4.1. Therapeutic indications

Dysport is indicated for symptomatic treatment of focal spasticity of:

- Upper limbs in adults

- Lower limbs in adults affecting the ankle joint

- Dynamic equinus foot deformity in ambulant paediatric cerebral palsy patients, two years of age or older

- Upper limbs in paediatric cerebral palsy patients, two years of age or older.

Dysport is indicated for the management of urinary incontinence in adults with neurogenic detrusor overactivity due to spinal cord injury (traumatic or non-traumatic) or multiple sclerosis, who are regularly performing clean intermittent catheterisation.

Dysport is indicated in adults for symptomatic treatment of:

- Spasmodic torticollis

- Blepharospasm

- Hemifacial spasm

- Severe primary hyperhidrosis of the axillae, which does not respond to topical treatment with antiperspirants or antihidrotics.

4.2. Posology and method of administration

The units of Dysport are specific to the preparation and are not interchangeable with other preparations of botulinum toxin.

Dysport should only be administered by an appropriately qualified healthcare practitioner with expertise in the treatment of the relevant indication and the use of the required equipment, in accordance with national guidelines.

For instructions on reconstitution of the powder for solution for injection, handling and disposal of vials please refer to section 6.6.

Focal spasticity in adults

Upper limb:

Posology

Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, and/or adverse event history with Dysport. In clinical trials, doses of 500 units and 1000 units were divided among selected muscles at a given treatment session as shown below.

No more than 1 ml should generally be administered at any single injection site. The total dose should not exceed 1000 units at a given treatment session.

Muscles Injected

Recommended Dose

Dysport (U)

Flexor carpi radialis (FCR)

Flexor carpi ulnaris (FCU)

100-200U

100-200U

Flexor digitorum profundus (FDP)

Flexor digitorum superficialis (FDS)

Flexor pollicis longus

Adductor pollicis

100-200U

100-200U

100-200U

25-50U

Brachialis

Brachioradialis

Biceps brachii (BB)

Pronator teres

200-400U

100-200U

200-400U

100-200U

Triceps brachii (long head)

Pectoralis major

Subscapularis

Latissimus dorsi

150-300U

150-300U

150-300U

150-300U

Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique, e.g. electromyography, electrical stimulation or ultrasound is recommended to target the injection sites.

Clinical improvement may be expected one week after injection and may last up to 20 weeks. Injections may be repeated every 12 - 16 weeks or as required to maintain response, but not more frequently than every 12 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Dysport and muscles to be injected.

Lower limb spasticity affecting the ankle joint:

Posology

In clinical trials, doses of 1000U and 1500U were divided among selected muscles.

The exact dosage in initial and sequential treatment sessions should be tailored to the individual based on the size and number of muscles involved, the severity of the spasticity, also taking into account the presence of local muscle weakness and the patient's response to previous treatment. However, the total dose should not exceed 1500U.

No more than 1 ml should generally be administered at any single injection site.

Muscle

Recommended Dose

Dysport (U)

Number of injection sites per muscle

Primary target muscle

Soleus muscle

300 - 550U

2 - 4

Gastrocnemius:

Medial head

Lateral head

100 - 450U

1 - 3

100 - 450U

1 - 3

Distal muscles

Tibialis posterior

100 - 250U

1 - 3

Flexor digitorum longus

50 - 200U

1 - 2

Flexor digitorum brevis

50 - 200U

1 - 2

Flexor hallucis longus

50 - 200U

1 - 2

Flexor hallucis brevis

50 - 100U

1 - 2

The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Dysport and muscles to be injected.

Although actual location of the injection sites can be determined by palpation, the use of injection guiding techniques, e.g. electromyography, electrical stimulation or ultrasound are recommended to help accurately target the injection sites.

Repeat Dysport treatment should be administered every 12 to 16 weeks, or longer as necessary, based on return of clinical symptoms but no sooner than 12 weeks after the previous injection.

Upper and Lower limbs:

If treatment is required in the upper and lower limbs during the same treatment session, the dose of Dysport to be injected in each limb should be tailored to the individual's need according to the relevant posology and without exceeding a total dose of 1500U.

Elderly patients (≥ 65 years): Clinical experience has not identified differences in response between the elderly and younger adult patients. In general, elderly patients should be observed to evaluate their tolerability of Dysport, due to the greater frequency of concomitant disease and other drug therapy.

