Product

Monograph
Therapeutic
 Product
Monograph
Therapeutic
Contents

Executive summary 8 8 Maximum recommended doses and overdose 38

8.1 Overview of maximum recommended doses for Dysport ®

8.2 Overdose
1 History of the botulinum neurotoxin type A 10
1.1 Early research
1.2 Clinical development 9 Toxicology 42
9.1 Local and systemic tolerance of Dysport ®

9.2 Reproductive toxicology of Dysport®

2 Product description 14
2.1 Denomination
2.2 Structural and molecular formula 10 Drug interactions 46
2.3 Vial composition 10.1 Systemic drug interactions with botulinum neurotoxin type A
10.2 Known interactions with other agents

3 Mechanism of action 18
3.1 BoNT cleavage targets 11 Special populations 48
3.2 Blockade of ACh release: Four-step mechanism of action 11.1 Paediatrics
3.3 Clinical effects of BoNT-A action 11.2 Elderly
11.3 Pregnancy and lactation

4 Pharmacology 22
4.1 Onset and duration of action 12 Size of the molecule, diffusion and spread 50
4.2 Assessment of in vivo pharmacodynamic effects 12.1 Key differences between ‘diffusion’ and ‘spread’ of BoNT-A
12.2 Complex size does not influence the diffusion profile of BoNT-A preparations
12.3 The diffusion profile of the various BoNT-A preparations does not differ
5 Pharmacokinetics of botulinum neurotoxin type A 26
12.4 Three factors affect diffusion and spread and need to be tailored to optimise treatment
5.1 Pharmacokinetics
12.5 Systemic spread of BoNT-A effects
5.2 Distribution
5.3 Metabolism
5.4 Diffusion 13 Treatment failure and immunogenicity 56
13.1 Causes of BoNT-A treatment failure
13.2 Neutralising versus non-neutralising antibodies
6 Contraindications, special warnings and precautions for use 30
13.3 Factors predicting neutralising antibody formation to BoNT-A
6.1 Contraindications
13.4 Patients treated with Dysport® rarely develop neutralising antibodies
6.2 Special warnings and precautions for use
13.5 Reducing the risk of neutralising antibody formation

7 Adverse reactions and safety profile 34 14 Storage and retention after opening 64
7.1 Adverse events with Dysport are those commonly associated
®
14.1 Storage
with botulinum neurotoxin type A treatments
14.2 Retention
7.2 Dysport® demonstrates a distinct safety profile
7.3 Dysport® has a well established long-term safety profile
Contents (continued)

15 Approved indications 66 Adult spasticity 98

16.1 Management of adult spasticity
16.2 Dysport® for the treatment of adult spasticity:
16 Therapeutic Indications 70 initial dosing, dose modification for subsequent treatment
16.3 Dysport® clinical trials efficacy in adult spasticity
Cervical dystonia (spasmodic torticollis) 70 16.4 Dysport® clinical trials safety in adult spasticity
16.1 Management of cervical dystonia 16.5 Dysport® in real-world clinical practice
16.2 Dysport® for the treatment of cervical dystonia: initial dosing 16.6 Hints for optimising outcomes in treating adult spasticity
16.3 Dysport® for the treatment of cervical dystonia: dose modification for subsequent treatment 16.7 Dysport® cost-effectiveness in adult spasticity
16.4 Dysport® clinical trials efficacy in cervical dystonia
16.5 Dysport® clinical trials safety in cervical dystonia Paediatric spasticity (cerebral palsy) 114
16.6 Dysport® in real-world clinical practice 16.1 Management of spasticity in paediatric cerebral palsy
16.7 Hints for optimising outcomes in treating cervical dystonia 16.2 Dysport® for the treatment of spasticity in paediatric cerebral palsy: initial dosing
16.8 Dysport® cost-effectiveness in cervical dystonia 16.3 Dysport® for the treatment of spasticity in paediatric cerebral palsy:
dose modification for subsequent treatment
Blepharospasm 82 16.4 Dysport® clinical trials efficacy in spasticity in paediatric cerebral palsy
16.5 Dysport® clinical trials safety in spasticity in paediatric cerebral palsy
16.1 Management of blepharospasm
16.6 Dysport® in real-world clinical practice
16.2 Dysport® for the treatment of blepharospasm: initial dosing
16.7 Hints for optimising outcomes in treating spasticity in paediatric cerebral palsy
16.3 Dysport® for the treatment of blepharospasm: dose modification for subsequent treatment
16.4 Dysport® clinical trials efficacy in blepharospasm
16.5 Dysport® clinical trials safety in blepharospasm 17 Reconstitution and injection technique 124
16.6 Dysport® in real-world clinical practice
17.1 Reconstitution
16.7 Hints for optimising outcomes in treating blepharospasm
17.2 Injection technique

Hemifacial spasm 90 18 Site of injection / Recommended dose per muscle 128

16.1 Management of hemifacial spasm
16.2 Dysport® for the treatment of hemifacial spasm: initial dosing
16.3 Dysport® for the treatment of hemifacial spasm: dose modification for subsequent treatment 19 Local labeling 132
16.4 Dysport clinical trials efficacy in hemifacial spasm
®

