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.

BOTOX is indicated for:

• the symptomatic relief of blepharospasm, hemifacial spasm and idiopathic cervical dystonia (spasmodic torticollis)

• the management of severe hyperhidrosis of the axillae, which does not respond to topical treatment with antiperspirants or antihidrotics

• the prophylaxis of headaches in adults with chronic migraine (headaches on at least 15 days per month of which at least 8 days are with migraine)

BOTOX is also indicated for focal spasticity, including the treatment of:

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

and

• wrist and hand disability due to upper limb spasticity associated with stroke in adults.

BOTOX is also indicated for the temporary improvement in the appearance of moderate to severe vertical lines between the eyebrows seen at frown (glabellar lines), in adults <65 years old, when the severity of these lines has an important psychological impact for the patient.

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

This product is for single use only and any unused solution should be discarded. The most appropriate vial size should be selected for the indication.

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 dilution table below) should be drawn up into a syringe.

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

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

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

Elderly population

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.

There is limited phase 3 clinical data with BOTOX for glabellar lines in patients older than 65 years (see section 5.1). Until more studies have been performed in this age group, BOTOX is not recommended in patients older than 65 years.

Paediatric population

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

The safety and efficacy of BOTOX in adolescents 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).

The safety and effectiveness of BOTOX in the treatment of glabellar lines and in the prophylaxis of chronic migraine headaches have not been demonstrated in individuals under 18 years of age. The use of BOTOX is not recommended in patients less than 18 years for these indications.

Posology

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

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 (0.05-0.1 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. 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 indefinitely. 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. The initial dose should not exceed 25 Units per eye. Normally no additional benefit is conferred by treating more frequently than every three months. It is rare for the effect to be permanent.

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

Hemifacial spasm

Patients with hemifacial spasm or VII^th nerve disorders should be treated as for unilateral blepharospasm, with other affected facial muscles being injected as needed. Electromyographic control may be necessary to identify affected small circumoral muscles.

Cervical dystonia

Several dosing regimens have been used in clinical trials for treatment of cervical dystonia with BOTOX. Dosing must be tailored to the individual patient based on the patient's head and neck position, location of pain, muscle hypertrophy, patient's body weight, and patient response.

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 injection 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 following doses are recommended:

The treatment of cervical dystonia typically may include 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 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.

A 25, 27 or 30 gauge/0.50-0.30 mm needle may be used for superficial muscles, and a 22 gauge needle may be used for deeper musculature. In case of any difficulty in isolating the individual muscles, injections should be made under electromyographic assistance.

Multiple injection sites allow BOTOX to have more uniform contact with the innervation areas of the dystonic muscle and are especially useful in larger muscles. The optimal number of injection sites is dependent upon the size of the muscle to be chemically denervated.

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.

Primary hyperhidrosis of the axillae

The recommended injection volume for intradermal injection in axillary hyperhidrosis is 0.1-0.2 ml. Reconstituted BOTOX (100 Units/4 mL) is injected using a 30 gauge needle. 50 Units of BOTOX is injected intradermally to each axilla, evenly distributed in multiple sites approximately 1-2 cm apart. The hyperhidrotic area to be injected 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. Treatment response has been reported to persist for 4-7 months. Injections should not be repeated more frequently than every 16 weeks (see section 5.1).

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 may be tailored to the individual based on the size, number and location of muscles involved, the severity of spasticity, the presence of local muscle weakness, and the patient response to previous treatment.

In the 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.

Chronic Migraine

The recommended reconstituted BOTOX dose for treating chronic migraine is 155 U to 195 U administered intramuscularly (IM) using a 30-gauge, 0.5 inch needle as 0.1 ml (5 U) injections to 31 and up to 39 sites. Injections should be divided across 7 specific head/neck muscle areas as specified in the diagrams 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:

BOTOX Dosing By Muscle:

^a1 IM injection site = 0.1 mL = 5 U BOTOX

^b Dose distributed bilaterally

The recommended re-treatment schedule is every 12 weeks.

Glabellar lines

Reconstituted BOTOX (50 U/1.25 mL) is injected using a sterile 30 gauge needle. A volume of 0.1 mL (4 U) is administered in each of the 5 injection sites: 2 injections in each corrugator muscle and 1 injection in the procerus muscle for a total dose of 20 U.

Before injection, the thumb or index finger are to be placed firmly below the orbital rim in order to prevent extravasation below the orbital rim. The needle should be oriented superiorly and medially during the injection. In order to reduce the risk of ptosis, injections near the levator palpebrae superioris muscle must be avoided, particularly in patients with larger brow-depressor complexes (depressor supercilii). Injections in the corrugator muscle must be done in the central part of that muscle, at least 1 cm above the arch of the eyebrows.

Care should be taken to ensure that BOTOX is not injected into a blood vessel when it is injected in the glabellar lines.

Improvement of severity of glabellar lines generally occurs within one week after treatment. The effect was demonstrated for up to 4 months after injection.