Method of administration

When treating focal spasticity affecting the upper and lower limbs in adults, Dysport is reconstituted with sodium chloride injection B.P. (0.9 % w/v) to yield a solution containing either 100 units per ml, 200 units per ml or 500 units per ml of Dysport (see section 6.6).

Dysport is administered by intramuscular injection into the muscles as described above.

Focal spasticity in paediatric cerebral palsy patients, two years of age or older

Dysport maximum total doses per treatment session and minimum times before retreatment

Limb

Maximum total dose of Dysport to be administered per treatment session

Minimum time before retreatment should be considered

Single lower limb

Both lower limbs

15 units/kg or 1000 units*

30 units/kg or 1000 units*

No sooner than 12 weeks

Single upper limb

Both upper limbs

16 units/kg or 640 units*

21 units/kg or 840 units *

No sooner than 16 weeks

Upper and lower limbs

30 units/kg or 1000 units*

No sooner than 12-16 weeks

*whichever is lower

Please see below for full posology and method of administration by treatment indication.

Dynamic equinus foot deformity due to focal spasticity in ambulant paediatric cerebral palsy patients, two years of age or older:

Posology

Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, and/or adverse event history with botulinum toxins. For treatment initiation, consideration should be given to start with a lower dose.

The maximum total dose of Dysport administered per treatment session must not exceed 15 units/kg for unilateral lower limb injections or 30 units/kg for bilateral injections. In addition, the total Dysport dose per treatment session must not exceed 1000 units or 30 units/kg, whichever is lower. The total dose administered should be divided between the affected spastic muscles of the lower limb(s). When possible, the dose should be distributed across more than 1 injection site in any single muscle.

No more than 0.5 ml of Dysport should be administered in any single injection site. See below table for recommended dosing:

Muscle

Recommended Dose Range per muscle per leg (U/kg Body Weight)

Number of injection sites per muscle

Gastrocnemius

5 to 15 U/kg

Up to 4

Soleus

4 to 6 U/kg

Up to 2

Tibialis posterior

3 to 5 U/kg

Up to 2

Total dose

Up to 15 U/kg in a single lower limb or 30 U/kg if both lower limbs injected and not exceeding 1000 U*

Note: For concomitant treatment of upper and lower limbs, the total dose should not exceed 30 U/kg or 1000 U*

*whichever is lower

Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique, e.g. electromyography, electrical stimulation or ultrasound is recommended to target the injection sites.

Repeat Dysport treatment should be administered when the effect of a previous injection has diminished, but no sooner than 12 weeks after the previous injection. A majority of patients in clinical studies were re-treated between 16 - 22 weeks; however, some patients had a longer duration of response, i.e. 28 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Dysport and muscles to be injected.

Clinical improvement may be expected within two weeks after injection.

Method of administration

When treating lower limb spasticity associated with cerebral palsy in children, Dysport is reconstituted with sodium chloride injection B.P. (0.9 % w/v) (see also section 6.6) and is administered by intramuscular injection as detailed above.

Focal spasticity of upper limbs in paediatric cerebral palsy patients, two years of age or older:

Posology

Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, and/or adverse event history with botulinum toxins. For treatment initiation, consideration should be given to start with a lower dose.

The maximum dose of Dysport administered per treatment session for unilateral upper limb injections must not exceed 16 U/kg or 640 U whichever is lower. When injecting bilaterally, the maximum Dysport dose per treatment session must not exceed 21 U/kg or 840 U, whichever is lower.

The total dose administered should be divided between the affected spastic muscles of the upper limb(s). No more than 0.5 ml of Dysport should be administered in any single injection site. See table below for recommended dosing:

Dysport Dosing by Muscle for Paediatric Upper Limb Spasticity

Muscle

Recommended Dose Range per muscle per upper limb

(U/kg Body Weight)

Number of injection sites per muscle

Brachialis

3 to 6 U/kg

Up to 2

Brachioradialis

1.5 to 3 U/kg

1

Biceps brachii

3 to 6 U/kg

Up to 2

Pronator teres

1 to 2 U/kg

1

Pronator quadratus

0.5 to 1 U/kg

1

Flexor carpi radialis

2 to 4 U/kg

Up to 2

Flexor carpi ulnaris

1.5 to 3 U/kg

1

Flexor digitorum profundus

1 to 2 U/kg

1

Flexor digitorum superficialis

1.5 to 3 U/kg

Up to 4

Flexor pollicis longus

1 to 2 U/kg

1

Flexor pollicis brevis/ opponens pollicis

0.5 to 1 U/kg

1

Adductor pollicis

0.5 to 1 U/kg

1

Pectoralis major

2.5 to 5 U/kg

Up to 2

Total dose

Up to 16 U/kg or 640 U* in a single upper limb (and not exceeding 21 U/kg or 840 U* if both upper limbs injected)

