dysport ct 12379inn botulinum toxin type a atc code (2011): m03ax01 (muscle relaxants, peripherally...

HAS - Medical, Economic and Public Health Assessmen t Division 1/21

The legally binding text is the original French ver sion

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Opinion

7 November 2012

DYSPORT 300 SPEYWOOD UNITS, powder for solution for injection Vial, B/1 (CIP code: 34009 577 649 0 6)

DYSPORT 500 SPEYWOOD UNITS, powder for solution for injection Vial, B/1 (CIP code: 34009 558 105 9 9)

Applicant: IPSEN PHARMA

INN botulinum toxin type A

ATC Code (2011): M03AX01 (Muscle relaxants, peripherally acting agents)

Reason for the review

Inclusion in a new indication

List concerned For hospital use (French Public Health Code L.5123- 2)

Indication concerned

“Adults: - Blepharospasm. - Hemifacial spasm. - Spasmodic torticollis. - Local symptomatic treatment of upper and/or lower limb spasticity (muscle hyperactivity). Children aged 2 years and over: Old indication (included in the new indication): treatment of dynamic equinus foot deformation in children with spasticity caused by cerebral palsy. New indication : local symptomatic treatment of lower limb spastic ity. This drug therapy treatment should form part of a wider multidisciplinary care approach (including a neurologist, paediatrician, physical medicine and rehabilitation specialist, orthopaedic surgeon etc.).”


AB Substantial

IAB On the basis of available data, DYSPORT does not offer any improvement in actual benefit (no IAB, level V) compared with BOTOX in the local symptomatic treatment of lower limb spasticity in children aged 2 years and over.

Therapeutic use First-line treatment of localised or multifocal spasticity (professional consensus)

Recommendations Opinion in favour of inclusion on the list of medicines approved for hospital use.


01 ADMINISTRATIVE AND REGULATORY INFORMATION

Marketing Authorisation

Initial dates (national procedure): - 11 October 1993: DYSPORT 500 - 30 July 2010: DYSPORT 300 Correction to the marketing authorisation of 13 February 2012 (extended indication)

General classification for supply / special status

List I Medicinal product reserved for hospital use The administration of DYSPORT botulinum toxin requires the giving of treatment which is currently in the course of being included in the joint classification of medical procedures (CCAM)

ATC classification

2011 M Musculoskeletal system M03 Muscle relaxants M03A Muscle relaxants, peripherally acting agents M03AX Other muscle relaxants, peripherally acting agents M03AX01 Botulinum toxin

02 BACKGROUND

This is a request for inclusion on the list of proprietary medicinal products approved for use by hospitals and various public services of DYSPORT 500 Speywood Units and DYSPORT 300 Speywood Units, powder for solution for injection, after an extension of the indication to the treatment of spasticity of all lower limbs in children aged 2 y ears and over, was obtained. The indication for these proprietary medicinal products was formerly limited to treatment of “dynamic equinus foot deformation caused by cerebral palsy.”

03 THERAPEUTIC INDICATIONS

“Adults: - Blepharospasm. - Hemifacial spasm. - Spasmodic torticollis. - Local symptomatic treatment of upper and/or lower limb spasticity (muscle hyperactivity). Children aged 2 years and over: Old indication (included in the new indication): treatment of dynamic equinus foot deformation in children with spasticity caused by cerebral palsy. New indication : local symptomatic treatment of lower limb spastic ity. This drug therapy treatment should form part of a wider multidisciplinary care approach (including a neurologist, paediatrician, physical medicine and rehabilitation specialist, orthopaedic surgeon etc.).


NB: DYSPORT must be administered by doctors who are already highly experienced in using the toxin in these indications.”

04 DOSAGE

“General recommendations: - The recommended doses of DYSPORT are not interchangeable with other preparations of botulinum toxin A. They are shown as Speywood units. - Minimum interval between two injections: the presence of botulinum toxin type A antibodies may reduce the efficacy of treatment with DYSPORT. Accordingly, as a precaution, there should be a minimum interval between two injection sessions: three months for local symptomatic treatment of lower limb spasticity in children aged 2 years and over. Local symptomatic treatment of lower limb spasticity (in children aged 2 years and over): Dosage and method of administration: Treatment should be tailored to each patient’s clinical condition. Caution should be used with children being given an injection of the product for the first time, and the initial dose should not exceed 10 units/kg in the case of unilateral injections, and 20 units/kg in the case of bilateral injections (with a total dose of no more than 1000 units/patient). The dose should be divided among the various spastic muscles of the lower limb (for example, the calf muscles, the hamstrings or the hip adductors). In the case of injection into the gastrocnemius muscles alone, the recommended initial dosage is 5 units/kg, into each of the heads of the gastrocnemius muscle. The exact dosage and number of injection sites should be individually tailored according to patient size, the number and position of the muscles involved, severity of spasticity, and the presence of local muscle weakness. The dosage should be reduced in children: - with associated concomitant disorders, including those with pre-existing respiratory or swallowing problems; - in whom the muscles to be treated are underdeveloped; - who require a multi-site injection; - who are being given injections under general anaesthesia. In all cases, when choosing the dose, the risk-benefit ratio should be assessed patient by patient, to reduce the risk of undesirable effects, including the risk of the spread of the toxin at a site distant from the administration site (see Special warnings and Precautions for use, Undesirable effects). At subsequent sessions, the dose used should be adjusted extremely carefully, depending on the response to the previous treatment, but should not exceed 15 units/kg in the case of unilateral injections, and up to a maximum total dose of 30 units/kg in the case of bilateral injections (and no more than 1000 units per patient). The total dose administered during one session of injections should never exceed 1,000 units or 30 units/kg (whichever is the lower). Clinical improvement generally occurs within two weeks of the injection session. The injection sessions should be repeated based on how long the clinical effect lasts. They should always be at least three months apart. Method of administration: Administration is by the IM route in one or two injection sites per muscle of the spastic lower limb. Electromyographic guidance should be used to identify the most active muscles.”