16.5 Dysport® clinical trials safety in hemifacial spasm

16.6 Hints for optimising outcomes in treating hemifacial spasm
 Acronym list

AAN: American Academy of Neurology HSA: human serum albumin

Ach: acetylcholine IM: intramuscular
AEs: adverse events kDa: kilodalton
AIMS: Abnormal Involuntary Movement Scale Kg: kilogram
AQoL: Assessment of Quality of Life LD50: Lethal Dose 50
ARA: Action Research Arm Test MAS: Modified Ashworth Scale
BAS: bulk active substance mL: millilitre
BB: biceps brachii MPA : mouse protective assay
BDS: Blepharospasm Disability Scale MPAD: maximum passive ankle dorsiflexion
BLP: blepharospasm MS: multiple sclerosis
BoNT: botulinum neurotoxin NAb: neutralising antibodies
BoNT-A; -B; -C; -D; -E; -F; -G: botulinum neurotoxin type A; -B; -C; -D; -E; -F; -G N-CAM: neural cell adhesion molecule
CAMR: Centre for Applied Microbiology Research NT: neurotoxin
CD: cervical dystonia ns: non-significant
CES-D: Center for Epidemiological Studies Depression OR: odds ratio
CDQ-24: Craniocervical Dystonia Questionnaire PNA: percentage of normal activity
CGI: Clinical Global Improvement scale QoL: quality of life
CI: confidence interval RCT: randomised controlled trial
cm: centimetre RIPA: radioimmunoprecipitation assay
CMAP: compound muscle action potential ROM: range of movement
CP: complexing proteins s: second
CP: cerebral palsy SCM: sternocleidomastoid muscle
DSS: Disease Severity Score SNARE: soluble N-ethylmaleimide-sensitive fusion protein attachment receptors
EDB: extensor digitorum brevis SV2: synaptic vesicle glycoprotein 2
EFNS : European Federation of Neurological Societies TEAE: treatment-emergent adverse event
EMG: electromyography TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale
FDA: Food and Drug Administration U: unit
GAS: Goal Attainment Scale UK: United Kingdom
6 GI: gastrointestinal ULS: upper limb spasticity 7
GMFCS: Gross Motor Function Classification System US: United Sates of America
HDA: hemidiaphragm assay VAMP: vesicle-associated membrane protein
HFS: hemifacial spasm VAS: visual analogue scale
HFS-30: QoL assessment hemifacial spasm 30 VGA: video gait analysis
 Executive Summary

T he therapeutic potential of botulinum neurotoxin (BoNT) as a muscle relaxant has long been recognised. Seven
serotypes of BoNT (A to G) have been identified, all of which act by preventing the release of acetylcholine
(ACh) from cholinergic nerves. This inhibition of ACh release subsequently results in the blockade of neuromuscular
Aesthetic licensed indications include facial wrinkles (glabellar lines, lateral canthal lines, frontalis region,
nasal dorsum region) and hyperhidrosis (excessive sweating).

