX for symptom relief in chronic migraine is not fully established. Pre-clinical and clinical pharmacodynamic studies suggest that BOTOX suppresses peripheral sensitisation, thereby possibly also inhibiting central sensitisation.

The main results achieved from the pooled efficacy analysis after two BOTOX treatments administered at a 12-week interval from two phase 3 clinical trials in chronic migraine patients, who during a 28-day baseline period had at least 4 episodes and 15 headache days (with at least 4 hours of continuous headache), with at least 50% of headache days being migraine/probable migraine days, are shown in the table below:

Although the studies were not powered to show differences in subgroups, the treatment effect appeared smaller in the subgroup of male patients (N=188) and non-Caucasians (N= 137) than in the whole study population.

General characteristics of the active substance:

Distribution studies in rats indicate slow muscular diffusion of ¹²⁵I-botulinum neurotoxin A complex in the gastrocnemius muscle after injection, followed by rapid systemic metabolism and urinary excretion. The amount of radiolabeled material in the muscle declined at a half-life of approximately 10 hours. At the injection site the radioactivity was bound to large protein molecules, whereas in the plasma it was bound to small molecules, suggesting rapid systemic metabolism of the substrate. Within 24 hours of dosing, 60% of the radioactivity was excreted in the urine. Toxin is probably metabolised by proteases and the molecular components recycled through normal metabolic pathways.

Classical absorption, distribution, biotransformation and elimination studies on the active substance have not been performed due to the nature of this product.

Characteristics in patients:

It is believed that little systemic distribution of therapeutic doses of BOTOX occurs. Clinical studies using single fibre electromyographic techniques have shown increased electrophysiologic neuromuscular activity in muscles distant to the injection site, unaccompanied by any clinical signs or symptoms.

Reproductive studies

When pregnant mice, rats and rabbits were given intramuscular injections of BOTOX during the period of organogenesis, the developmental No Observed Adverse Effect Level (NOAEL) was 4, 1 and 0.125 Units/kg, respectively. Higher doses were associated with reductions in foetal body weights and/or delayed ossification and in rabbits abortions were noted.

Fertility and reproduction

The reproductive NOEL following i.m. injection of BOTOX was 4 Units/kg in male rats and 8 Units/kg in female rats. Higher dosages were associated with dose-dependent reductions in fertility. Provided impregnation occurred, there were no adverse effects on the numbers or viability of the embryos sired or conceived by treated male or female rats.

Other studies

In addition to the reproductive toxicology, the following preclinical safety studies of BOTOX have been performed: Acute toxicity, toxicity on repeated injection, local tolerance, mutagenicity, antigenicity, human blood compatibility. These studies revealed no special hazard for humans at clinically relevant dose levels. The maximum recommended dose in humans at one treatment session is 300 Units (corresponding to 6 Units/kg in a 50 kg person). The published intramuscular LD₅₀ in juvenile monkeys is 39 Units/kg.

No systemic toxicity was observed following a single intradetrusor injection of <50 Units/kg BOTOX in rats. To simulate inadvertent injection, a single dose of BOTOX (~7 Units/kg) was administered into the prostatic urethra and proximal rectum, the seminal vesicle and urinary bladder wall, or the uterus of monkeys (~3 Units/kg) without adverse clinical effects. In a 9 month repeat dose intradetrusor study (4 injections), ptosis was observed at 24 Units/kg, and mortality was observed at doses 24 Units/kg. Myofibre degeneration/regeneration was observed in skeletal muscle of animals dosed with 24 Units/kg and higher. These myopathic changes were considered secondary effects of systemic exposure. In addition, myofibre degeneration was observed in one animal dosed with 12 Units/kg. The lesion in this animal was minimal in severity and considered not to be associated with any clinical manifestations. It could not be determined with certainty if it was related to the BOTOX treatment. The dose of 12 Units/kg corresponds to a 3-fold greater exposure to BOTOX than the recommended clinical dose of 200 Units for urinary incontinence due to neurogenic detrusor overactivity (based on a 50 kg person).

Human albumin

Sodium chloride

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years.

Microbiological and potency studies have demonstrated that the product may be stored for up to 5 days at 2 - 8°C following reconstitution.

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 – 8°C.

After reconstitution in the vial, stability has been demonstrated for 24 hours at 2°C – 8°C.

Store in a refrigerator (2°C-8°C), or store in a freezer (at or below -5°C).

For storage conditions of the reconstituted medicinal product see section 6.3.

Uncoloured Type I glass vial, of 5 ml nominal capacity, fitted with chlorobutyl rubber stopper and tamper-proof aluminium seal.

Each pack contains 1, 2, 3, 6 or 10 vials.

Not all pack sizes may be marketed.

It is good practice to perform vial reconstitution and syringe preparation over plastic-lined paper towels to catch any spillage.

BOTOX must only be reconstituted with sterile sodium chloride 9 mg/ml (0.9%) solution for injection. The appropriate amount of diluent should be drawn up into a syringe. See section 4.2 for dilution instructions for urinary incontinence due to neurogenic detrusor overactivity.

Dilution table for BOTOX 50, 100 and 200 Allergan Units vial size for all other indications:

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, BOTOX 100 Allergan Units and BOTOX 200 Allergan Units. Each syringe should be labelled accordingly.

Since BOTOX is denatured by bubbling or similar vigorous agitation, the diluent should be gently injected into the vial. The vial should be discarded if a vacuum does not pull the diluent into the vial. Reconstituted BOTOX is a clear colourless to slightly yellow solution free of particulate matter. The reconstituted solution should be visually inspected for clarity and absence of particles prior to use. When reconstituted in the vial, BOTOX may be stored in a refrigerator (2-8°C) for up to 24 hours prior to use. The date and time of reconstitution should be recorded on the space of the label. When BOTOX is further diluted for urinary incontinence in a syringe, it should be used immediately. This product is for single use only and any unused solution should be discarded.

For safe disposal, unused vials should be reconstituted with a small amount of water and then autoclaved. Any used vials, syringes, and spillages etc. should be autoclaved, or the residual BOTOX inactivated using dilute hypochlorite solution (0.5%) for 5 minutes.

Any unused product or waste material should be disposed of in accordance with local requirements.

Allergan Pharmaceuticals Ireland

Castlebar Road

Westport

County Mayo

Ireland

PA 0148/060/2

First authorisation: 18 January 2008

Last renewal: 28^th February 2009

25 November 2011