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Document: Dysport 500 units powder for solution for injection ENG SmPC change

• Dysport 500 units powder for solution for injection SmPC
• Dysport 500 units powder for solution for injection ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

DYSPORT 500 U, powder for solution for injection.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Clostridium botulinum toxin type A haemagglutinin complex 500 units (U*)

*One unit (U) is defined as the mean lethal intraperitoneal dose in mice.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Dysport is indicated for:

4.2 Posology and method of administration

Dysport should only be administered by appropriately trained physicians.

The units given for Dysport are specific and are not interchangeable with other preparations of botulinum toxin.

Reconstitution instructions are specific for the 500 Unit vial. These volumes yield concentrations specific for the use for each indication.

For pes equinus due to spastic cerebral paralysis in ambulant paediatric patients, which is dosed using unit per body weight, further dilution may be required to achieve the final volume for injection.

Symptomatic treatment of focal spasticity affecting the upper limbs in adults

Posology

The maximum dose administered must not exceed 1000 units when the arm muscles are injected and 1500 units when also the shoulder muscles are injected.

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 Toxin Type A-Hemagglutinin Complex. In clinical trials, doses of 500 Units, 1000 Units and 1500 Units were divided among selected muscles at a given treatment session as shown below. Doses greater than 1000U and up to 1500U can be administered, as per the physician´s judgement based on efficacy and safety response of each patient to previous treatment cycles when the shoulder muscles are injected in addition to other muscles of the upper limb. The total dose recommended in the selected shoulder muscles is up to 500U.

No more than 1 mL should generally be administered at any single injection site. Doses exceeding 1500U of Dysport were not investigated for the treatment of upper limb spasticity in adults.

Although actual location of the injection sites can be determined by palpationthe 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 retreated between 12-16 weeks; however some patients had a longer duration of response, i.e. 20 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 one week after administration of Dysport.

Children:

Safety and effectiveness of the product in the treatment of upper limb spasticity in children have not been demonstrated.

Elderly patients (≥ 65 years): Clinical experience has not identified differences in response between the elderly and younger adult patients.

Method of Administration

When treating focal spasticity affecting the upper limbs in adults, Dysport is reconstituted with Sodium chloride injection (0.9%) to yield a solution containing either 100 units per ml, 200 units per ml or500 units per ml of Dysport. Dysport is administered by intramuscular injection into the muscles described above.

Spasmodic torticollis

Posology

The doses recommended for the treatment of torticollis are applicable to adults of all ages, provided they are of normal weight with no sign of low neck muscle mass. A reduced dose may be required in patients who are clearly underweight or in the elderly where reduced muscle mass may be found.

The initial recommended dose for the treatment of spasmodic torticollis is 500 units, which should be administered as a divided dose and injected in the two or three most active neck muscles.

On subsequent administration, doses may be adjusted according to both the clinical response and the 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 symptoms of torticollis may be expected to diminish within a week of 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.

In rotation torticollis, it is recommended that the 500 units are divided as follows: 350 units administered in to the splenius capitis muscle ipsilateral to the direction of the chin or head’s rotation and 150 units into the sternocleidomastoid muscle contralateral to the rotation.

In laterocollis, it is recommended that the 500 units are divided as follows: 350 units into the ipsilateral splenius capitis muscle and 150 units into the ipsilateral sternocleidomastoid muscle.

If elevation of the shoulder is involved, the ipsilateral trapezius or levator scapulae muscles may also require treatment if hypertrophy of the muscles is noticeable or is observed when examined by electromyogram (EMG). When three muscles need to be injected it is recommended that the 500 units are divided up as follows:

300 units into the splenius capitis, 100 units into the sternocleidomastoid and 100 units in to the third muscle.

In retrocollis distribute the 500 units by administrating 250 units into each splenius capitis muscle. Bilateral injections into splenius muscles may increase the risk for weakness in the neck muscles.