Note: For concomitant treatment of upper and lower limbs the total dose should not exceed 30 U/kg or 1000 U*

*whichever is lower

Although actual location of the injection sites can be determined by palpation the use of injection guiding technique, e.g. electromyography, electrical stimulation or ultrasound is recommended to target the injection sites.

Repeat Dysport treatment should be administered when the effect of a previous injection has diminished, but no sooner than 16 weeks after the previous injection. A majority of patients in the clinical study were retreated between 16-28 weeks; however, some patients had a longer duration of response, i.e. 34 weeks or more. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Dysport and muscles to be injected.

Method of administration

When treating upper limb spasticity associated with cerebral palsy in children, Dysport is reconstituted with sodium chloride injection (0.9% w/v) (see section 6.6) and is administered by intramuscular injection as detailed above.

Focal spasticity of upper and lower limbs in paediatric cerebral palsy patients, two years of age or older:

Posology

When treating combined upper and lower spasticity in children aged 2 years or older refer to the posology section for the individual indications above. The dose of Dysport to be injected for concomitant treatment should not exceed a total dose per treatment session of 30 U/kg or 1000 U, whichever is lower.

Retreatment of the upper and lower limbs combined should be considered no sooner than a 12 to 16-week window after the previous treatment session. The optimal time to retreatment should be selected based on individuals progress and response to treatment.

Method of administration

When treating combined upper and lower spasticity associated with cerebral palsy in children refer to the method of administration section for the individual indications above.

Urinary incontinence due to neurogenic detrusor overactivity:

Posology

The recommended dose is 600 U. In case of insufficient response, such as in patients with a severe disease presentation, a dose of 800 U may be used.

Dysport should be administered to patients who are regularly performing clean intermittent catheterisation.

The total dose administered should be divided across 30 intradetrusor injections evenly distributed throughout the detrusor muscle, avoiding the trigone. Dysport is injected via a flexible or rigid cystoscope and each injection should be to a depth of approximately 2 mm with the delivery of 0.5 mL to each site. For the final injection, approximately 0.5 mL of sterile normal saline should be injected to ensure that the full dose is delivered.

Prophylactic antibiotics should be commenced in line with the local guidelines and protocols or as used in the clinical studies (see Section 5.1). Medications with anticoagulant effects should be stopped at least 3 days prior to Dysport administration and only restarted on the day after administration. If medically indicated, low molecular weight heparins may be administered 24 hours prior to Dysport administration.

Prior to injection, local anaesthesia to the urethra or lubricating gel can be administered to facilitate comfortable cystoscope insertion. If required, either an intravesical instillation of diluted anaesthetic (with or without sedation) or general anaesthesia may also be used.

If a local anaesthetic instillation is performed, the local anaesthetic solution must be drained, then the bladder instilled (rinsed) with saline and drained again before continuing with the intradetrusor injection procedure.

Prior to injection, the bladder should be instilled with enough saline to achieve adequate visualisation for the injections.

After administration of all 30 intradetrusor injections, the saline used for bladder wall visualisation should be drained. The patient should be observed for at least 30 minutes post-injection.

Onset of effect is usually observed within 2 weeks of treatment. Repeat Dysport treatment should be administered when the effect of a previous injection has diminished, but no sooner than 12 weeks after the previous injection. The median time to retreatment in patients treated with Dysport was between 39 to 47 weeks, although a longer duration of response may occur as more than 40% of patients had not been retreated by 48 weeks.

Method of administration

When treating urinary incontinence due to neurogenic detrusor overactivity, Dysport is reconstituted with sodium chloride injection (0.9% w/v) to yield a 15 mL solution containing either 600 units or 800 units. For additional reconstitution instruction please see section 6.6.

Dysport is administered by intradetrusor injection as detailed above.

Spasmodic torticollis

Posology

The doses recommended for torticollis are applicable to adults of all ages, provided the adults are of normal weight with no evidence of reduced neck muscle mass. A lower dose may be appropriate if the patient is markedly underweight or in the elderly, where reduced muscle mass may exist.

