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). It is indicated for the management of severe hyperhidrosis of the axillae, which does not respond to topical treatment with antiperspirants or antihidrotics.

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

The injections should be administered by appropriately trained personnel in hospital specialist centres.

The safety and effectiveness of BOTOX in the treatment of blepharospasm, hemifacial spasm, or idiopathic cervical dystonia, or focal hyperhidrosis in children have not been demonstrated.

Doses recommended for BOTOX are not interchangeable with other preparations of botulinum toxin.

Adequate studies on geriatric dosing have not been performed. Dose selection should be the same; however, the lowest effective dose is recommended.

Blepharospasm

After reconstitution, BOTOX is injected using a sterile, 27-30 gauge 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. 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 VIIth 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 practice, the maximum total dose is not usually more than 200 Units. No more than 50 Units should be given at any one injection site. The dilutions suggested are indicated in the following table:

The following doses are recommended:

The treatment of cervical dystonia typically may include injection of BOTOX into the sternocleidomastoid, levator scapulae, scalene, splenius capitis, and/or the trapezius muscle(s). The muscle mass and the degree of hypertrophy are factors to be taken into consideration when selecting the appropriate dose.

The sternocleidomastoid muscle should not be injected bilaterally as there is an increased risk of adverse effects (in particular dysphagia) when bilateral injections or doses in excess of 100 Units are administered to this muscle.

A 25, 27 or 30 gauge needle may be used for superficial muscles, and a 22 gauge needle may be used for deeper musculature. For cervical dystonia, localisation of the involved muscles with electromyographic guidance may be useful.

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.

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.

Clinical improvement generally occurs within the first week after injection. Repeat injections of axillary hyperhidrosis should be administered when effects from previous injections subside. Treatment response has been reported to persist for 4-7 months.

Paediatric cerebral palsy

Diluted BOTOX is injected using a sterile 23-26 gauge needle. It is administered into each of two sites in the medial and lateral heads of the affected gastrocnemius muscle. The recommended total dose is 4 Units/kg body weight. When both lower limbs are to be injected on the same occasion this dose should be divided between the two limbs.

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 two months.

Focal 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, and the presence of local muscle weakness.

In the controlled Phase 3 clinical trial the following doses were administered:

In all clinical trials, the doses did not exceed 360 Units divided among selected muscles at any treatment session.

Clinical improvement in muscle tone generally occurs within two weeks following treatment and the peak effect is generally seen within four to six weeks following treatment. Data on the repeated and long-term treatment are limited.

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).

The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering BOTOX. 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. Please see section 4.8c) 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' for further information).

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.

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.

BOTOX contains human serum albumin. When medicinal products derived from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. To reduce the risk of transmission of infective agents, stringent controls are applied to the selection of blood donors and donations. In addition, virus inactivation procedures are included in the production process.

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 pathology. 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.

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.

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.

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. tubocurarine-type muscle relaxants).

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 lactation cannot be recommended.

The effects of BOTOX on the ability to drive or to use machines can only be assessed after treatment.

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 (16%) of participants in clinical trials treated with BOTOX for focal spasticity of the upper limb associated with stroke experienced an adverse reaction.

In general, adverse reactions occur within the first few days following injection and are transient.

In rare cases, adverse reactions may have a duration of several months or longer.

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

As is expected for any injection procedure, localised pain, tenderness and/or bruising may be associated with the injection. 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, <1/10); Uncommon (>1/1,000, <1/100); Rare (>1/10,000, <1/1,000); Very Rare (<1/10,000).

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.

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; pyrexia; focal facial paralysis; hypoaesthesia; malaise; myalgia; pruritus; hyperhidrosis; diarrhoea; anorexia; hypoacusis; tinnitus; radiculopathy; syncope; myasthenia gravis; 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 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 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..

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 supervised for several days for signs and symptoms of systemic weakness or muscle paralysis.

Patients presenting with the symptoms of botulinum toxin type A poisoning (generalised weakness, ptosis, diplopia, swallowing and speech disorders, or paresis of the respiratory muscles) should be considered for admission to hospital.

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.

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.

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

22^nd May 2009