All other forms of torticollis call for specialist knowledge and EMG for identification and treatment of the most active muscles. EMG should be used diagnostically in all complex instances of torticollis, in reassessment of non-complicated cases where treatment has not produced a satisfactory result and for guidance in injections into deep muscles and in overweight patients with neck muscles which are difficult to palpate.

Children:

Safety and effectiveness of the product in the treatment of spasmodic torticollis in children have not been demonstrated.

Method of administration

When treating spasmodic torticollis Dysport is reconstituted with 1.0 ml of sodium chloride injection (0.9%) to yield a solution containing 500 units per ml of Dysport. Dysport is administered by intramuscular injection as above when treating spasmodic torticollis.

Paediatric cerebral palsy spasticity

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.

The maximum total dose of Dysportadministered 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 30 units/kg or 700 units 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/leg

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 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.

The symptoms may be expected to fade within two weeks of the injection.

Method of administration

When treating paediatric cerebral palsy spasticity, Dysport is reconstituted with 1.0 ml of sodium chloride injection (0.9%) to yield a solution containing 500 units per ml of Dysport. Dysport is administered by intramuscular injection into the calf muscles when treating spasticity.

Blepharospasm and hemifacial spasm

Posology

In the treatment of bilateral blepharospasm the recommended initial dose is 40 units per eye. At the next treatment session dosage should be adjusted to clinical response and the side effects observed. An increase of the dose to 80 units per eye may result in a longer duration of effect but may also lead to an increase in side effects, especially ptosis.

In the treatment of blepharospasm and hemifacial spasm, the maximum dose must not exceed the total dose of 120 units per eye.

Injection of 10 units (0.05ml) should be made medially and of 10 units (0.05 ml) should be made laterally 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. 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,dosage should be adjusted to clinical response and the side effects observed. 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 frontalis muscle above 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 2.5ml of sodium chloride injection to yield a solution containing 200 units per 1 ml of Dysport. 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.

Axillary hyperhidrosis

Posology

The maximum dose administered must not exceed 200 units per axilla.

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 area to be injected should 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, 100 units per axilla, are then administered. The maximum effect should be seen by week two after injection. In the majority of cases, the recommended dose will provide adequate suppression of sweat secretion for approximately 1 year. The time point for further applications should be determined on an individual basis, when the clinical effect of a previous injection diminishes and the treating physician deems it necessary. Injections should not be repeated more frequently than every 16 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

The exposed central portion of the rubber stopper should be cleaned with alcohol immediately prior to piercing the septum. A sterile 23 or 25 gauge needle should be used.

When treating axillary hyperhidrosis, Dysport is reconstituted with 2.5ml of sodium chloride injection (0.9%) to yield a solution containing 200 units per ml of Dysport. Dysport is administered by intradermal injection at ten sites per axilla when treating axillary hyperhidrosis.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Dysport should only be administered by appropriately trained physicians.

Adverse effects resulting from the distribution of the effects of the toxin to sites remote from the site of administration have been reported (see section 4.8). Patients treated with therapeutic doses may present excessive muscle weakness. The risk of occurrence of such undesirable effects may be reduced by using the lowest effective dose and by not exceeding recommended dose.

Very rare cases of death, occasionally in a context of dysphagia, pneumopathy (including but not limited to dyspnoea, respiratory failure, respiratory arrest)and/or in patients with significant asthenia have been reported after 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 existing problems in swallowing or breathing as these problems 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.

Dysport should only be used with caution and under close medical supervision in patients with clinical or sub-clinical evidence of marked defective neuro-muscular transmission (e.g. myasthenia gravis). Such patients may have an increased sensitivity to agents such as Dysport, which may result in excessive muscle weakness.

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 of immediate medical treatment in case of problems with swallowing, speech or respiratory disorders.

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

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

Dysport should only be used to treat a single patient, during a single session. Any unused product remaining should be disposed of in accordance with Section 6.6 (instructions for use, handling and disposal). Specific precautions must be taken for the preparation and administration of the product; the inactivation and disposal of any unused reconstituted solution (see Section 6.6).

This product contains a small amount of human albumin. The risk of transmission of a viral infection cannot be excluded with absolute certainty following the use of human blood or blood products.