05 THERAPEUTIC NEED

Muscle spasticity is an increased contraction in response to stretching and a pathological increase in muscle tone (hypertonia) caused by hyperactivity of the afferent fibres. It may give rise to pain and spasms and cause disability of the upper or lower limbs. Spasticity is caused by vascular, traumatic, infectious or degenerative disorders of the central nervous system. There is frequently a link between spasticity and central neuropathic pain. Spasticity often has a deleterious effect on motor function and the musculoskeletal system, but it may not be troublesome and may even be useful. Not all spastic patients routinely require treatment. Spasticity as a symptom should be analysed using an identical approach, whatever the aetiology. A possible exacerbating cause or nociceptive stimulus should be sought. Cerebral palsy (CP) is the most common cause of physical disability in children. Description of therapeutic use with the aim of iden tifying need and suitable response. The aim of treatment sought is to induce a localised reduction in muscle activity in order to improve motor function and reduce the disability and impaired function caused by spasticity. Drug therapy, when justified, must always be combined with physiotherapy. First-line therapy is considered on the basis of whether the spasticity is localised or diffuse and according to aetiology. Drug therapy of spasticity in children1: Intramuscular botulinum toxin A can be used as first-line therapy for localised or multifocal spasticity. For oral treatment, only baclofen has a marketing authorisation (age 6 years and over). However, its use cannot be recommended from current data. Diazepam is frequently used even though there is no marketing authorisation for this indication. In view of its sedative effect, it should be used with caution and for a short period only (professional consensus). Intrathecal baclofen is effective in spasticity. It is recommended mainly for people with spinal cord injuries and for multiple sclerosis (Grade A) in patients in whom the lower limb spasticity is diffused over a large area, sometimes as far as the trunk (Grade A). Alcohol and phenol are not considered as first-line local treatment except in certain cases of particularly diffuse and troublesome spasticity where they can sometimes be used to complement another local treatment (botulinum toxin) (professional consensus). In children aged under 10 years, extreme caution should be used when administering these products.

06 CLINICALLY RELEVANT COMPARATORS

The clinically relevant comparator(s) of the medica tion being assessed are medicinal products or any o ther non-medicinal therapy (medical devices, procedures etc.) available at the same stage of therapeutic us e and intended for the same population, at the assessment date. Depending on the context, the route and rate of adm inistration, the pharmaceutical form, packaging, pharmacotherapeutic category etc. may be included i n the notion of a clinically relevant comparator.

1 Recommandations de bonne pratique – Traitements médicamenteux de la spasticité – AFSSAPS, June 2009 (updated February 2011)


06.1 Medicinal products

NAME (INN)

Pharmaceutical company

Identical pharmaco-therapeutic

category Yes

no (state)

Similar indication Date of opinion AB IAB

(Description) Funding Yes/no

BOTOX 50, 100 and 200 UNITS, ALLERGAN, powder for solution for injection (botulinum toxin type A) ALLERGAN

yes Adults and children aged 2 years and over: Local symptomatic treatment of upper and/or lower limb spasticity (muscle hyperactivity).

13 January

2010

substantial Minor IAB (level IV) in terms of efficacy in the treatment of upper and/or lower limb spasticity

Yes

The other proprietary medicinal products based on botulinum toxin type A (XEOMIN 100 UNITS LD50, powder for solution for injection) and type B (NEUROBLOC, solution for injection, 5000 IU/ml) are not indicated in local symptomatic treatment of lower limb spasticity in children aged 2 years and over. They are therefore not relevant comparators with DYSPORT. Other muscle relaxants are used1 in children for certain forms of lower limb spasticity. They are mentioned for information purposes only since they do not count as relevant comparators with DYSPORT. They are as follows: Oral use: - LIORESAL (baclofen, Novartis Pharma SAS) for oral use (10 mg/tablet). This is indicated in children aged over 6 years (children weighing over 33 kg) to treat:

- Spastic contractions in multiple sclerosis. - Spastic contractions in spinal injury (caused by infection, degeneration, trauma or neoplasia). - Spastic contractions of cerebral origin.

Nevertheless, “The data do not permit recommendation for its use”. - “Diazepam is frequently used, in spite of the absence of Marketing Authorisation in this indication. It can be recommended (grade B) but in view of its GABAergic effect, it needs to be used with care and for a short period only (professional consensus).” Intrathecal use: - LIORESAL (baclofen) in solution for injection is indicated for intrathecal use in the symptomatic treatment of severe chronic spasticity of medullary origin or secondary to cerebral palsy in children or adults. It is reserved for spasticity that impairs posture, nursing or rest; interferes with autonomy including gait; is responsible for pain (professional consensus). It can be expected to have a favourable effect on autonomic hyperreflexia in people with spinal cord injuries.

06.2 Other health technologies

Topical treatment: 50% alcohol, 5% phenol (off-label use) but they do not represent the first-line topical treatment except in certain cases of particularly diffuse and troublesome spasticity, where they can sometimes be used to complement another topical treatment (botulinum toxin) (professional consensus).