transmission, leading to paralysis and autonomic disturbance. At present, the development of BoNT for therapeutic
use has focused on serotypes A (BoNT-A) and B (BoNT-B).
The active ingredient of the muscle relaxant Clostridium botulinum type A toxin haemagglutinin complex
(trade name Dysport®) is purified BoNT-A. This neurotoxin complex is composed of BoNT-A associated with
two complexing proteins: haemagglutinin and non-toxic non-haemagglutinin. Following the administration of Dysport®,
the complexing proteins rapidly dissociate from the neurotoxin and, therefore, have no role in the toxic action. Results
from clinical and non-clinical studies have demonstrated similar diffusion profiles between Dysport® and other BoNT-A
preparations at equipotent doses. Despite this high predictability and comparability in the diffusion characteristics
between BoNT preparations, care should be taken with regards to injection technique, dose and administration volume
to limit the risk of side effects.
Dysport® is administered as an intramuscular, intradermal or subcutaneous injection depending on the indication.
Injections can be repeated every 12–16 weeks; more frequent injections are not recommended. Dysport® is licensed
for use in a number of therapeutic and aesthetic indications.
Therapeutic licensed indications for Dysport® (where BoNT-A is considered the treatment of choice) include:
cervical dystonia; blepharospasm; hemifacial spasm; adult upper- and lower-limb spasticity; and paediatric spasticity,
which is a common feature of cerebral palsy.
For all indications, clinical trial data and reports from clinical practice have showed promising results for
the use of Dysport®. For example, with regards to cervical dystonia, significant improvements in clinical rating scales
(e.g. Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and visual analogue scale (VAS) pain scores)
were observed for up to 12 weeks in subjects who received Dysport®. There was also a significant increase in the
number of subjects who became pain-free after treatment with Dysport®. Three clinical studies comparing Dysport®
to active control have demonstrated Dysport® to be more efficacious than trihexyphenidyl; and a long-term study
8 of 137 subjects treated with Dysport® showed a moderate to marked effect on severity and functioning of 2.5 ± 0.3
using the Clinical Global Impression Scale (CGI). Likewise, treatment with BoNT-A represents a major advancement
in the management of adult and paediatric spasticity (in children aged 2 years and older). Common treatment goals in
patients with spasticity are to improve posture, minimise contractures and deformities, reduce pain, and improve mobility,
dexterity and ease of care. Dysport® has been demonstrated to provide significant benefits in reducing spasticity in adult
patients with upper limb spasticity and has been shown to be effective in improving gastrocnemius muscle length,
muscle tone, gait, and dynamic range of movement in children with lower limb spasticity associated with cerebral palsy.
Preclinical studies showed Dysport® to be well tolerated in animals. Findings from toxicology studies in rats and/or
rabbits using single doses of Dysport® showed no major local reactions, whilst studies using repeated doses showed
only side effects related to known pharmacologic effect of Dysport® following local injections.
There has been no evidence to suggest that Dysport® has an effect on fertility and, due to its lack of direct interaction
with DNA and other chromosomal material, it is unlikely to have genotoxic or carcinogenic potential. The safety profile
of Dysport® in humans is well established, with an estimated exposure of approximately 2,318,739 treatment-years
across all licensed indications. In clinical trials, approximately 25% of subjects treated with Dysport® have experienced
an adverse event, the majority of which were mild/moderate in severity. In line with the main adverse events
associated with BoNT-A, common adverse events with Dysport® include pain/bruising at the injection site and
generalised weakness. Evidence from clinical studies indicates a low incidence (<2%) of neutralising antibody
formation in subjects treated with Dysport®, a comparable rate to that of other BoNT-A preparations.
Despite the low incidence of serious adverse events, caution is advised in subjects with difficulty swallowing
or breathing as these individuals could experience a worsening of symptoms if Dysport® were to reach
the relevant muscles. It should also be noted that, due to its mechanism of action, the therapeutic effect of Dysport®
could be potentiated by concomitant drugs affecting neuromuscular function and that these drugs should be used
with caution.
Dysport® is an effective and well tolerated therapy for a wide variety of therapeutic and aesthetic indications.
This monograph provides details of the structure of Dysport®, its mechanism of action, licensed indications and
considerations for use.
9
 1 History of the botulinum neurotoxin type A

1.1 Early research FIGURE 1. A history of botulinum toxin therapeutic use

The therapeutic potential of botulinum neurotoxin has been recognized for nearly 200 years, since its discovery
in the early 1800s. The history of botulinum neurotoxin therapy is illustrated in FIGURE 1. The German physician
Justinus Kerner first described the characteristic symptoms of the disease induced by the toxin in his scientific
papers published between 1817 and 1822 [Erbguth, 2004]. Kerner named the toxin the ‘sausage poison’, because
“Botulism” first described by the German
the illness followed ingestion of spoiled sausage. As the symptoms of illness included generalised muscle 1817-
physician Justinus Kerner although was known
1822
weakness, Kerner hypothesised that there were therapeutic possibilities for use as a muscle relaxant and research as the “sausage poison”
into the toxin began [Erbguth, 2004; Erbguth, 2009]. Isolation of the bacteria responsible for the disease
(Clostridium botulinum) and subsequent purification [see FIGURE 1] were key steps in the history of the toxin, The toxin is given the name
“botulism” (from the Latin root botulus, 1870
providing researchers with adequate amounts of toxin for experimentation.
which means “sausage”) by John Muller

1895 Clostridium botulinum bacterium first isolated

1.2 Clinical development by a bacteriologist, Emile Pierre Marie van Ermengen
There are seven serotypes of botulinum neurotoxin (BoNT) A to G; of which, BoNT type A and B (BoNT-A, BoNT-B) Two strains of toxin identified Early
have been the focus of development for therapeutic use. (later to be named Type A and B) 1900s