Antibody formation to botulinum toxin has been reported rarely in patients receiving Dysport. Clinically, neutralising antibodies might be suspected by substantial deterioration in response to therapy and/or a need for consistent use of increased doses. The risk of antibody formation increases when high doses of Dysport are used and when the intervals between injections are short. For all indications, the interval between injections should be at least 3 months, and booster injections should not be given.

Paediatric population

For the treatment of spasticity associated with cerebral palsy in children, Dysport should only be used in children over 2 years of age.

4.5 Interaction with other medicinal products and other forms of interaction

The effects of botulinum toxin may be potentiated by drugs interfering directly or indirectly with the neuromuscular function and such drugs should be used with caution in patients treated with botulinum toxin.

4.6 Fertility, pregnancy and lactation

There are limited data from the use of Clostridium botulinum toxin type A – haemagglutinin complex in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development other than at high doses causing maternal toxicity (see Preclinical Safety section).

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

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

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

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).

In patients who were treated with Dysport in clinical trial programme approximately 25% experienced an adverse event.

General

The following adverse reaction were seen in patients treated across variety of indications including blepharospasm, hemifacial spasm, torticollis, spasticity associated with cerebral palsy, spasticity in upper limbs in adults and axillary hyperhidrosis:

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

Nervous system disorders

Rare: Neuralgic amyotrophy

Skin and subcutaneous tissue disorders

Uncommon: Pruritus

Rare: Rash

Musculoskeletal and connective tissue disorders

Common: Local muscle weakness

General disorders and administration site conditions

Common: Asthenia, fatigue, influenza like illness, injection site pain/bruising

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

Symptomatic treatment of focal spasticity affecting the upper limbs in adults

The following adverse events were observed in patients treated with Dysport for symptomatic treatment of focal spasticity affecting the upper limbs in adults.

Musculoskeletal and connective tissue disorders

Common: Muscular weakness

General disorders and administration site conditions

Common: Injection site reactions (e.g. pain, erythema, swelling etc.) have been reported following administration, Asthenia, Influenza like illness.

Uncommon: Fatigue

In the Open-Label studies the following undesirable effects were also observed:

Nervous system disorders

Hypertonia

Gastrointestinal disorder

Dysphagia

Musculoskeletal and connective tissue disorders

Musculoskeletal pain, Pain in extremity

General disorders and administration site conditions

Gait disturbance, Injection site bruising and haemorrhage

Spasmodic torticollis

The following adverse events were observed in patients treated with Dysport for spasmodic torticollis.

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.

In severely affected patients, an accumulation of saliva has been demonstrated at laryngoscopy.

Pediatric leg spasticity due to cerebral palsy

The following adverse events were observed in patients treated with Dysport for paediatric leg spasticity due to cerebral palsy.

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

Blepharospasm and hemifacial spasm

The following adverse events were observed in patients treated with Dysport for Blepharospasm and hemifacial spasm.

Nervous system disorders

Common: Facial paresis

Uncommon: VIIth nerve paralysis

Eye disorders

Very common: Ptosis

Common: Diplopia, dry eye, lacrimation increased

Rare: Opthalmoplegia

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

The following adverse events were observed in patients treated with Dysport for hyperhidrosis:

Nervous system disorders

Uncommon: Dizziness, headache, paraesthesia, involuntary muscle contractions of the yelid

Vascular disorders

Uncommon: Flushing

Respiratory, thoracic and mediastinal disorders

Common:Dyspnoea

Uncommon: Epistaxis

Skin and subcutaneous tissue disorders

Common: Compensatory sweating

Rare: Allergic reactions such as skin rashes may also occur

Musculoskeletal and connective tissue disorders

Common: Pain in the shoulder, upper arm and neck, myalgia of the shoulder and calf

Post-marketing experience

The profile of adverse reactions reported to the Company during post-marketing use reflects the pharmacology of the product and those seen during clinical trials. There have been sporadic reports of hypersensitivity.