In children aged under 10 years, extreme caution is advisable. However, this type of treatment may be used, solely in contact with the nerve, and especially for the obturator nerve; the most suitable cases are trophic indications and to aid comfort (professional consensus). Non-drug therapies: - Surgery for spasticity (posterior rhizotomy, selective neurotomy, surgery on the muscles/tendons or bones/joints), - Rehabilitation: kinesiotherapy, occupational therapy, physiotherapy. �� Conclusion Among the comparator drugs mentioned above, only BO TOX2 which is also botulinum toxin A, is a relevant comparator since it is available a t the same stage of therapeutic use and is intended for the same population. There are not many treatment alternatives. There is a therapeutic need.

2 Transparency Committee opinion on BOTOX of 13/01/2010


07 INTERNATIONAL INFORMATION ON THE MEDICINAL PRODUCT

In European Union countries, DYSPORT has the status of a medicinal product for hospital use; it is indicated (in particular) for treating lower limb spasticity in children (dynamic equinus foot deformation) caused by cerebral palsy.

08 ANALYSIS OF AVAILABLE DATA

The pharmaceutical company has provided a study the aim of which was to assess the efficacy of botulinum toxin A (DYSPORT) in the treatment of lower limb spasticity: the pivotal study A-94-52120-094 (094), the main objective of which was to compare the efficacy of an injection of DYSPORT with an injection of placebo in the treatment of spasticity of the adductor muscles of the lower limb in 61 children with cerebral palsy. The pharmaceutical company has also filed the results of two observational, non-comparative studies aimed at assessing the effect of DYSPORT to treat spastic muscles of the lower limbs in children (Study 047 and BOTULOSCOPE observational study). There are no studies comparing DYSPORT with BOTOX in terms of efficacy or safety in this medical condition.

08.1 Efficacy

8.1.1 Study 094

Methodology: phase II, randomised, comparative study of DYSPORT versus placebo in 61 children with cerebral palsy, followed up for 12 weeks. Inclusion criteria: children aged from 18 months to 10 years suffering from cerebral palsy with bilateral spasticity of the adductor muscles and a Reimers migration index (RMI)3 of < 50%. Treatment: - an injection of DYSPORT 30 U/kg (solution of 250 Speywood units/ml), 2/3 injected into the adductor muscles and 1/3 into the hamstrings (no more than two injections per muscle with a maximum dose per muscle group of 1,500 U), n=33. - placebo, n=28. Primary efficacy endpoints: - knee-knee distance at a fast speed (fast-stretch Intermedial Condyle – IMC) - amplitude of hip movements (abduction/adduction measured by goniometry – ROM). Secondary endpoints: including those relating to functional endpoints: - muscle tone assessed by the modified Ashworth scale (MAS), - motor function assessed by the GMFM, PEDI and PRS scales. - achievement of therapeutic objectives defined together with the patient before treatment (GAS). - pain. These endpoints were measured 4 and 12 weeks after the injection. 3 Subluxations and dislocations of the hip are assessed by the Reimers migration index, corresponding to the percentage of the femoral head with no coverage. It is defined by the ratio between the width of the femoral head extending laterally beyond the Perkins line and its total width measured in millimetres. The hip is considered to be partly dislocated if the percentage is ≥ 33% and totally dislocated if the Reimers index is > 90% or there is no contact between the femoral head and the acetabulum.


Results : Characteristics of children included:

The median age of the children at enrolment was 5.9 years. There were fewer female children in the DYSPORT group (33%) than in the placebo group (50%). Two-thirds (2/3) of the children (65.6%) had spastic quadriplegia of the lower limbs. The severity of the handicap was rated at a level ≥III on the GMFCS4 in 85.2% of the patients included. Impaired cognitive function was reported in 68.9% of patients. The level of mental handicap was assessed as moderate to severe in 43% of the children. More than half the children (57.6%) required a walking aid. The dose of DYSPORT injected was between 22.9 U/kg and 32.7 U/kg (median 30.0 U/kg). Results for the primary efficacy endpoints:

A difference of 4.7 cm in knee-knee distance in movement (95% CI: [2.2; 7.1], p < 0.001) was observed in the DYSPORT group – an improvement in comparison with the placebo group – after four weeks. At week 12 the improvement in this endpoint was 3.2 cm for DYSPORT compared with placebo (95% CI: [0.9; 5.4], p = 0.008) (see Table 1).

Table 1: Assessment of knee-knee distance in movement in the ITT population

Mean +/- standard deviation compared with value at enrolment (cm)

Visit DYSPORT

(N=31)

Placebo

(N=27)

p value

Week 4 6.4 ± 5.8 1.9 ± 3.5 < 0.001

Week 12 3.4 ± 4.9 0.4 ± 4.4 0.008

Improved amplitude of hip movements (abduction/adduction) assessed by goniometry at week 4 was observed in the DYSPORT group compared with the placebo group. The difference favouring DYSPORT was 6° (95% CI [0.2°; 11.2°], p = 0.04). No difference was observed at week 12 (see Table 2).

Table 2: Assessment of the amplitude of hip movements in the ITT population

Mean +/- standard deviation compared with value at enrolment (°)

Visit DYSPORT

(N=32)

Placebo

(N=26)

p value

Week 4 4.8 ± 12.4 0.5 ± 12.1 0.04

Week 12 1.9 ± 11.1 2.0 ± 10.2 0.68 (NS)

4 The GMFCS (Gross Motor Function Classification Scale) assesses physical severity according to five stages of increasing severity.


Secondary endpoint results:

- Muscle tone assessed by the modified Ashworth scale (MAS), see Table 3:

Table 3: Muscle tone assessed by the MA scale in th e ITT population

Estimated effect of treatment (95% CI)

Visit Muscle DYSPORT

(N=32)

Placebo

(N=26)

p value

Adductors 1.1 (0.3, 1.8) 0.008 Week 4

Hamstrings N/Aa Adductors 0.3 (-0.4, 1.1) 0.38 (NS)

Week 12 Hamstrings 1.2 (0.4, 2.0) 0.005

a Estimate not possible at Week 4. The reduction in spasticity was greater with DYSPORT than with placebo for the adductor muscles alone at week 4.