The clinical development of BoNT-A began around 1970, when it was investigated for use as a non-surgical 1928 Botulinum toxin type A first purified
alternative for the treatment of strabismus [Truong et al, 2009]. Initial research was conducted in primates, with
Role of toxin in locking
the US Food and Drug Administration (US FDA) approving human studies in 1989 for the treatment of 1949
neuromuscular transmission identified
strabismus and blepharospasm [Truong et al, 2009].
Researchers investigate the use of BoNT
1970s
At around the same time, the Centre for Applied Microbiology Research (CAMR) in Porton Down in the UK (now as a non-surgical alternative to strabismus
known as Public Health England) was also producing purified toxin for therapeutic use. The first reports of First studies of botulinum toxin in strabismus,
blepharospasm and cervical dystonia 1980s
this preparation for the treatment of strabismus and blepharospasm were published in 1985 [Elston & Russell, are published
1985; Elston et al, 1985; Scott et al, 1985] and then for cervical dystonia [Stell et al, 1988a; Stell et al, 1988b].
Dysport® approved for use in the United Kingdom
The first license for clinical use of Dysport® was obtained in December 1990. The product was named Dysport®
1990 in December, manufactured by Porton Products
(based on Dystonia Porton Products) and commercially manufactured by Porton Products Limited, later to be (later to be re-named Speywood Pharmaceuticals)
re-named Speywood Pharmaceuticals Limited. In 1994, Beaufour Ipsen Pharmaceuticals acquired Speywood
Beaufour Ipsen Pharmaceutical laboratory
Pharmaceuticals and the rights to market Dysport®. Since approval in 1990, all Dysport® batches have been
acquired Speywood Pharmaceuticals 1994
produced using essentially the same method and have been shown to have a high degree of consistency [Panjwani and the rights to market Dysport®
et al, 2008].
FDA introduces new established names for
To date, there are approximately 200 documented therapeutic and aesthetic applications for BoNT-A [Wortzman 2009 BoNT-A preparations; Dysport® also known as
abobotulinumtoxinA
& Pickett, 2009] and because of the wide range of applications, BoNT-A has become one of the most widely used
biological agents worldwide [Wortzman & Pickett, 2009].
10 11
Dysport® is currently approved and marketed for use in more than 75 countries on five continents, including
the United States and Europe. Around the globe, therapeutic licensed indications for Dysport® include
cervical dystonia, blepharospasm, hemifacial spasm, adult upper and lower limb spasticity, and paediatric spasticity
affecting the lower limbs in children aged 2 years and older. Aesthetic licensed indications include glabellar lines,
lateral canthal lines, forehead region, nasal dorsum region, and hyperhidrosis. There are rare instance in a small BoNT: botulinum neurotoxin; BoNT-A: botulinum neurotoxin type A; FDA: US Food and Drug Administration.

number of countries where Dysport® is known by other names such as Dyslore. For aesthetic indications, Dysport®
is referred to as Azzalure® in some European markets.
 1 History of the botulinum neurotoxin type A

References

Elston JS, Lee Jp, Powell CM, et al. Treatment of strabismus in adults with botulinum toxin A. Br J Ophthalmol
1985; 69: 718-24.

Elston JS, Russell RW. Effect of treatment with botulinum toxin on neurogenic blepharospasm. Br Med J 1985;
290; 1857-9.

Erbguth FJ. Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic
use of the toxin. Mov Disord 2004; 19 (Suppl 8): S2-6.

Erbguth FJ. The pretherapeutic history of botulinum toxin. In: Truong D, Dressler D, Hallett M (eds.) Manual of
botulinum toxin therapy. Cambridge: Cambridge University Press; 2009.

Panjwani N, O’Keeffe R, Pickett A. Biochemical, functional and potency characteristics of type A botulinum toxin
in clinical use. The Botulinum J 2008; 1: 153-66.

Scott AB, Kennedy RA, Stubbs HA. Botulinum toxin injection as a treatment for blepharospasm. Arch Ophthalmol
1985; 103: 347-50.

Stell R, Coleman R, Thompson P, et al. Botulinum toxin treatment of spasmodic torticollis. BMJ 1988a; 297: 616.

Stell R, Thompson PD, Marsden CD. Botulinum toxin in spasmodic torticollis. J Neurol Neurosurg Psychiatry 1988b;
51: 920-3.

Truong D, Dressler D, Hallett M. Botulinum toxin: history of clinical development. In: Truong D, Dressler D, Hallett M
(eds.) Manual of botulinum toxin therapy. Cambridge: Cambridge University Press; 2009.

Wortzman MS, Pickett A. The science and manufacturing behind botulinum neurotoxin type A-ABO in clinical use.
Aesthet Surg J 2009; 29: S34-42.

12 13
 2 Product description

2.1 Denomination FIGURE 1. Structure of Dysport®

Trade name: Dysport ®

Chemical name: Clostridium botulinum type A toxin haemagglutinin complex

United States non-proprietary name: AbobotulinumtoxinA

2.2 Structural and molecular formula

Seven serotypes of botulinum neurotoxin (BoNT) have been identified, which are produced from different strains
of Clostridium botulinum and are denoted A to G [Swaminathan, 2011]. These serotypes share sequence homology
but also demonstrate differences such as variations in their three-dimensional structure [Lacy et al, 1998;
Swaminathan, 2011].

The active ingredient in Dysport® is a purified BoNT type A (BoNT-A) complex produced by fermentation of
Clostridium botulinum type A, Hall Strain. It is purified from the culture supernatant by a series of precipitation,
dialysis, and chromatography steps. The neurotoxin complex is composed of the neurotoxin and associated proteins
(haemagglutinin and non-toxic non-haemagglutinin).

BoNT-A neurotoxin structure

BoNT-A comprises 1296 amino acids that form a 150 kilodalton (kDa) single polypeptide chain with an important
intrachain disulphide bond [Minton, 1995].

After synthesis, the neurotoxin is cleaved by a bacterial enzyme (endoprotease) in a process called proteolysis to
create a protein with a heavy and a light chain linked by the disulphide bond [see FIGURE 1] [Krieglstein et al,
1994]. These two chains serve distinct roles in the action of BoNT serotypes [see TABLE 1 below]. The resulting
dichain molecule mediates blockade of neuromediator release at cholinergic nerve endings [Herreros et al, 1999;
Simpson, 2004].