Adverse effects resulting from distribution of the effects of the toxin to sites remote from the site of injection have been very rarely reported (excessive muscle weakness dysphagia, aspiration pneumonia that may be fatal) (see section 4.4).

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 national reporting system listed in
[To be completed nationally]

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. There is no specific antidote; antitoxin should not be expected to be beneficial and general supportive care is advised.

In the event of overdose the patient should be medically monitored for any 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 accidential injection or oral ingestion occur the patient should be medically supervised for several weeks for any signs and/or symptoms of excessive muscle weakness or muscle paralysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other Muscle relaxants, peripherally acting drugs. ATC code: M03AX01

Pharmacotherapeutic group: Antihidrotics. ATC code: D11AA

Clostridium botulinum, toxin haemagglutinin complex A blocks peripheral cholinergic transmission at the neuromuscular junction by a pre-synaptic action when acetylcholine is released. The toxin acts in the nerve endings by counteracting the processes controlled by calcium ions and which lead to the liberation of the transmitters. Post-ganglionic cholinergic or sympathetic transmission are not affected.

The effect of the toxin involves an initial binding step in which the toxin attaches rapidly to the pre-synaptic nerve membrane. This is followed by an internalisation step in which the toxin crosses the pre-synaptic membrane without causing paralysis. Finally the toxin inhibits the release of acetylcholine by interrupting the calcium ion mediated mechanism for acetylcholine release, thereby reducing the nerve end-plate potential and causing paralysis. The recovery of the impulse transmission occurs gradually as new nerve terminals sprout and make contact with the post-synaptic motor endplate. This process takes 6-8 weeks in animal models.

Symptomatic treatment of focal spasticity affecting the upper limbs in adults

The efficacy and safety of Dysport for the treatment of upper limb spasticity was evaluated in a randomized, multi-centre, double-blind, placebo-controlled study that included 238 patients (159 Dysport and 79 placebo) with upper limb spasticity who were at least 6 months post-stroke or post-traumatic brain injury. The cause of spasticity in the study was stroke in 90.3% of subjects and traumatic brain injury in 9.7% of subjects.

The primary efficacy variable was the primary targeted muscle group (PTMG) muscle tone at week 4, as measured by the Modified Ashworth Scale (MAS) and the first secondary endpoint was the Physician Global Assessment (PGA) of response to treatment. The main results achieved at Week 4 and Week 12 are shown below:

	Week 4			Week 12
	Placebo (N=79)	Dysport (500 units) (N=80)	Dysport (1000 units) (N=79)	Placebo (N=79)	Dysport (500 units) (N=80)	Dysport (1000 units) (N=79)
LS Mean Change from Baseline in PTMG Muscle Tone on the MAS	-0.3	-1.2**	-1.4**	-0.1 n=75	-0.7** n=76	-0.8** n=76
LS Mean PGA of Response to Treatment	0.7	1.4*	1.8**	0.4 n=75	0.5 n=76	1.0* n=76
LS Mean Change from Baseline in Wrist Flexor Muscle Tone on the MAS	-0.3 n=54	-1.4** n=57	-1.6** n=58	-0.3 n=52	-0.7* n=54	-0.9* n=56
LS Mean Change from Baseline in Finger Flexor Muscle Tone on the MAS	-0.3 n=70	-0.9* n=66	-1.2** n=73	-0.1 n=67	-0.4* n=62	-0.6* n=70
LS Mean Change from Baseline in Elbow Flexor Muscle Tone on the MAS	-0.3 n=56	-1.0* n=61	-1.2** n=48	-0.3 n=53	-0.7* n=58	-0.8* n=46
Mean Change from Baseline in Shoulder Extensors Muscle Tone on the MAS (1)	-0.4 n=12	-0.6 n=7	-0.7 n=6	0.0 n=12	-0.9 n=7	0.0 n=6
*p<0.05; ** p<0.0001; LS = Least Square (1) No statistical tests performed due to low frequency by treatment and placebo groups