- Motor function assessed by the GMFM scale5: no difference in terms of improved motor function was demonstrated between DYSPORT and placebo. - Assessment of achievement of abjectives (GAS):

Table 4: Investigator assessment of improvement in the therapeutic objectives of the GAS scale in study 094 in the ITT population

Percentage of patients for whom no improvement in therapeutic objectives

was observed by the investigator Visit

DYSPORT

(N=32)

Placebo

(N=26)

p value

Week 4 38.7% 61.5% 0.10 (NS)

Week 12 37.5% 57.7% 0.08

Table 5: Parental assessment of improvement in the therapeutic objectives of the GAS scale in study 094 in the ITT population

Percentage of patients for whom no improvement in therapeutic objectives

was observed by the parents Visit

DYSPORT

(N=32)

Placebo

(N=26)

p value

Week 4 41.9% 61.5% 0.13

Week 12 43.8% 61.5% 0.11 (NS)

5 The GMFM is a standard observational scale measuring changes in gross motor function in young children with cerebral palsy. It is made up of 88 items used for assessing motor function activities in five dimensions.


Assessment of pain:

Table 6: Change from Baseline in the mean score for the six items in the pain assessment scale in study 094 in the ITT population

Mean +/- standard deviation compared with the initial value of the mean pain

score for the 6 items Visit

DYSPORT

(N=32)

Placebo

(N=26)

p value

Week 4 -0.3 ± 0.8 0.0 ± 0.7 0.19 (NS)

Week 12 -0.3 ± 1.2 -0.1 ± 0.8 0.18 (NS) - Assessment of the child’s daily life via a questionnaire completed by the parents.

Table 7: Change from Baseline in the mean score res ulting from the 11 questionnaire items in study 094 in the ITT population

Mean +/- standard deviation compared with the initial value of the mean score

for the 11 items Visit

DYSPORT

(N=32)

Placebo

(N=26)

p value

Week 4 -0.2 ± 0.3 -0.1 ± 0.4 0.08

Week 12 -0.2 ± 0.5 -0.1 ± 0.4 0.21 (NS) 8.1.2 Observational study 047

Study objectives: to assess the efficacy and safety of DYSPORT in the treatment of spasticity in children.

Study methodology: retrospective, non-comparative, phase II study analysing patient files. It was conducted between 1990 and 1999 in Germany, the Czech Republic, Italy, Slovakia and the United Kingdom.

Inclusion criteria: children previously treated (mostly by DYSPORT) for spasticity in one or more muscle groups (mostly lower limb muscles).

Primary efficacy endpoint: overall response to treatment assessed by a 4-item scale:

- “Good”: response to treatment with improved function

- “Minimal”: response to treatment, improved function not observed

- “None”: no response observed

- “Negative”: response to treatment where the effect was harmful to the patient.

Also assessed were the impact of age, the dose injected and injection into just one or several muscle groups in terms of evaluating overall response to treatment.

Among the secondary endpoints:

- duration of response to treatment,

- achievement of functional objectives: improved posture, carrying out personal hygiene, improvement in walking distance, improved tolerance (safety) of orthosis wearing, pain relief etc.). These objectives were set by the patient and therapist. They were attached to a muscle group. Several categories of functional objectives were created, with each depending on a muscle group.

For instance:


- Functional objectives associated with the hip adductor muscles (for example: improvement in “scissor” gait, slowing of hip migration, pain relief, improvement in “seated” posture, improvement in personal hygiene, improved tolerance (safety) of orthosis wearing).

- Functional objectives associated with the hip flexor muscles (for example: improved mobility and posture, pain relief, improvement in personal hygiene, improved tolerance (safety) of orthosis wearing).

- Functional objectives associated with the hamstrings (for example: reduction of energy expended in walking, increased amplitude of a step, pain relief, improved posture).

Results : Sample size: out of the 768 patients screened, 758 were included in the analysis. They received a total of 1,594 injections of DYSPORT.

Primary efficacy endpoint: the overall response to treatment was considered to be “good” in 82% of cases. The proportion of “good” response to treatment depended on the age of the child (it was lower the higher the age) and the dose injected (it was greater when the dose injected was between 250 and 750 U or greater than 20 – 30 U/kg), and the number of muscle groups injected.

Secondary endpoints:

- Mean duration of the effect of treatment: this was 19 weeks (min: two weeks; max: 100 weeks). It was longer in quadriplegic patients (27 weeks) than in diplegic (16 weeks) or hemiplegic (14 weeks) patients.

- Functional secondary endpoints: taking all patients together, 5,504 functional endpoints were set: 145 (3%) of the predefined endpoints were fully achieved, 2,270 (44%) were moderately well achieved, 2,558 (50%) had a level of achievement described as detectable and 131 (3%) were not achieved (no improvement compared with level at enrolment). Among the 5,504 functional objectives set, 1,100 concerned patients with spasticity of the hip adductor muscles, 1,518 related to patients with spasticity of the hamstring muscles and 670, patients with spasticity of the hip flexor muscles. The main results in these three categories of objectives are set out below:

Table 8: Functional objectives for patients with sp asticity in study 047

Predefined objectives for hip

adductors

Predefined objectives for hamstrings

Predefined objectives for hip flexor muscles

Total (n) 1,100 1,518 670 Result “Moderate”, n (%) 507 (50) 672 (47) 217 (33) Result “Detectable”, n (%) 445 (44) 695 (49) 449 (67)

The functional results associated with spasticity by muscle group were as follows:

- Hip adductor muscles: the functional objectives most frequently set were improvement in seated position (29%), scissor gait (22%) and personal hygiene (20%), and the slowing of hip displacement (17%). These objectives were rated as “moderately well achieved” or “fully achieved” in 48%, 53%, 47% and 68% of cases respectively. Patients who were set these objectives were mainly quadriplegic or diplegic.