TABLE 1. Structural and functional characteristics of the BoNT heavy and light chain
[Simpson, 2004]

Chain Molecular weight (kDa) Function

Heavy ~100 Highly selective binding of the toxin to neurones

14 15
of motor endplates and internalisation into the axon

Associated proteins
Light ~50 Cleavage of protein substrates (SNARE complex)
involved in neurotransmitter release The gene that encodes the neurotoxin is found in a cluster of genes responsible for the following proteins [Simpson, 2004]:

Non-toxic non-haemagglutinin protein,

kDa: kilodalton; SNARE: soluble N-ethylmaleimide-sensitive fusion protein attachment receptors.
Haemagglutinin proteins (HA70, HA34 and HA17),

Regulator protein.
 2 Product description

Proteins from the gene cluster have been confirmed in Dysport®. The associated proteins and their products (except References
the regulator protein) form a complex with the neurotoxin [Inoue et al, 1996; Chen et al, 1998]. Associated
proteins do not play a direct role in toxic action, rather their presence provides protection for the delicate structure Chen F, Kuziemko GM, Stevens RC. Biophysical characterization of the stability of the 150-kilodalton botulinum
of the neurotoxin. toxin, the nontoxic component, and the 900-kilodalton botulinum toxin complex species. Infect Immun 1998;
66: 2420-5.

2.3 Vial composition Herreros J, Lalli G, Montecucco C, et al. Pathophysiological properties of clostridial neurotoxins. In: Freer JH &
Dysport® is supplied in the form of a white lyophilised powder in a 3.0 mL clear glass vial and requires Alouf JE (eds.) The Comprehensive Sourcebook of Bacterial Protein Toxins. London: Academic Press; 1999.
reconstitution. Inoue K, Fujinaga Y, Watanabe T, et al. Molecular composition of Clostridium botulinum type A progenitor toxins.
Dysport® contains the active ingredient Clostridium botulinum type A neurotoxin haemagglutinin complex. Infect Immun 1996; 64: 1589-94.
The exact composition of Dysport®, including relative amounts of active substance and excipients, is detailed Ipsen Biopharm Ltd. 2012. Dysport®. Investigator’s brochure. Version 10.0.
in TABLE 2 below.
Krieglstein KG, Dasgupta BR, Henschen AH. Covalent structure of botulinum neurotoxin type A: location
of sulfhydryl groups, and disulfide bridges and identification of C-termini of light and heavy chains. J Protein Chem
TABLE 2. Composition of Dysport® per vial [Ipsen Biopharm Ltd, 2012] 1994; 13: 49-57.

Lacy DB, Tepp W, Cohen AC, et al. Crystal structure of botulinum neurotoxin type A and implications for toxicity.
Ingredients Quantity Function
Nature Struct Biol 1998; 5: 898-902.
300 U 500 U
Minton NP. Molecular genetics of clostridial neurotoxins. Curr Top Microbiol Immunol 1995; 195: 161-94.
Active substance
Panjwani N, O'Keeffe R, Pickett A. Biochemical, functional and potency characteristics of type A botulinum toxin
Clostridium botulinum type A 300 LD50 U* 500 LD50 U* Active substance
in clinical use. The Botulinum J 2008; 1: 153-66.
neurotoxin haemagglutinin complex
Pickett A, O'Keeffe R, Judge A, et al. The in vivo rat muscle force model is a reliable and clinically relevant test
Excipients
of consistency among botulinum toxin preparations. Toxicon 2008; 52: 455-64.
Human serum albumin 125 µg 125 µg Stabiliser
Lactose monohydrate 2.5 mg 2.5 mg Bulking agent Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol 2004; 44:
167-93.

LD50: Lethal Dose 50; U: Unit. Swaminathan S. Molecular structures and functional relationships in clostridial neurotoxins. FEBS J 2011; 278:
*One unit (U) of Dysport® corresponds to the median lethal intraperitoneal dose (LD50 ) in mice. Units of Dysport® are not 4467-85.
interchangeable with units of any other BoNT-A preparation.

Batch reproducibility
While historically manufactured at the Centre for Applied Microbiology Research (CAMR; now known as Public
16 Health England), current bulk active substance (BAS) lots are produced at the Ipsen Biopharm Limited facility. 17
A study conducted in the rat muscle force pharmacodynamic model demonstrated batch equivalence and
consistency of the BAS lots from the two sites, as evidenced by similar effects on muscle force and weight
[Pickett et al, 2008]. In addition, reproducibility data from bulk neurotoxin batches of Dysport® over a 14-year
manufacturing history confirm batch-to-batch consistency of toxin protein content (mean 4.35 ng per 500 LD50 U
vial) [Panjwani et al, 2008].
 3 Mechanism of action

Dysport®, a botulinum neurotoxin type A (BoNT-A) preparation, is a muscle relaxant agent that achieves
FIGURE 1. Mechanism of action of Dysport®
its therapeutic effects through the blockade of acetylcholine (ACh) release [Bakheit, 2006; Wortzman & Pickett, 2009].
The application of Dysport® triggers a sequence of physiological events that culminate in the observed clinical
effects of the preparation.

