Active Ingredient and Strength	CLOSTRIDIUM BOTULINUM TYPE A TOXIN-HAEMAGGLUTININ COMPLEX - 300 UNITS/VIAL
Dosage Form	INJECTION, POWDER, FOR SOLUTION
Manufacturer and Country	IPSEN BIOPHARM LTD - UNITED KINGDOM
Registration Number	SIN15238P
Licence Holder	IPSEN PHARMA SINGAPORE PTE. LTD.
Forensic Classification	PRESCRIPTION ONLY MEDICINES
Anatomical Therapeutic Chemical (ATC) code	M03AX01

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 due to stroke or traumatic brain injury (TBI)
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 in adults for symptomatic treatment of:

Spasmodic torticollis
Blepharospasm
Hemifacial spasm
Axillary hyperhidrosis

Dysport is indicated for the temporary improvement in the appearance of moderate to severe:

Glabellar lines (vertical lines between the eyebrows) seen at maximum frown and/or
Lateral canthal lines (crow's feet lines) seen at maximum smile

in adult patients under 65 years, when the severity of these lines has an important psychological impact on the patient.

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 appropriately trained physicians.
For the treatment of focal spasticity, Dysport can also be administered by healthcare professionals having received appropriate training and qualification in accordance with national guidelines (e.g., Royal College of Physicians).

For instructions on reconstitution of the powder for solution for injection, handling and disposal of vials, please refer to section 6.6 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information.

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.

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 1000 units and 1500 units 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 1500 units.

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

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 1500 units.

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 adult, 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 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

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

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

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:

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 retreated 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 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information) 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

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

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 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information) 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 units/kg or 1000 units, 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.

Spasmodic torticollis

Posology
The doses recommended 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 a reduced muscle mass may exist.

The initial recommended initial 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 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

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 12 weeks or as required to prevent recurrence of symptoms but not more frequently than every 12 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 BP (0.9% w/v) to yield a solution containing 200 units per mL of Dysport (see section 6.6 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

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.

Moderate to severe glabellar lines and/or lateral canthal lines

Posology
The treatment interval depends on the individual patient's response after assessment. Treatment interval with Dysport should not be more frequent than every three months.

Remove any make-up and disinfect the skin with a local antiseptic.

Intramuscular injections should be performed using a sterile 29 – 30 gauge needle. The recommended injection points for glabellar lines and lateral canthal lines are described below:

Glabellar lines

The recommended dose is 50 units (0.25 mL of reconstituted solution) of Dysport to be divided into 5 injection sites, 10 units (0.05 mL of reconstituted solution) are to be administered intramuscularly, at right angles to the skin, into each of the 5 sites: 2 injections into each corrugator muscle and one into the procerus muscle near the nasofrontal angle as shown in the diagram above.

The anatomical landmarks can be more readily identified if observed and palpated at maximum frown. Before injection, place the thumb or index finger firmly below the orbital rim in order to prevent extravasation below the orbital rim.

The needle should be pointed upwards and medially during the injection. In order to reduce the risk of ptosis, avoid injections near the levator palpebrae superioris muscle, particularly in patients with larger brow-depressor complexes (depressor supercilii). Injections into the corrugators muscle must be made into the central part of that muscle, at least 1 cm above orbital rim.

In clinical studies, an optimal effect, in glabellar lines, was demonstrated for up to 4 months after injection. Some patients were still responders at 5 months (see section 5.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Lateral canthal lines

The recommended dose per side is 30 units (60 units for both sides, 0.30 mL of reconstituted solution) of Dysport, to be divided into 3 injection sites; 10 units (0.05 mL of reconstituted solution) are to be administered intramuscularly into each injection point.
Injection should be lateral (20 – 30° angle) to the skin and very superficial. All injection points should be at the external part of the orbicularis oculi muscle and sufficiently far from the orbital rim (approximately 1 – 2 cm) as shown above.
The anatomical landmarks can be more readily identified if observed and palpated at maximal smile. Care must be taken to avoid injecting the zygomaticus major/minor muscles to avoid lateral mouth drop and asymmetrical smile.

General information
In the event of treatment failure or diminished effect following repeat injections, alternative treatment methods should be employed. In case of treatment failure after the first treatment session, the following approaches may be considered:

Analysis of the causes of failure, e.g. incorrect muscles injected, inappropriate injection technique, and formation of toxin-neutralizing antibodies
Re-evaluation of the relevance of treatment with Dysport

The efficacy and safety, of repeat injections of Dysport, has been evaluated in glabellar lines up to 24 months and up to 8 repeat treatment cycles and for lateral canthal lines up to 12 months and up to 5 repeat treatment cycles.

Children: The safety and effectiveness of Dysport in treating moderate to severe glabellar lines and lateral canthal lines in individuals under 18 years of age have not been demonstrated.

Method of administration
For moderate to severe glabellar lines or lateral canthal lines, Dysport is reconstituted with sodium chloride injection BP (0.9% w/v) to yield a solution containing 200 units per mL of Dysport (see section 6.6 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Dysport is administered by intramuscular injection as described above.

Axillary hyperhidrosis

Posology
The recommended initial dose is 100 units per axilla (armpit). If the desired effect is not achieved, up to 200 units per axilla may be administered in subsequent injections. The maximum dose administered should not exceed 200 unit per axilla.

The injection site may be determined beforehand by using the iodine starch test. Both armpits should be cleaned thoroughly 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 treating axillary hyperhidrosis in children has not been demonstrated.

Method of administration
When treating axillary hyperhidrosis, Dysport is reconstituted with 2.5 mL of sodium chloride solution (0.9% w/v) to yield a solution containing 200 units per mL of Dysport. In treating axillary hyperhidrosis, Dysport is administered by intradermal injections as described above.

4.3 Contraindications

Known hypersensitivity to the active substance or to any excipients listed in section 6.1 – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information.