Allergan Ltd

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4.1

Therapeutic indications

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BOTOX is indicated for:

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

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

Ø  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:

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

            and

Ø  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, idiopathic cervical dystonia, chronic migraine and focal hyperhidrosis have not been demonstrated in children.

4.2

Posology and method of administration

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

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

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.

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

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

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

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

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 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)

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 After reconstitution, BOTOX is injected using a sterile, 27-30/0.40-0.30mm 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.  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:

PLEASE SEE PICTURES IN PUBLISHED SPC.

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 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.  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.  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 dilutions suggested are indicated in the following table:

Diluent added                          Resulting dose in units per 0.1 ml

0.5 ml                                      40 Units

1 ml                                         20 Units

2 ml                                         10 Units

4 ml                                         5 Units

8 ml                                         2.5 Units

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.

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 30/0.50-0.30mm gauge 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. 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.

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 Hhyperhidrosis 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. 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. Injections should not be repeated more frequently than every 16 weeks (see section 5.1).

Paediatric cerebral palsy

ReconstitutedDiluted BOTOX is injected using a sterile 23-26/0.60-0.45mm gauge needle.  It is administered as a divided dose through single injections into each of two sites in the medial and lateral heads of the affected gastrocnemius muscle.  In hemiplegia, the initial The recommended total dose is 4 Units/kg body weight the affected limb.  In diplegia, the initial recommended total dose is 6 Units/kg body weight When both lower limbs are to be injected on the same occasion this dose should be divided between the two 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 two 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, and the presence of local muscle weakness, and the patient response to previous treatment.

In the controlled Phase 3 clinical trial 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 all clinical trials, the doses did not exceed 360 Units divided among selected muscles at any 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. 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.

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:

PLEASE SEE PICTURES IN PUBLISHED SPC

         BOTOX  Dosing By Muscle

^a1IM injection site = 0.1 mL = 5 U BOTOX

^bDose distributed bilaterally

The recommended retreatment schedule is every 12 weeks.

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.

4.4

Special warnings and precautions for use

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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.

 (see section 4.8c 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 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.

BOTOX contains human 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 exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders 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,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 Hhyperhidrosis 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 4.28).

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).

4.5

Interaction with other medicinal products and other forms of interaction

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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-type muscle relaxants). 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.

4.8

Undesirable effects

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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 experienced an adverse reaction.

In controlled clinical trials, adverse events considered by the investigators to be related to BOTOX were reported in 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 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 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, 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. 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 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

Nervous system disorders

Uncommon:                Dizziness, facial paresis and facial palsy.

Eye Disorders

Very common:                        Eyelid ptosis.

Common:                    Punctate keratitis, lagophthalmos, dry eye, photophobia, eye irritation and lacrimation increase.

Uncommon:                Keratitis, ectropion, diplopia, entropion, visual disturbance and vision         blurred.

Rare:                           Eyelid oedema.

Very rare:                    Corneal ulceration, corneal epithelium defect and corneal perforation.

Skin and subcutaneous tissue disorders

Common:                    Ecchymosis

Uncommon:                Rash/dermatitis.

General disorders and administration site conditions

Common:                    Irritation and face oedema.

Uncommon:                Fatigue.

Cervical dystonia

Infections and infestations

Common:                    Rhinitis and upper respiratory infection.

Nervous system disorders

Common:                    Dizziness, hypertonia, hypoaesthesia, somnolence and headache.

Eye Disorders

Uncommon:                Diplopia and eyelid ptosis.

Respiratory, thoracic and mediastinal disorders

Uncommon:                Dyspnoea and dysphonia.

Gastrointestinal disorders

Very common:                        Dysphagia (see section c. “Additional Information” below).

Common:                    Dry mouth and nausea.

Musculoskeletal and connective tissue disorders

Very common:                        Muscular weakness.

Common:                    Musculoskeletal stiffness and soreness.