3.1 BoNT cleavage targets

BoNT-A, along with other serotypes of botulinum neurotoxin (BoNT) B to G, all act by blocking neuromuscular
transmission. BoNT serotypes are responsible for cleaving one of three proteins of the soluble N-ethylmaleimide-
sensitive fusion protein attachment receptors (SNAREs) [Binz et al, 2010]:

Vesicle-associated membrane protein (VAMP; synaptobrevin): BoNT-B, -D, -F, and –G,

Synaptosomal associated protein of 25 kDa (SNAP-25): BoNT-A, -C, and –E,

Syntaxin: BoNT-C.

By cleaving the SNARE complex proteins, each of the BoNT serotypes prevents the release of ACh from cholinergic
nerves.

3.2 Blockade of ACh release: Four-step mechanism of action

Following injection of Dysport®, the BoNT-A complex rapidly dissociates to separate associated proteins
(haemagglutinin and non-toxic/non-haemagglutinin) from the neurotoxin. Thereafter, a four-step sequence
of physiological events leads to the inhibition of ACh release [see FIGURE 1] [Rossetto et al, 2013]:

STEP 1: Cell surface binding

The neurotoxin binds to polysialogangliosides that are present on the outer membrane leaflet of peripheral nerve
terminals, and accumulates.

STEP 2: Internalisation (endocytosis)

Upon exocytosis, the intraluminal domains of synaptic vesicle proteins are exposed and are used as second receptor
[synaptic vesicle glycoprotein 2 (SV2) for Dysport®] by the neurotoxin for internalisation into the synaptic vesicles
[Hoch et al, 1985; Black & Dolly, 1986].

STEP 3: Translocation
Once internalised, acidification of the lumen pH into vesicles allows the active subunit of the neurotoxin
(the light chain) to translocate into the cytosol [Blasi et al, 1993].
18 19
STEP 4: Proteolysis
The light chain of the neurotoxin, a zinc-metalloendopeptidase, cleaves a SNARE protein (SNAP-25 for Dysport®)
impairing function of the neuroexocytosis machinery [Blasi et al, 1993] (this accounts for the therapeutic utility
of the toxin in diseases characterised by excessive efferent activity in motor nerves).
 3 Mechanism of action

The effects of BoNT are not permanent. A final step in the sequence of physiological events associated with BoNT-A References
action is the gradual resumption of transmission as the neuromuscular junction recovers from the blockade
of exocytosis and as new nerve endings are formed [see FIGURE 2] [de Paiva et al, 1999; Foran et al, 2003]. Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicol
2005; 26: 785-93.

Bakheit AM. The possible adverse effects of intramuscular botulinum toxin injections and their management. Curr
FIGURE 2. Neuromuscular transmission
Drug Safety 2006; 1: 271-9.

Binz T, Sikorra S, Mahrhold S. Clostridial neurotoxins: mechanism of SNARE cleavage and outlook on potential
substrate specificity reengineering. Toxins 2010; 2: 665-82.

Black JD, Dolly JO. Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic
evidence for its uptake into motor nerves by acceptor-mediated endocytosis. J Cell Biol 1986; 103: 535-44.

Blasi J, Chapman ER, Link E, et al. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25.
Nature 1993; 365: 160-3.

De Paiva A, Meunier FA, Molgo J, et al. Functional repair of motor endplates after botulinum neurotoxin type A
poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad
Sci USA 1999; 96: 3200-5.

Dolly JO, Aoki KR. The structure and mode of action of different botulinum toxins. Eur J Neurol 2006; 13
(Suppl 4): 1-9.

Dressler D, Benecke R. Pharmacology of therapeutic botulinum toxin preparations. Disabil Rehabil 2007;
29: 1761-8.

Foran PG, Mohammed N, Lisk GO, et al. Evaluation of the therapeutic usefulness of botulinum neurotoxin B,
C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central
neurons. J Biol Chem 2003; 278: 1363-71.

Hoch DH, Romero-Mira M, Ehrlich BE, et al. Channels formed by botulinum, tetanus, and diphtheria toxins in
planar lipid bilayers: relevance to translocation of proteins across membranes. Proc Natl Acad Sci USA 1985;
82: 1692-6.

Mense S. Neurobiological basis for the use of botulinum toxin in pain therapy. J Neurol 2004; 251 (Suppl 1): I1-7.