The initial recommended dose for the treatment of spasmodic torticollis is 500 units per patient given as a divided dose and administered into the two or three most active neck muscles.

• For rotational torticollis distribute the 500 units by administering 350 units into the splenius capitis muscle, ipsilateral to the direction of the chin/head rotation and 150 units into the sternomastoid muscle, contralateral to the rotation.

• For laterocollis, distribute the 500 units by administering 350 units into the ipsilateral splenius capitis muscle and 150 units into the ipsilateral sternomastoid muscle. In cases associated with shoulder elevation the ipsilateral trapezoid or levator scapulae muscles may also require treatment, according to visible hypertrophy of the muscle or electromyographic (EMG) findings. Where injections of three muscles are required, distribute the 500 units as follows, 300 units splenius capitis, 100 units sternomastoid and 100 units to the third muscle.

• For retrocollis distribute the 500 units by administering 250 units into each of the splenius capitis muscles. Bilateral splenii injections may increase the risk of neck muscle weakness.

• All other forms of torticollis are highly dependent on specialist knowledge and EMG to identify and treat the most active muscles. EMG should be used diagnostically for all complex forms of torticollis, for reassessment after unsuccessful injections in non-complex cases, and for guiding injections into deep muscles or in overweight patients with poorly palpable neck muscles.

On subsequent administration, the doses may be adjusted according to the clinical response and side effects observed. Doses within the range of 250 - 1000 units are recommended, although the higher doses may be accompanied by an increase in side effects, particularly dysphagia. The maximum dose administered must not exceed 1000 units.

The relief of symptoms of torticollis may be expected within a week after the injection.

Injections may be repeated approximately every 16 weeks or as required to maintain a response, but not more frequently than every 12 weeks.

Children: The safety and effectiveness of Dysport in the treatment of spasmodic torticollis in children have not been demonstrated.

Method of administration

When treating spasmodic torticollis, Dysport is reconstituted with sodium chloride injection B.P. (0.9 % w/v) to yield a solution containing 500 units per ml of Dysport (see section 6.6).

Dysport is administered by intramuscular injection as described above.

Blepharospasm and hemifacial spasm

Posology

In a dose ranging clinical trial on the use of Dysport for the treatment of benign essential blepharospasm, a dose of 40 units per eye was significantly effective. Doses of 80 units and 120 units per eye resulted in a longer duration of effect. However, the incidence of local adverse events, specifically ptosis, was dose related. In the treatment of blepharospasm and hemifacial spasm, the maximum dose used must not exceed a total dose of 120 units per eye.

An injection of 10 units (0.05 ml) medially and 10 units (0.05 ml) laterally should be made into the junction between the preseptal and orbital parts of both the upper (3 and 4) and lower orbicularis oculi muscles (5 and 6) of each eye. In order to reduce the risk of ptosis, injections near the levator palpebrae superioris should be avoided.

For injections into the upper lid the needle should be directed away from its centre to avoid the levator muscle. A diagram to aid placement of these injections is provided above. The relief of symptoms may be expected to begin within two to four days with maximal effect within two weeks.

Injections should be repeated approximately every twelve weeks or as required to prevent recurrence of symptoms but not more frequently than every twelve weeks.

On such subsequent administrations, if the response from the initial treatment is considered insufficient, the dose per eye may need to be increased to:

- 60 units: 10 units (0.05 ml) medially and 20 units (0.1 ml) laterally;

- 80 units: 20 units (0.1 ml) medially and 20 units (0.1 ml) laterally; or

- up to 120 units: 20 units (0.1 ml) medially and 40 units (0.2 ml) laterally,

above and below each eye in the manner previously described. Additional sites in the frontalis muscle above the brow (1 and 2) may also be injected if spasms here interfere with vision.

In cases of unilateral blepharospasm the injections should be confined to the affected eye. Patients with hemifacial spasm should be treated as for unilateral blepharospasm. The doses recommended are applicable to adults of all ages including the elderly.

Children: The safety and effectiveness of Dysport in the treatment of blepharospasm and hemifacial spasm in children have not been demonstrated.

Method of administration

When treating blepharospasm and hemifacial spasm, Dysport is reconstituted with sodium chloride injection B.P. (0.9 % w/v) to yield a solution containing 200 units per ml of Dysport (see section 6.6).