General disorders and administration site conditions

Very common:                        Pain.

Common:                    Asthenia, influenza like illness and malaise.

Uncommon:                Pyrexia.

Paediatric cerebral palsy

Infections and infestations

Very common:                        Viral infection and ear infection.

Nervous system disorders

Common:                    Somnolence,gait disturbance and paraesthesia.

Skin and subcutaneous tissue disorders

Common:                    Rash.

Musculoskeletal and connective tissue disorders

Common:                    Myalgia and muscular weakness and pain in extremity.

Renal and urinary disorders

Common:                    Urinary incontinence.

Injury, poisoning and procedural complications

Common:                    Fall.

General disorders and administration site conditions

Common:                    Gait disturbance and malaise. Malaise, injection site pain and asthenia.

Focal upper limb spasticity associated with stroke

Psychiatric disorders

Uncommon:                Depression and insomnia.

Nervous system disorders

Common:                    Hypertonia

Uncommon:                Hypoaesthesia, headache, paraesthesia, incoordination and                                                             amnesia.

Ear and labyrinth disorders

Uncommon:                Vertigo.

Vascular disorders

Uncommon:                Orthostatic hypotension.

Gastrointestinal disorders

Uncommon:                Nausea and paraesthesia oral.

Skin and subcutaneous tissue disorders

Common:                    Ecchymosis and purpura.

Uncommon:                Dermatitis, pruritus and rash.

Musculoskeletal and connective tissue disorders

Common:                    Pain in extremity and muscle weakness.

Uncommon:                Arthralgia and bursitis.

General disorders and administration site conditions

Common:                  Injection site pain, pyrexia, influenza-like illness, injection site                     

                                  haemorrhage and injection site irritation.

Uncommon:              Asthenia, pain, injection site hypersensitivity, malaise and oedema

peripheral.

Some of the uncommon events may be disease related.

Primary hyperhidrosis of the axillae

Nervous system disorders

Common:                  Headache and paraesthesia.

Vascular disorders

Common:                  Hot flushes.

Gastrointestinal disorders

Uncommon:              Nausea

Skin and subcutaneous tissue disorders

Common:                    Hyperhidrosis (non-axillary sweating) skin odour abnormal, pruritus, subcutaneous nodule and alopecia.

Uncommon:              Pruritus.

Musculoskeletal and connective tissue disorders

Common:                   Pain in extremity

Uncommon:              Muscular weakness, myalgia, and arthropathy and pain in extremity.

General disorders and administration site conditions

Common:                  Injection site reactions and pain.

Uncommon:              PainAsthenia, injection site oedema, and injection site pain

                                  haemorrhage, injection site hypersensitivity, injection site irritation,                

                                  asthenia and injection site reactions.

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

Nervous system disorders

Common:        Headache*, migraine*, facial paresis

Eye disorders

Common:        Eyelid ptosis

Uncommon:    Eyelid oedema           

Skin and subcutaneous tissue disorders

Common:        Pruritus, rash

Uncommon:    Pain of skin

Musculoskeletal and connective tissue disorders

Common:        Neck pain, myalgia, musculoskeletal pain,

              musculoskeletal stiffness, muscle spasms, muscle tightness,

                        muscular weakness

Uncommon:    Pain in jaw

General disorders and administration site conditions

Common:        Injection site pain

Gastrointestinal disorders

Uncommon:    Dysphagia

* 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.

c)    Additional information

Dysphagia ranges in severity from mild to severe, with potential for aspiration, which occasionally may require medical intervention (sSee 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) (sSee 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; focal facial paralysis; 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. 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.

4.9

Overdose

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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.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.

5.1

Pharmacodynamics properties

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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 conclusively 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.

Chronic migraine patients without any concurrent headache prophylaxis who, during a 28-day baseline, had at least 4 episodes and ³ 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.

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

10

Date of Revision of Text

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 08 July 2010 28^th September 2011