- Hamstring muscles: the functional objectives most frequently set were improved posture (29%) and reduction of the flexed position of the knee (22%). These objectives were rated as “moderately well achieved” or “fully achieved” in 46% and 52% of cases respectively. Patients who selected these objectives were mainly quadriplegic or diplegic.

- Hip flexor muscles: the functional objectives most frequently set were improved posture (44%) and improved mobility (42%). These objectives were rated as “moderately well achieved” or “fully achieved” in 32% and 30% of cases respectively. The greatest improvement was observed in pain relief (50%). Patients who selected these objectives were mainly quadriplegic or hemiplegic.


8.1.3 BOTULOSCOPE observational study

This clinical and economic observational study of the use of botulinum toxin to treat spasticity of limbs was set up by the French Ministry of Health in connection with the STIC (support for innovative and costly techniques) programme. Methodology: Observational study of a consecutive series of 704 patients (395 adults and 309 children) with disabling spasticity, monitored for 12 months. Note: the target for inclusions was initially set at 430 children and 530 adults so that, 12 months on, 70% of patients would have achieved the objective defined at the pre-injection visit. Inclusion criteria: Patients receiving targeted treatment for disabling spasticity:

- focal spasticity of children with CP aged 2 to 16 years (equinus foot), - spasticity of the upper limbs in hemiplegic adults (> 16 years) after a stroke, - other types of disabling focal spasticity,

In the context of an initial or further injection of BTX-A. Collection of data: a specific case report form was created for each patient. The data were collected prospectively by a CRA and entered anonymously on a secure web site. Analysis of data: The data for children and adults were analysed separately and “per protocol”. Analysis of clinical benefit: Before the first injection, the treatment objectives were defined by the doctors and patients and prioritised (objective no. 1 and so on); they were then classified into three themes: “functional aspects”, “independence and quality of life” and “management”. The improvement in the objectives was defined by the median and quartiles of the scores obtained on the VAS; priority was given to assessing objective no. 1 as defined by the doctors and their patients. Treatments: of the 509 injections, 68% were with BOTOX and 32% with DYSPORT. The mean dose injected was 10.4 ± 5 U/kg with BOTOX and 26.6 ± 14 U/kg with DYSPORT. Results: (see Table 2, per-protocol analysis) Of the 282 patients enrolled:

- 247/282 (88%) had cerebral palsy, - 61/282 were hemiplegic, 155/282 (55%) diplegic and 63/282 (22%) were quadri- or

triplegic. The mean age was 6.3 ± 2.8 years (50% aged over 6 years).

Table 9: Improvement score for objective no. 1 asse ssed at 1, 3 and 12 months by VAS (median [Q1-Q3]).

Theme of objective After 1 month After 3 months After 12 months Functional aspects (n=209) 5 [3-7] 5 [3-7] 6 [4-8] Independence and quality of life (n=32) 4 [0 -6] 5.85 [3-7] 6 [3-8] Care and management (n=26) 7 [5-8] 7.5 [5-8] 7.5 [3-8] After 12 months’ follow-up, functional aspects, independence and quality of life had improved by 60% in 50% of the patients assessed; care and management had improved by 75%.


08.2 Adverse effects/Undesirable effects

8.2.1 Data from clinical studies assessing DYSPORT in the local symptomatic treatment of spasticity of the limbs in children

Study 094

Sixty-one per cent (61% (20/33) of patients on DYSPORT and 46% receiving placebo experienced at least one treatment-emergent adverse event (TEAE), considered to be linked to treatment in 24% (8/33) and 14% (4/28) of cases respectively under DYSPORT or placebo. None of these events was severe. The adverse events considered to be linked to treatment are shown in the table below:

Table 10: Adverse events linked to treatment in stu dy 094

DYSPORT Placebo Size of population: (N=33) (N=28)

N* (%) n (%) All TEAEs 20 (60.6) 13 (46.4)

Muscle weakness 3 (9.1) 0 Dysarthria 2 (6.1) 0 Hypotonia 1 (3.0) 0 Urinary incontinence 1 (3.0) 0 Motor skills disorders 0 1 (3.6) Strabismus 0 1 (3.6) Abnormal gait 1 (3.0) 0 Fatigue 1 (3.0) 0 Weakness 1 (3.0) 1 (3.6) Dysphagia 1 (3.0) 1 (3.6) Pollakiuria 1 (3.0) 0

N: number of patients suffering from the TEAE. Adverse events at a site distant from the administration site: In pivotal study 094, 18% (6/33) patients treated with DYSPORT experienced eight events considered by the investigator to be mild or moderate in severity and possibly linked to the toxin spreading some distance. These were: dysphagia (two cases), dysarthria (two cases), muscle weakness (two cases), weakness (one case) and hypotonia (one case). Two events (dysarthria and muscle weakness), observed in the same patient 17 days after the injection, were considered by the investigator to be serious and mild to moderate in severity and led to the patient leaving the study. Observational study 047 The adverse events were collected retrospectively in the 758 patients. In all, 90 patients experienced 174 adverse events, of which 7% (12/174) were severe. Bearing in mind that the causal link for these events was not assessed during the study, the most frequently reported were: - localised muscle weakness: 16/758 (2%) including two severe cases, - urinary incontinence: 10/758 (1%) including three severe cases,