Dysport is administered by subcutaneous injection medially and laterally into the junction between the preseptal and orbital parts of both the upper and lower orbicularis oculi muscles of the eyes as described above.

Axillary hyperhidrosis

Posology

The recommended initial dosage is 100 units per axilla. If the desired effect is not attained, up to 200 units per axilla can be administered for subsequent injections. The maximum dose administered should not exceed 200 units per axilla.

The area to be injected may be determined beforehand using the iodine-starch test. Both axillae should be cleaned and disinfected. Intradermal injections at ten sites, each site receiving 10 units, i.e., to deliver 100 units per axilla, are then administered. The maximum effect should be seen by week two after injection. In many cases, the recommended dose will provide adequate suppression of sweat secretion for approximately 48 weeks. The time point for further applications should be determined on an individual basis according to clinical need. Injections should not be repeated more frequently than every 12 weeks. There is some evidence for a cumulative effect of repeated doses so the time of each treatment for a given patient should be assessed individually.

Children: The safety and effectiveness of Dysport in the treatment of axillary hyperhidrosis in children has not been demonstrated.

Method of administration:

When treating axillary hyperhidrosis, Dysport is reconstituted with sodium chloride solution B.P. (0.9 % w/v) to yield a solution containing 200 units per ml of Dysport (see section 6.6).

Dysport is administered by intradermal injection as described above.

4.3. Contraindications

- Known hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Urinary tract infection at the time of treatment for the management of urinary incontinence due to neurogenic detrusor overactivity.

4.4. Special warnings and precautions for use

Side effects related to spread of toxin distant from the site of administration have been reported (see section 4.8) which, in some cases, was associated with dysphagia, pneumonia and/or significant debility resulting, very rarely, in death. Patients treated with therapeutic doses may present with excessive muscle weakness. The risk of occurrence of such undesirable effects may be reduced by using the lowest effective possible dose and by not exceeding the maximum recommended dose.

Dysport should only be used with caution and under close medical supervision in patients with subclinical or clinical evidence of marked defective neuromuscular transmission (e.g. myasthenia gravis). Such patients may have an increased sensitivity to agents such as Dysport, which may result in excessive muscle weakness with therapeutic doses. Patients with underlying neurological disorders are at increased risk of this side effect.

Caution should be exercised when treating adult patients especially the elderly, with focal spasticity affecting the lower limbs, who may be at increased risk of fall. In placebo-controlled clinical studies, where patients were treated for lower limb spasticity, 6.3% and 3.7% of patients experienced a fall in the Dysport and placebo groups, respectively.

Dry eye has been reported with the use of Dysport in the treatment of blepharospasm and hemifacial spasm (see section 4.8). Reduced tear production, reduced blinking, and corneal disorders, may occur with the use of botulinum toxins, including Dysport.

Very rare cases of death, occasionally in the context of dysphagia, pneumopathy (including but not limited to dyspnoea, respiratory failure, respiratory arrest) and/or in patients with significant asthenia have been reported following treatment with botulinum toxin A or B. Patients with disorders resulting in defective neuromuscular transmission, difficulty in swallowing or breathing are more at risk of experiencing these effects. In these patients, treatment must be administered under the control of a specialist and only if the benefit of treatment outweighs the risk.

Dysport should be administered with caution to patients with pre-existing swallowing or breathing problems as these can worsen following the distribution of the effect of toxin into the relevant muscles. Aspiration has occurred in rare cases and is a risk when treating patients who have a chronic respiratory disorder.

The recommended posology and frequency of administration for Dysport must not be exceeded (see section 4.2).

Patients and their care-givers must be warned of the necessity to seek immediate medical treatment in case of swallowing, speech or respiratory problems.

Dysport should not be used to treat spasticity in patients who have developed a fixed contracture.

As with any intramuscular injection, Dysport should only be used where strictly necessary in patients with prolonged bleeding times, infection or inflammation at the proposed site(s) of injection.

Autonomic dysreflexia associated with the treatment procedure for neurogenic detrusor overactivity can occur. Prompt medical attention may be required.

Caution should be taken when Dysport is used where the targeted muscle shows excessive weakness or atrophy.

Dysport should only be used to treat a single patient, during a single session. Specific precautions must be taken during the preparation and administration of the product (see section 4.2) and for the inactivation and disposal of any unused reconstituted solution (see section 6.6).

Antibody formation to botulinum toxin has been noted rarely in patients receiving Dysport. Clinically, neutralising antibodies might be suspected by a substantial deterioration in response to therapy and/or the need for consistent use of increased doses.