Rossetto O, Megighian A, Scorzeto M, et al. Botulinum neurotoxins. Toxicon 2013; 67: 31-6.
3.3 Clinical effects of BoNT-A action
Wortzman MS, Pickett A. The science and manufacturing behind botulinum neurotoxin type A-ABO in clinical use.
Blockade of ACh release results in the prevention of transmission at the neuromuscular junction and cholinergic
Aesthet Surg J 2009; 29: S34-42.
20 autonomic nerves, which manifests clinically as paralysis and reduction of autonomic disturbance [Dolly & Aoki, 2006]. 21
The action of BoNT-A on the release of ACh from neuromuscular junctions parallels pharmacological characteristics
observed in the clinical setting; i.e., a correlation between dose and effect or duration (although the latter is
typically reaching a 12-16 week ceiling depending on therapeutic use). BoNT may also block transmission of sensory
neurotransmitters, providing an analgesic effect independent of muscle relaxation [Mense, 2004; Aoki, 2005; Dolly
& Aoki, 2006]. However, it is not known to what extent the observation in laboratory studies translates to a clinical
anti-nociceptive effect [Dressler & Benecke, 2007].
 4 Pharmacology

The main physiologic effect of Dysport® is the chemically-induced loss of nerve input to the treated muscle, which 4.2 Assessment of in vivo pharmacodynamic effects
results in a measurable decrease of the compound muscle action potential (muscle function) and consequent
Two animal (rat) models have been developed as functional measures of the pharmacological effect of Dysport®
localised reduction of muscle activity.
when administered intramuscularly [see TABLE 1].
Studies show that the effects of Dysport®, although persisting up to several months, are reversible. Several
underlying mechanisms may account for the duration of effect of Dysport®. TABLE 1. Animal models of BoNT pharmacodynamics [Ipsen Biopharm Ltd, 2012]

Model Description of method Measure of BoNT effect

4.1 Onset and duration of action
In humans, the first effects of botulinum neurotoxin type A (BoNT-A) can be detected within 2 to 3 days following Rat Muscle Force Model 1. Injection of test article/control with varying Chemo-denervation in
injection depending on the detection methods used. The maximum effect of BoNT-A occurs at 1 to 2 weeks concentrations of Dysport® injected muscles
[Dressler et al, 2009]. (into gastrocnemius muscle of the left leg)
Studies conducted in animals and humans record a long duration of botulinum neurotoxin (BoNT) action, the exact 2. Muscle force generated in the left and right leg
length of which is specific to the various BoNT serotypes [Eleopra et al, 1998; Adler et al, 2001; Foran et al, 2003; before and ≤74 days post-injection is measured
Keller, 2006]. For example, the effect of Dysport® typically persists for 12 to 16 weeks in humans [Ipsen Biopharm
Ltd, 2012]. Glycogen depletion 1. Intramuscular administration of Dysport® into Muscle activity
the left tibialis anterior muscle
The effects of acetylcholine (Ach) release inhibition by BoNT (i.e., paralysis) are reversible. Blockade of
2. Electrical stimulation of the sciatic nerve
neurotransmitter release at the neuromuscular junction elicits the same natural physiological response as a loss
of the nerve connection (denervation). Accordingly, a prominent response is ‘sprouting’, which involves the BoNT: botulinum neurotoxin.
generation of new nerve terminals in nerve fibres in an effort to innervate the muscles that have lost functional
input due to the blockade of exocytosis in the original nerve endings. Some or all of the original muscle function
will be regained when the new fibres re-establish functional contact with the underlying muscle [Foran et al,
Studies of Dysport®
2003; Keller, 2006].
Results from studies employing the two animal models are consistent with the pharmacological action of Dysport®.
Mechanism of BoNT duration of effect The Rat Muscle Force Model showed that administration in the gastrocnemius of 3, 6, 12 and 18 U/Kg of Dysport®
The gradual recovery of function is likely to be an important determining factor in the duration of BoNT-A action. led to a significant decrease in force and weight in the muscles of the triceps surae group (gastrocnemius, plantaris
In addition to this natural physiological recovery, other mechanisms, either alone or in combination, may also and soleus). These effects tended to recover over time from 7-24 days post-injection [Center for Drug Evaluation
underlie the long duration of BoNT-A effect [Fernandez-Salas et al, 2004a; Fernandez-Salas et al, 2004b]: and Research, 2009].

Tight binding to the site of action – BoNT-A is able to remain tightly bound to the internal surface of Glycogen depletion is a marker of muscle activity. In this model, intramuscular administration of Dysport® was
the neuronal membrane, which is also the location of its substrate SNAP-25. associated with a dose-related inhibition of glycogen depletion in rat tibialis anterior and digitorum longus muscles
following electrical stimulation of the sciatic nerve [Center for Drug Evaluation and Research, 2009].
Mechanism for metabolism and/or removal of the light chain – the way in which intraneuronal toxin is
eliminated from the nerve ending has not been fully determined but there is a growing body of evidence that
22 the ubiquitin-proteasome system is involved in the degradation of the light chain [Shoemaker & Oyler, 2013]. 23
It is likely that some or all of the toxin is degraded and thus intact toxin probably does not leave the cell in
amounts that would affect neighboring nerve cells [Center for Drug Evaluation and Research, 2009].
 4 Pharmacology

References

Adler M, Keller JE, Sheridan RE, et al. Persistence of botulinum neurotoxin A demonstrated by sequential
administration of serotypes A and E in rat EDL muscle. Toxicon 2001; 39: 233-43.

Center for drug evaluation and research. 2009. Pharmacology Review. Dysport®.