To investigate the effect of treatment on functional impairment, assessments on the Disability Assessment Scale [DAS] were performed. The second secondary endpoint was the mean change from baseline in the Principal Target of Treatment [PPT] of the DAS. Some improvements in the mean change from baseline in the PTT of the DAS were observed at Week 4 in the Dysport groups compared to placebo, but did not reach statistical significance. The DAS score responders (subjects achieving a one grade or greater improvement) for the PPT (ITT Population) was a tertiary endpoint, results of this analysis are shown below:

Both 500U and 1000U resulted in statistically significant improvements in spasticity angle and spasticity grade, as assessed by the Tardieu Scale, at week 4 in all muscle groups (finger, wrist or elbow flexors) when compared to placebo. Reductions in spasticity grade were also significant at week 12 for all muscle groups at the 1000U dose when compared to placebo.

Dysport 1000 U statistically improved the active range of motion (AROM) by clinically meaningful margins in the elbow (+18.3 degrees), wrist (+35.2 degrees) and finger muscles (+11.8 degrees) at Week 4 while there was no improvement in placebo group. Dysport 500 U showed similar benefit on finger muscles AROM.

Improvements in ease of applying a splint by the subject were statistically significantly greater in the Dysport 1000 U and 500 U treatment groups than in the placebo group at Weeks 4 and 12.

There were no statistically significant differences in changes from baseline to End of Study/Early Withdrawal Visit between the Dysport 500 U, 1000 U and placebo groups in the Short Form (36) Health Survey^®(SF-36) and European Quality of Life 5 Dimensions (EQ-5D) QoL questionnaires.

In a subsequent open-label extension study, re-treatment was determined by clinical need after a minimum of 12 weeks. Doses greater than 1000U and up to 1500U were permitted when the shoulder muscles were injected. After repeated administration, the efficacy of Dysport is maintained for up to 1 year.

Pes equinus due to spastic cerebral paralysis in ambulant paediatric patients over 2 years of age

A double-blind, placebo-controlled multicentre study (Study Y-55-52120-141) was conducted in children with dynamic equinus foot deformity due to spasticity in children with Cerebral Palsy. A total of 235 botulinum toxin naïve or non-naïve patients with a Modified Ashworth Score (MAS) of grade 2 or greater were enrolled to receive Dysport 10 Units/kg/leg, Dysport 15 Units/kg/leg or placebo. Forty one percent of patients were treated bilaterally resulting in a total Dysport dose of either 20 Units/kg or 30 Units/kg. The primary efficacy variable was the mean change from baseline in MAS in ankle plantar flexors at Week 4. Secondary efficacy variables were the mean Physicians Global Assessment (PGA) score and Mean Goal Attainment Scaling (GAS) score at Week 4. Patients were followed up for at least 12 weeks post-treatment and up to a maximum of 28 weeks.

MAS Change from Baseline at Week 4 and week 12, PGA and GAS at Week 4 and Week 12 (ITT Population)

Parameter	Placebo (N=77)	DYSPORT
		10 U/kg/leg (N=79)	15 U/kg/leg (N=79)
LS mean change from baseline in ankle plantar MAS score
Week 4	-0.5	-0.9 **	-1.0 ***
Week 12	-0.5	-0.8 *	-1.0 ***
LS mean score for PGA response to treatment [b]
Week 4	0.7	1.5 ***	1.5 ***
Week 12	0.4	0.8 *	1.0 **
LS mean GAS score [a]
Week 4	46.2	51.5 ***	50.9 **
Week 12	45.9	52.5 ***	50.5 *
* p≤ 0.05; **p≤ 0.003; *** p≤ 0.0006 compared to placebo; LS=least square [a] GAS score measures progress towards goals that were selected at baseline from a list of twelve categories. The five most commonly selected goals were improved walking pattern (70.2%), improved balance (32.3%), decreased frequency of falling (31.1%), decreased frequency of tripping (19.6%) and improved endurance (17.0%)

Improvement in the spasticity of the ankle plantar flexors was observed, as assessed by the Tardieu scale. The spasticity grade (Y) was statistically significantly improved compared to placebo for both the 10 U/kg/leg and 15 U/kg/leg Dysport treatment groups at Week 4 and Week 12, and the angle of catch (Xv3) was significant for the 10 U/kg/leg Dysport group at Week 12 and at both Week 4 and Week 12 for the 15 U/kg/leg Dysport group.