Careful consideration should be given before the injection of patients who have experienced a previous allergic reaction to a product containing botulinum toxin type A. The risk of a further allergic reaction must be considered in relation to the benefit of treatment.

Paediatric use

For the treatment of spasticity associated with cerebral palsy in children, Dysport should only be used in children of 2 years of age or over. Post-marketing reports of possible distant spread of toxin have been very rarely reported in paediatric patients with comorbidities, predominantly with cerebral palsy. In general, the dose used in these cases was in excess of that recommended (see section 4.8).

There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin, including following off-label use (e.g. neck area). Extreme 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. Treatment in patients with poor underlying health status should be administered only if the potential benefit to the individual patient is considered to outweigh the risks.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

4.5. Interaction with other medicinal products and other forms of interaction

The effects of botulinum toxin may be potentiated by drugs interfering either directly or indirectly with neuromuscular function (e.g. aminoglycosides, curare-like non-depolarising blockers, muscle relaxants) and such drugs should be used with caution in patients treated with botulinum toxin due to the potential for undesirable effects.

4.6. Fertility, pregnancy and lactation

Pregnancy:

There are limited data from the use of Clostridium botulinum type A toxin-haemagglutinin complex in pregnant women. Studies in animals have shown reproductive toxicity at high doses causing maternal toxicity (see section 5.3).

Dysport should be used during pregnancy only if the benefit justifies any potential risk to the foetus. Caution should be exercised when prescribing to pregnant women.

Breast-feeding:

It is not known whether Clostridium botulinum type A toxin-haemagglutinin complex is excreted in human milk. The excretion of Clostridium botulinum type A toxin-haemagglutinin complex in milk has not been studied in animals. The use of Clostridium botulinum type A toxin-haemagglutinin complex during lactation cannot be recommended.

Fertility:

Studies in male and female rats have shown effects on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

There is a potential risk of muscle weakness or visual disturbances which, if experienced, may temporarily impair the ability to drive or operate machinery.

4.8. Undesirable effects

General

Side effects related to spread of toxin distant from the site of administration have been reported, such as dry mouth, exaggerated muscle weakness, dysphagia, aspiration/aspiration pneumonia, with fatal outcome in some very rare cases (see section 4.4). Hypersensitivity reactions have also been reported post-marketing.

The frequency of adverse reactions reported in placebo-controlled trials after a single administration 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); not known (cannot be estimated from the available data).

The following adverse reactions were seen in patients treated across a variety of indications including blepharospasm, hemifacial spasm, torticollis, spasticity associated with either cerebral palsy or stroke/TBI and axillary hyperhidrosis:

System Organ Class

Frequency

Adverse Drug Reaction

Nervous system disorders

Rare

Neuralgic amyotrophy

Skin and subcutaneous tissue disorders

Uncommon

Pruritus

Rare

Rash

General disorders and administration site conditions

Common

Asthenia, fatigue, influenza like illness and injection site reactions (e.g. pain, bruising, pruritus, oedema)

Frequency of specific adverse reactions by indication

In addition, the following adverse reactions specific to individual indications were reported:

Focal spasticity affecting the upper limbs in adults

System Organ Class

Frequency

Adverse Drug Reaction

Gastrointestinal disorders

Uncommon

Dysphagia*

Musculoskeletal and connective tissue disorders

Common

Muscular weakness, musculoskeletal pain, pain in the extremity

*The frequency for Dysphagia was derived from pooled data from open-label studies. Dysphagia was not observed in the double-blind studies in the Adult Upper Limb (AUL) indication.

Focal spasticity affecting the lower limbs in adults

System Organ Class

Frequency

Adverse Drug Reaction

Gastrointestinal disorders

Common

Dysphagia

Musculoskeletal and connective tissue disorders

Common

Muscular weakness, myalgia

General disorders and administration site conditions

Common

Asthenia, fatigue, influenza-like illness, injection site reactions (pain, bruising, rash, pruritus)

Injury, poisoning and procedural complications

Common

Fall

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

System Organ Class

Frequency

Adverse Drug Reaction

Musculoskeletal and connective tissue disorders

Common

Myalgia, muscular weakness

Renal and urinary disorders

Common

Urinary incontinence

General disorders and administration site conditions

Common

Influenza-like illness, injection site reaction (e.g. pain, erythema, bruising etc.), gait disturbance, fatigue