The adverse effects (AEs) were analysed by age and dose injected: - By age: the proportions of children reporting AEs were similar in different sub-groups of age over two years (10% to 14%):

Table 11: Adverse events by age in study 047

Age (years) < 2 2 to 5 > 5 to 8 > 8 to 12 > 12 Total patients, N 31 261 213 149 103 Total treatments, n 51 596 395 283 268 Median dose, (U) 250 336 435 500 500 Median dose, U/kg 26 24 23 19 15 Adverse events, n 0 61 53 37 23 Patients with AEs, n (%) 0 26 (10) 30 (14) 20 (13) 14 (14)

N=number of patients in the safety population; n=number of treatments/AEs/patients with AEs. - By injected dose: the frequency of AEs was greater for injected doses of more than 1,000 Units (38% as against 7 to 13% in other sub-groups of doses):

Table 12: Adverse events by total dose (units) in s tudy 047

≤ 250 U >250-500 U >500-750 U >750-1000 U >1000 U Total patients (n) 246 495 136 104 16 Total treatments (n) 400 826 189 145 27 Undesirable events (n) 36 67 28 21 13 Patients with AEs, n (%) 18 (7) 40 (8) 18 (13) 11 (11) 6 (38)

- By doses in relation to the weight of the child: the frequency of AEs was highest for injected doses of more than 30 U/kg. In contrast, it was similar in the various sub-groups of doses for doses up to 30 U/kg:

Table 13: Adverse events by dose (units/kg) in study 047

Dose (U/kg) ≤ 10 > 10 and ≤ 20 > 20 and ≤ 30 > 30 and ≤ 40 > 40 Total patients, N 124 274 373 148 33 Total treatments, n 181 415 530 208 43 Undesirable events, n 22 35 45 39 10 Patients with AEs, n (%) 11 (9) 18 (7) 29 (8) 21 (14) 4 (12)

N=number of patients in the safety population n=number of treatments/AEs/patients with AEs.

There was no evidence that AEs in children who had received multi-site injections (32/417 patients; 8%) were more frequent than in children who had received DYSPORT at a single site (59/467; 13%). Adverse effects at a site distant from the administration site were reported: 6% of children (43/758) reported 76 AEs. Of these effects, the most common were: muscle weakness (12% (9/76)), urinary incontinence (10.5% (8/76)), drowsiness (10.5% (8/76)) and fatigue (9% (7/76). Flu-like symptoms and asthenia each represented 7% of these AEs (5/76)). None of these AEs were considered serious by the investigator. BOTULOSCOPE observational study

Adverse events were reported with 35% (177/509) of injections of botulinum toxin A. The most common adverse events were:

- weakness: 72/177 (41%), - pain: 67/177 (38%), - enuresis: 18/177 (10%),


- falls: 14/177 (8%) - flu-like symptoms: 9/177 (5%) - swallowing disorders: 3/177 (2%).

Adverse effects at a site distant from the administration site:

- generalised weakness: 72/93 (77%), - enuresis: 18/93 (19%) - swallowing disorders: 3/93 (4%).

Falls (14 cases) were reported as being possibly linked to a manifestation that was either local or at a site distant from the localised muscle weakness. 8.2.2 Data on the paediatric use of DYSPORT from PSURs

Over an 18-year period (up to 30 September 2008), 137 medically confirmed cases involving children (representing 206 adverse events) were notified to the pharmaceutical company. Of these, 52 were considered serious. Children treated with botulinum toxin for lower limb spasticity not associated with cerebral palsy: 23 cases The mean age of the children, reported in 20 cases, was 6 years. The spasticity was associated with various disorders: hereditary spastic paraplegia, equinus foot, dystonia etc. Five cases were judged as severe and possibly caused by botulinum toxin type A, in view of the fact that overdose was reported for four of them (> 30 U/kg). These events were as follows: respiratory failure (in a child given a tracheotomy), generalised hypotonia, generalised muscle weakness, localised muscle weakness of the lower limb, dislocation of the hip and strabismus. No cases led to the death of the child. Cases involving children treated with botulinum toxin for lower limb spasticity associated with cerebral palsy: 86 cases (128 AEs, of which 56 were serious) Of these, 44/86 (51%) were possibly caused by botulinum toxin. The most common were: muscle weakness (the most frequently reported risk: 51 AEs), asthenia, fever, ptosis, inefficacy and urinary incontinence. High dosage was reported for most of the adverse effects arising at a site distant from the injection site – overdose in one-third of cases. 8.2.3 Data from the SmPC

In dynamic equinus foot deformation in children with cerebral palsy, an accurate initial functional assessment should be made in a specialist unit. This will make it possible to: - assess the relevance of the indication: predominant spasticity; absence of muscle weakness sometimes masked by hypertonia. This weakness might be aggravated by an injection of botulinum toxin; absence of substantial fixed retraction or post-surgery scar making a botulinum toxin injection unnecessary; - decide on the various components of treatment (physiotherapy, wearing braces etc.); - adjust the treatment in line with the clinical course. In local, symptomatic treatment of lower limb spasticity in children aged 2 years and over, common undesirable effects (≥ 100 and < 1/10) were: abnormal gait, asthenia, flu-like symptoms, pain at the injection site, diarrhoea, urinary incontinence, muscle weakness. Accidental injury due to falling and abnormal gait may have been due to the over-weakening of the target muscle and/or the local spread of DYSPORT to other muscles involved in ambulation and balance. Adverse effects that are independent of the injection site are also mentioned: - Effects associated with the spread of the toxin at a site distant from the injection site have been reported very rarely (excessive muscle weakness, dysphagia, aspiration pneumonia, which can be fatal). In general, the dose used in these cases was above the recommended dose. - Rare general allergic reactions (rash, erythema, pruritus).