Both Dysport treatment groups, 10 U/kg/leg and 15 U/kg/leg, demonstrated a significant improvement from baseline in the Observational Gait Scale (OGS) overall score at Week 4 when compared to placebo and a statistically significantly higher proportion of patients were treatment responders for initial foot contact on the OGS at Week 4 and Week 12.

Parents completed the condition-specific Module for CP for the Paediatric Quality of Life Inventory. There was a statistically significant improvement from baseline in fatigue at Week 12 in the Dysport 10 U/kg/leg and 15 U/kg/leg DYSPORT treatment groups compared to placebo. No other statistically significant improvements were observed in the other subscales.

5.2 Pharmacokinetic properties

Investigations using I¹²⁵labelled toxin have demonstrated that receptor bonding is specific. Dose-response studies in apes have shown that at low doses there is a delay of 2-3 days with a maximum effect 5-6 days after the injection.

Period of effect – measured as changes in ocular line as well as muscular paralysis ranged from 2 weeks to 8 months. This pattern is also seen in humans and is ascribed to the binding of the toxin, transport across the nerve membranes and the change in neuromuscular transfer.

5.3 Preclinical safety data

In a chronic toxicity study performed in rats up to 12 units/animal, there was no indication of systemic toxicity. Reproductive toxicity studies in pregnant rats and rabbits given Clostridium botulinum toxin type A – haemagglutinin complex by daily intramuscular injection, at doses of 79 units/kg and 42 units/kg in rats and rabbits respectively, did not result in embryo/fetal toxicity. Severe maternal toxicity associated with implantation losses were observed at higher doses in both species. Clostridium botulinum toxin type A – haemagglutinin complex demonstrated no teratogenic activity in either rats or rabbits and no effect were observed in the pre- and post-natal study on the F1 generation in rats. Fertility of the males and females was decreased due to reduced mating secondary to muscle paralysis at high doses.

In a juvenile toxicity study, rats treated weekly from the age of weaning on Postnatal Day 21 up to 13 weeks of age comparable to children of 2 years old, to young adulthood (11 administrations over 10 weeks, up to total dose of approximately 33U/kg) do not show adverse effects on postnatal growth (including skeletal evaluation), reproductive, neurological and neurobehavioral development.

Effects in reproduction, juvenile and chronic toxicity non-clinical studies were limited to changes on injected muscles related to the mechanism of action of Clostridium botulinum toxin type A – haemagglutinin complex.

There was no ocular irritation following administration of Clostridium botulinum toxin type A – haemagglutinin complex onto the eye of rabbits.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Albumin, lactose monohydrate.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in 6.6.

6.3 Shelf life

2 years.

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

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C.

6.4 Special precautions for storage

Store at 2C - 8C. Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

3ml vials - colourless glass (type I) sealed with a rubber stopper and aluminium cap.

Packs of 1 x 1 and 2 x 1 injection bottles.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Dysport injection substance which is a white freeze-dried powder should be dissolved before use in 1 ml, 2.5 ml or 5 ml sodium chloride 9mg/ml (0.9%) solution for injection to produce a solution of 500, 200 or 100 units per ml. The exposed centre of the rubber stopper should be cleaned with alcohol before the needle is inserted into the septum. A size 23 or 25 needle should be used. Dysport must be administered intramuscularly, intradermally or subcutaneously.

All used injection bottles, syringes and items with spillage must be autoclaved or any remaining botulinum toxin A inactivated using diluted hypochlorite solution (0.5%).

7. MARKETING AUTHORISATION HOLDER

Institut Produits Synthèse (IPSEN) AB

Kista Science Tower

Färögatan 33

164 51 Kista

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16 July 1999

Date of latest renewal: 16 July 2009

10. DATE OF REVISION OF THE TEXT

10 November 2016