Uncommon

Asthenia

Injury, poisoning and procedural complications

Common

Fall

Focal spasticity of upper limbs in paediatric cerebral palsy patients, two years of age or older

System Organ Class

Frequency

Adverse Drug Reaction

Musculoskeletal and connective tissue disorders

Common

Muscular weakness, Pain in extremity

Uncommon

Myalgia

General disorders and administration site conditions

Common

Influenza-like illness, Asthenia, Fatigue, Injection site bruising

Uncommon

Injection site eczema, Injection site pain, Injection site rash, Injection site swelling

Skin and subcutaneous tissue disorders

Common

Rash

Focal spasticity of upper and lower limbs in paediatric cerebral palsy patients, two years of age or older

When treating upper and lower limbs concomitantly with Dysport at a total dose of up to 30 U/kg or 1000 U whichever is lower, there are no safety findings in addition to those expected from treating either upper limb or lower limb muscles alone.

Urinary incontinence due to neurogenic detrusor overactivity

System Organ Class

Frequency

Adverse Drug Reaction

Infections and infestations

Very common

Urinary tract infectiona,b

Common

Bacteriuriaa

Nervous system disorders

Uncommon

Hypoaesthesia

Gastrointestinal disorders

Common

Constipation

Musculoskeletal and connective tissue disorders

Uncommon

Muscle weakness

Renal and urinary disorders

Common

Haematuriaa

Reproductive system and breast disorders

Common

Erectile dysfunction

General disorders and administration site conditions

Uncommon

Fatigue, influenza-like illness

a Procedure related event

bIn the pivotal double blind placebo-controlled studies, over the first 12 weeks of treatment, urinary tract infections were reported in 15.8% of Dysport treated patients and 17.4% of placebo treated patients.

Spasmodic torticollis

System Organ Class

Frequency

Adverse Drug Reaction

Nervous system disorders

Common

Headache, dizziness, facial paresis

Eye disorders

Common

Vision blurred, visual acuity reduced

Uncommon

Diplopia, ptosis

Respiratory, thoracic and mediastinal disorders

Common

Dysphonia, dyspnoea

Rare

Aspiration

Gastrointestinal disorders

Very common

Dysphagia, dry mouth

Uncommon

Nausea

Musculoskeletal and connective tissue disorders

Very common

Muscle weakness

Common

Neck pain, musculoskeletal pain, myalgia, pain in extremity, musculoskeletal stiffness

Uncommon

Muscle atrophy, jaw disorder

Dysphagia appeared to be dose related and occurred most frequently following injection into the sternomastoid muscle. A soft diet may be required until symptoms resolve. These side effects may be expected to resolve within two to four weeks.

Blepharospasm and hemifacial spasm

System Organ Class

Frequency

Adverse Drug Reaction

Nervous system disorders

Common

Facial paresis

Uncommon

VIIth nerve paralysis

Eye disorders

Very common

Ptosis

Common

Diplopia, dry eye, lacrimation increased

Rare

Ophthalmoplegia

Skin and subcutaneous tissue disorders

Common

Eyelid oedema

Rare

Entropion

Side effects may occur due to deep or misplaced injections of Dysport temporarily paralysing other nearby muscle groups.

Axillary hyperhidrosis

System Organ Class

Frequency

Adverse Drug Reaction

Skin and subcutaneous tissue disorders

Common

Compensatory sweating

Post-marketing experience

System Organ Class

Frequency

Adverse Drug Reaction

Immune system disorders

Not known

Hypersensitivity

Nervous system disorders

Not known

Hypoaesthesia

Musculoskeletal and connective tissue disorders

Not known

Muscle atrophy

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Excessive doses may produce distant and profound neuromuscular paralysis. Overdose could lead to an increased risk of the neurotoxin entering the bloodstream and may cause complications associated with the effects of oral botulinum poisoning (e.g. dysphagia and dysphonia). Respiratory support may be required where excessive doses cause paralysis of respiratory muscles. General supportive care is advised. In the event of overdose, the patient should be medically monitored for signs and/or symptoms of excessive muscle weakness or muscle paralysis. Symptomatic treatment should be instigated if necessary.

Symptoms of overdose may not present immediately following injection. Should accidental injection or oral ingestion occur, the patient should be medically supervised for several weeks for signs and/or symptoms of excessive muscle weakness or muscle paralysis.