- Pain/burning sensation at the injection site.

The development of botulinum toxin antibodies, and therefore resistance to treatment, is also possible.

08.3 Summary and discussion

Summary of main efficacy results A randomised study compared DYSPORT (dose between 22.9 U/kg and 32.7 U/kg) with placebo, in 61 children aged from 18 months to 10 years suffering from cerebral palsy with bilateral spasticity of the adductor muscles and a Reimers migration index of < 50% (study 094). In the fourth week following the injections, spasticity as assessed by measuring the knee-knee distance at a fast speed and the amplitude of hip movements was less with DYSPORT than with placebo but the effect size was modest. In the 12th week, only spasticity as assessed by measuring the knee-knee distance was still less with DYSPORT than with placebo.

An observational study (047) on 758 patients who received a total of 1,594 injections of DYSPORT revealed an overall response considered to be good in 82% of cases and a mean duration of response estimated at 19 weeks. These results suggest that in real conditions of use, DYSPORT contributes to improved function in children with lower limb spasticity. An observational study of the treatment of spasticity of the limbs with botulinum toxin set up by the Ministry of Health (BOTULOSCOPE) included 282 children with a mean age of 6.3 ± 2.8 years who received 509 injections of botulinum toxin (32% of which were DYSPORT at a mean dose of 26.6 ± 14 U/kg). After 12 months’ follow-up, a 60% improvement in functional aspects, independence and quality of life was observed in 50% of patients, and care and management had improved by 75%. Summary of the main safety results In clinical studies, most treatment-related adverse effects were mild to moderate in severity. The most common were abnormal gait, asthenia, flu-like symptoms, pain at the injection site, falling, diarrhoea, urinary incontinence and muscle weakness. Adverse effects that may or may not be caused by spreading of the toxin, sometimes serious (swallowing disorders, muscle weakness with falling), are also possible. The frequency of AEs increases with the dose, particularly if it is > 30 U/kg. To limit this risk, it is therefore essential to comply with the dosage (dose administered per injection, total dose).

The presence of botulinum toxin type A antibodies may reduce the efficacy of treatment. Accordingly, as a precaution, there should be a minimum interval between two injection sessions. Main discussion points regarding data 1) Methodological critique for assessing effect siz e and clinical benefit In comparative study 094, the choice of placebo as comparator (rather than BOTOX) was unfortunate but acceptable because the clinical development of DYSPORT and BOTOX took place concurrently. The primary efficacy endpoints are not measures that directly assess limb function. The endpoint “amplitude of hip abduction” is, however, relevant in so far as spasticity of the lower limb adductors is responsible for progressive dislocation of the hip. The knee-knee distance is not measured routinely. The observed differences in favour of DYSPORT after an injection and in comparison with placebo were slight: 3.2 cm after 12 weeks for the knee-knee-distance and a 6° gain in amplitude of hip movements after four weeks, with no significant difference from placebo after 12 weeks. It is difficult to assess the impact of these results, since their functional effect cannot be evaluated. Although observational study 047 involved a large number of patients, these results should be interpreted with caution, particularly because of its retrospective, non-comparative methodology and the multiplicity of the functional endpoints assessed. As a result of this, the effect size of


DYSPORT versus placebo or (indirectly) versus BOTOX cannot be accurately quantified. The observed effects may also be explained by rehabilitation therapy. Overall, these data seem to demonstrate that DYSPORT offers a degree of short-term clinical benefit in reducing muscle spasticity, though this is not accurately quantified. 2) Missing data There is no assessment of the long-term clinical efficacy (functional objectives, quality of life and morbidity/mortality) after several injections of DYSPORT. The volumes of DYSPORT administered are smaller than those of BOTOX, which may be beneficial in children. A comparison between BOTOX and DYSPORT would make it possible to establish whether the different dosage regimens of the two medicinal products result in any differences of efficacy or adverse effects.

08.4 Study programme

In view of the possible occurrence of effects from botulinum toxin at a site distant from the target muscle injected, a European risk management plan (RMP) has been set up for all proprietary medicinal products containing botulinum toxin (rapporteur country: Sweden).

Moreover, at the national level, the ANSM is requesting: - the provision of information documents addressed to patients and prescribers (documents

not available at the date of this opinion), - a usage study (protocol under discussion).


09 THERAPEUTIC USE

Place of DYSPORT in the local symptomatic treatment of lower limb spasticity in children 6: Intramuscular botulinum toxin A can be used as first-line therapy for localised or multifocal spasticity (professional consensus). It represents a reversible, adaptable, topical treatment. In children, most of the results come from studies involving patients with cerebral palsy. However, the use of botulinum toxin may be considered for any disorder in question (AFSSAPS agreement, June 2009), with an indication that is symptomatic rather than aetiological. Bearing in mind that botulinum toxins are not inter changeable and that the treatment regimen mentioned in the marketing authorisation fo r each proprietary medicinal product should be followed, DYSPORT represents an alternati ve to BOTOX for children aged over 2 years. Botulinum toxin type A (BOTOX, DYSPORT) should be administered by specialist doctors experienced in its use in this indication. It is advisable to use a follow-up diary and an information sheet. Furthermore, traceability of the injected product, the batch number, the total dose and the dose per muscle, together with the dilution, is strongly recommended. According to a recent report by the British National Institute of Clinical Excellence (NICE): (“Spasticity in children and young people with non-progressive brain disorders. Management of spasticity and co-existing motor disorders and their early musculoskeletal complications.” Issued: July 2012):

Botulinum toxin type A treatment can be considered: - when the localised lower limb spasticity hinders major motor function, compromises rehabilitation and hygiene, causes pain, disturbs sleep, is distressing for the child (“causing cosmetic concerns to the child or young person”), or prevents the use of other treatment, such as orthoses and equipment to support posture; - in the event of a non-progressive acquired brain injury, if the rapid onset of spasticity leads to postural or functional difficulties.