Treatment intervals should not be more frequent than every three months. In the event of treatment failure or diminished effect following repeat injections, alternative treatment methods should be employed.

In case of insufficient dose and in the absence of any undesirable effects secondary to the first treatment session, adjusting the total dose up to 40 or 50 units should be considered in a second treatment session, taking into account the analysis of the previous treatment failure (see information in All indications).

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:

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. Please see “Additional information” in section 4.8 for further 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 Lambert-Eaton 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.

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.

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, predominantly 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.

Chronic migraine

No efficacy has been shown for BOTOX in the prophylaxis of headaches in patients with episodic migraine (headaches on < 15 days per month).

Glabellar lines

It is mandatory that BOTOX is used for one single patient treatment only during a single session. The excess of unused product must be disposed of as detailed in section 6.6. Particular precautions should be taken for product preparation and administration as well as for the inactivation and disposal of the remaining unused solution (see section 6.6).

The use of BOTOX is not recommended in individuals under 18 years and in patients older than 65 years.

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 depolarising (succinylcholine) and non-depolarising (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 unless clearly necessary.

Lactation

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

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

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% for blepharospasm, 28% for cervical dystonia, 17% for paediatric cerebral palsy and 11% for primary hyperhidrosis of the axillae. Sixteen percent of participants in clinical trials treated with BOTOX for focal spasticity of the upper limb associated with stroke and 23% with glabellar lines experienced an adverse reaction. 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).

Blepharospasm/hemifacial spasm

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).

Chronic Migraine

* In placebo-controlled trials, headache and migraine, including serious cases of intractable or worsening of headache/migraine, were reported more frequently with BOTOX (9%) than with placebo (6%). They typically occurred within the first month after the injections and their incidence declined with repeated treatments.

Glabellar lines

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; anaphylactic reaction (angiodema, bronchospasm).

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, e.g. syncope, hypotension, etc.

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 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 hospitalisation.

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.

ATC class M03A X01 and ATC class D11AX_.

The active constituent in BOTOX is a protein complex derived from Clostridium botulinum. The protein consists of type A neurotoxin and several other proteins. Under physiological conditions it is presumed that the complex dissociates and releases the pure neurotoxin.

Clostridium botulinum toxin type A neurotoxin complex blocks peripheral acetyl choline release at presynaptic cholinergic nerve terminals.

Intramuscular injection of the neurotoxin complex blocks cholinergic transport at the neuromuscular junction by preventing the release of acetylcholine. The nerve endings of the neuromuscular junction no longer respond to nerve impulses and secretion of the chemotransmitter is prevented (chemical denervation). Re-establishment of impulse transmission is by newly formed nerve endings and motor end plates. 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 for about 4-7 months in patients treated with 50 Units per axilla.

There is limited clinical trial experience of the use of BOTOX in primary axillary hyperhidrosis in adolescents 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 established.

BOTOX blocks the release of neurotransmitters associated with the genesis of pain. The presumed mechanism for headache prophylaxis is by blocking peripheral signals to the central nervous system, which inhibits central sensitization, as suggested by pre-clinical and clinical pharmacodynamic studies.

Clinical Data

Chronic Migraine

Chronic migraine patients without any concurrent headache prophylaxis who, during a 28-day baseline, had at least 4 episodes and 15 headache days (with at least 4 hours of continuous headache) with at least 50% being migraine/probable migraine, were studied in two Phase 3 clinical trials. Patients were allowed to use acute headache treatments and 66% overused acute treatments during the baseline period.

During the double-blind phase of the trials, the main results achieved after two BOTOX treatments administered at a 12-week interval are shown in the table below.

* Headache Impact Test

The treatment effect appeared smaller in the subgroup of male patients (N=188) than in the whole study population.

Glabellar Lines

537 patients with moderate to severe glabellar lines at maximum frown have been included in clinical studies.

BOTOX injections significantly reduced the severity of glabellar lines for up to 4 months, as measured by the investigator assessment of glabellar line severity at maximum frown and by subject’s global assessment of change in appearance of his/her glabellar lines. None of the clinical endpoints included an objective evaluation of the psychological impact. Thirty days after injection 80% (325/405) of BOTOX-treated patients were considered by investigators as treatment responders (none or mild severity at maximum frown), compared to 3% (4/132) of placebo-treated patients. At this same timepoint, 89% (362/405) of BOTOX-treated patients felt they had a moderate or better improvement, compared to 7% (9/132) of placebo-treated patients.

BOTOX injections also significantly reduced the severity of glabellar lines at rest. Of the 537 patients enrolled, 39% (210/537) had moderate to severe glabellar lines at rest (15% had no lines at rest). Of these, 74% (119/161) of BOTOX-treated patients were considered treatment responders (none or mild severity) thirty days after injection, compared with 20% (10/49) of placebo-treated patients.

There is limited phase 3 clinical data with BOTOX in patients older than 65 years. Only 6.0% (32/537) of subjects were >65 years old and efficacy results obtained were lower in this population.

a) General characteristics of the active substance:

Classical absorption, distribution, biotransformation and elimination studies on the active substance have not been performed due to the extreme toxicity of botulinum toxin type A.

b) Characteristics in patients:

Human ADME studies have not been performed due to the nature of the product. It is believed that little systemic distribution of therapeutic doses of BOTOX occurs. BOTOX is probably metabolised by proteases and the molecular components recycled through normal metabolic pathways.

Acute toxicity

In monkeys receiving a single intramuscular (i.m.) injection of BOTOX, the No Observed Effect Level (NOEL) ranged from 4 to 24 Units/kg. The i.m. LD₅₀ was reported to be 39 Units/kg.

Toxicity on repeated injection

In three different studies (six months in rats; 20 weeks in juvenile monkeys; 1 year in monkeys) where the animals received i.m. injections, the NOEL was at the following respective BOTOX dosage levels: < 4 Units/kg, 8 Units/kg and 4 Units/kg. The main systemic effect was a transient decrease in body weight gain.

There was no indication of a cumulative effect in the animal studies when BOTOX was given at dosage intervals of 1 month or greater.

Local toxicity

BOTOX was shown not to cause ocular or dermal irritation, or give rise to toxicity when injected into the vitreous body in rabbits.

Allergic or inflammatory reactions in the area of the injection sites are rarely observed after BOTOX administration. However, formation of haematoma may occur.

Reproduction toxicology

Teratogenic effects

When pregnant mice and rats were injected intramuscularly during the period of organogenesis, the developmental NOEL of BOTOX was at 4 Units/kg. Reductions in ossification were observed at 8 and 16 Units/kg (mice) and reduced ossification of the hyoid bone at 16 Units/kg (rats). Reduced foetal body weights were observed at 8 and 16 Units/kg (rats).

In a range-finding study in rabbits, daily injections at dosages of 0.5 Units/kg/day (days 6 to 18 of gestation), and 4 and 6 Units/kg (administered on days 6 and 13 of gestation), caused death and abortions among surviving dams. External malformations were observed in one foetus each in the 0.125 Units/kg/day and the 2 Units/kg dosage groups. The rabbit appears to be a very sensitive species to BOTOX treatment.

Impairment of 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.

Pre- and post-natal developmental effects

In female rats, the reproductive NOEL was 16 Units/kg. The developmental NOEL was 4 Units/kg.

Mutagenicity

BOTOX has been evaluated and shown to be non-mutagenic in a number of in vitro and in vivo systems including the Ames test, the AS52/XPRT Mammalian Cell Forward Gene Mutation assay and the CHO test, and non-clastogenic in the mouse PCE test.

Carcinogenicity

No animal studies have been conducted.

Antigenicity

BOTOX showed antigenicity in mice only in the presence of adjuvant. BOTOX was found to be slightly antigenic in the guinea pig.

Blood compatibility

No haemolysis was detected up to 100 Units/ml of BOTOX in normal human blood.

Human albumin

Sodium chloride

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

3 years.

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

From a microbiological point of view, the product should be used immediately. If not used immediately, 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 (see also section 6.6).

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.

Clear glass vial, with rubber stopper and tamper-proof aluminium seal, containing white powder for solution for injection.

Pack size:

• Carton comprising one 100 Allergan Unit vial and package leaflet.

• Packs containing two, three or six cartons.

Not all pack sizes may be marketed.

BOTOX is reconstituted prior to use with sterile unpreserved normal saline (0.9% sodium chloride for injection). It is good practice to perform vial reconstitution and syringe preparation over plastic-lined paper towels to catch any spillage. An appropriate amount of diluent (see dilution table below) is drawn up into a syringe. The exposed portion of the rubber septum of the vial is cleaned with alcohol (70%) prior to insertion of the needle. Since BOTOX is denatured by bubbling or similar violent agitation, the diluent should be injected gently into the vial. Discard the vial 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. When reconstituted, BOTOX may be stored in a refrigerator (2-8°C) for up to 24 hours prior to use. After this period used or unused vials should be discarded.

Care should be taken to use the correct diluent volume for the presentation chosen to prevent accidental overdose.

Each vial is for single use only.

The 'unit' by which the potency of preparations of BOTOX is measured should be used to calculate dosages of BOTOX only and is not transferable to other preparations of botulinum toxin.

An injection volume of approximately 0.1 ml is recommended. A decrease or increase in the BOTOX dose is possible by administering a smaller or larger injection volume. The smaller the injection volume the less discomfort and less spread of toxin in the injected muscle occurs. This is of benefit in reducing effects on nearby muscles when small muscle groups are being injected.

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

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

Allergan Ltd.,

Marlow International,

The Parkway, Marlow,

Bucks, SL7 1YL, UK

PL 00426/0074

17 May 1994

24 November 2011