Botulinum toxin type A can be considered (“Consider a trial of botulinum toxin type A treatment”) in the event of spasticity with focal dystonia that causes substantial problems such as postural or functional difficulties and pain (“spasticity in whom focal dystonia is causing serious problems, such as postural or functional difficulties or pain”). It should be used with caution in cases of coagulation disorder and in children who have generalised spasticity or permanent muscle contraction (“fixed muscle contractures”) or marked bone deformities (“marked bony deformity”).

Apart from a history of allergies or adverse effects arising after a previous administration (“previous adverse reaction”), it is not recommended in children with substantial muscle weakness (“severe muscle weakness”) and in cases of current aminoglycoside treatment.

6 Recommandations de bonne pratique – Traitements médicamenteux de la spasticité – AFSSAPS, June 2009 (updated February 2011)


010 TRANSPARENCY COMMITTEE CONCLUSIONS

In view of all of the above data and information an d following the debate and vote, the Committee’s opinion is as follows:

010.1 Actual benefit

�� Spasticity is a disabling handicap in addition to that of the underlying aetiology, it can detract from quality of life and have a considerable impact on social and family life. �� These proprietary medicinal products fall under the category of symptomatic treatment. �� The efficacy/safety ratio of botulinum toxin type A is modest in this indication. �� There are not many treatment alternatives and they are administered systemically. There is a therapeutic need. �� It is a first-line therapy to be used in addition to physiotherapy.

�� Public health benefit: The burden of spasticity arises from the functional disability and loss of independence that it causes. Its repercussions on psychosocial and family life may also be substantial. Given the heterogeneity of patients and the very variable degree of disability caused by spasticity, the public health burden may be regarded as moderate. However, it is low in the smaller population affected by DYSPORT’s indication (children aged between 2 and 12 years). The reduction in functional sequelae and the improved quality of life of people with disabilities, whether related to ageing, chronic diseases, or perinatal/traumatic injuries, constitutes a public health need that is already an established priority (Law of 9 August 2004 on public health policy – Objective 35, Plan to improve the quality of life of patients with chronic disease). However, the data available are not sufficient to quantify the expected impact of DYSPORT on the improvement in functional ability and thus disability and on the improved quality of life of spastic patients, even in the short term. In view of the data from study 094 and in the absence of any study versus an active comparator, DYSPORT is not expected to have a greater impact than BOTOX, which is already available in this indication. It is not certain that the study results can be transposed to clinical practice (just one study involving a limited number of patients, no information on associated physiotherapy, no French patients, limited duration of the studies in view of the long-term nature of treatment). Furthermore, as with the other botulinum toxin type A, its performance is dependent on the existence of a multidisciplinary medical and paramedical organisation, trained and experienced clinicians and customised patient follow-up. In view of these points and as with BOTOX, the public health benefit of DYSPORT in this indication cannot be quantified.

Taking account of these points, the Committee consi ders that the actual benefit of DYSPORT is substantial in the extended indication. The Committee recommends inclusion on the list of m edicines approved for hospital use in the new indication “ Local symptomatic treatment of lower limb spasticity in children aged 2 years and over” and at the dosages in the marketing authorisation .

010.2 Improvement in Actual Benefit (IAB)

In summary, the Commission considered that BOTOX (another botulinum toxin type A) provides a minor improvement in actual benefit (IAB IV) in terms of efficacy in the treatment of upper and/or lower limb spasticity (muscle hyperactivity) in children aged 2 years and over. (Opinion of the Committee of 13/01/2010).


On the basis of available data, DYSPORT does not pr ovide any improvement in actual benefit (IAB V) compared with BOTOX in the local sy mptomatic treatment of lower limb spasticity in children aged 2 years and over.

010.3 Target population

The target population is represented by children aged 2 years and over with lower limb spasticity from various causes (stroke, MS, brain injury, spinal cord injury, cerebral palsy etc.). This target population cannot be estimated from the available data. Only the population of patients with ‘dynamic equinus foot deformation in children with spasticity caused by cerebral palsy’ can be quantified in terms of a target population. It can be estimated from the following data. Estimate The target population is made up of children born with cerebral palsy (CP) who have unilateral spasticity that has led to an equinus foot deformity. The incidence of cerebral palsy (CP) is estimated to be 2 per 1,000 births.7 According to data from INSEE (the French national institute for statistics and economic studies), around 827,000 births were recorded in 2011. Thus, children born with CP represent around 1,654 births every year. Around 85% of these children have spasticity.8 Equinus foot is generally a unilateral disorder, i.e. 35% of cases (expert opinion), which represents 492 children every year. The duration of treatment covers the period of growth, estimated to be an average of 10 years. Conclusion On this basis, the target population of DYSPORT in this indication would be in the order of 5,000 patients.

011 TRANSPARENCY COMMITTEE RECOMMENDATIONS

�� Packaging Appropriate for the prescription conditions according to the indication, dosage and treatment period. �� Particular requirements inherent in treatment: none . �� Requests for data: none.

7 Cans Ch. et al. “Epidémiologie de la Paralysie Cérébrale”, Motricité Cérébrale 2005; 26:51-58 8 Cans Ch. et al. “Epidémiologie de la Paralysie Cérébrale”, Motricité Cérébrale 2005; 26:51-58.

dysport ct 12379inn botulinum toxin type a atc code (2011): m03ax01 (muscle relaxants, peripherally...

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