Dressler D, Biglake H. Pharmacology of botulinum toxin drugs. In: Truong DMD, Dressler D, Hallett M & Pathak M
(eds.) Manual of botulinum toxin therapy. Cambridge: Cambridge University Press; 2009.

Eleopra R, Tugnoli V, Rossetto O, et al. Different time courses of recovery after poisoning with botulinum
neurotoxin serotypes A and E in humans. Neurosci Lett 1998; 256: 135-8.

Fernandez-Salas E, Ho H, Garay P, et al. Is the light chain subcellular localization an important factor in botulinum
toxin duration of action? Mov Disord 2004a; 19 (Suppl 8): S23-34.

Fernandez-Salas E, Steward LE, Ho H, et al. Plasma membrane localization signals in the light chain of botulinum
neurotoxin. Proc Natl Acad Sci USA 2004b; 101: 3208-13.

Foran PG, Mohammed N, Lisk GO, et al. Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1,
E, and F compared with the long lasting type A: Basis for distinct durations of inhibition of exocytosis in central
neurons. J Bio Chem 2003; 278: 1363-71.

Ipsen Biopharm Ltd. 2012. Dysport®. Investigator’s brochure. Version 10.0.

Keller JE. Recovery from botulinum neurotoxin poisoning in vivo. Neuroscience 2006; 139: 629-37.

Shoemaker CB, Oyler GA. Persistence of Botulinum neurotoxin inactivation of nerve function. Curr Top Microbiol
Immunol. 2013; 364: 179-96.

24 25
 5 Pharmacokinetics of botulinum neurotoxin type A

Since its discovery, botulinum neurotoxin type A (BoNT-A) has been extensively studied and a great deal is known The time-course of tissue distribution of radioactively-labelled BoNT-A has been studied in rats and rabbits
about its structure and function. However, due to the unique properties of the BoNT-A molecule, there are several [Tang-Liu et al, 2003].
challenges to studying its absorption, distribution, metabolism, and elimination.
Findings in rats [Tang-Liu et al, 2003]

5.1 Pharmacokinetics
In humans, the amount of BoNT-A in the systemic circulation following local administration is below detectable
limits. Based on the high potency, low therapeutic dose, and localised mechanism of action, standard systemic
pharmacokinetics studies cannot be conducted with Dysport® and thus human pharmacokinetics studies have not
been performed.
Following injection of radioactively-labelled BoNT-A complex into the gastrocnemius muscle of rats, the majority
of radioactivity was found in the injected muscle, only minimal levels of radioactivity were found outside
the injection such as in the non-injected contralateral gastrocnemius muscle, plasma, gastrointestinal tissue, liver
and skin. The percentage of initial dose of injected neurotoxin-complex was (0.5 h after injection) was as follows:
~70% in the injected muscle,

Using high doses of inactivated iodinated BoNT-A the serum half-life of BoNT-A has been established in mice and ~5% in the contralateral muscle,
rats [see TABLE 1] [Ravichandran et al, 2006]. However results from study  conducted in rats  indicates that <1% in the sciatic nerve, brain, lungs or kidneys,
it is unlikely that BoNT-A would result in measurable peripheral blood levels since following intramuscular
~3% in the gastrointestinal (GI) tract,
injection of  radioiodinated BoNT-A it was observed that most of the BoNT-A did not diffuse from the site of
administration [Tang-Liu et al, 2003]. <2% in the GI tract tissue,

<2% in the liver.

TABLE 1. Serum half-life of BoNT-A in animals
These findings suggest that the majority of toxin remained localised at the site of the injection.

Animal Native toxin dose Serum half-life

Findings in rabbits
Rats (Ravichandran et al, 2006) 36 ng/animal by single intravenous administration 255 mins Tissue distribution was investigated in rabbits after periocular administration of radioactively labelled BoNT-A
complex in the eyelid. BoNT-A complex remained localised at the injection site and did not spread into the eye
Mice (Ravichandran et al, 2006) 36 ng/animal by single intravenous administration 231 mins [Tang-Liu et al, 2003].

BoNT-A: botulinum neurotoxin type A; mins: minutes. Plasma protein binding studies
No plasma protein binding studies have been performed in humans and thus available data comes from animal
studies.

Aside from lethality, research into the pharmacokinetics of BoNT-A in both animals and humans is challenging,
as the sensitivity of the bioanalytical methods validated for use on clinical samples is not high enough for
pharmacokinetic studies. Research into methods to better study the pharmacokinetics of BoNT-A is ongoing.
New bioanalytical methods with higher sensitivity have been reported [Mason et al, 2006; Bagramyan et al, 2008;
Singh et al, 2013]. The use of these methods to the detection of unlabelled BoNT-A in clinical samples is ongoing.
26
In vitro binding studies with rat serum albumin suggest that blood does not tightly bind or otherwise sequester
BoNT-A [Ravichandran et al, 2006]. The majority of BoNT-A (85–95%) can be recovered in the plasma or serum,
and this fractional recovery remained constant over time. Nothing in plasma or serum was found to which the BoNT-A
becomes tightly associated.
27

5.2 Distribution
Information on the distribution of BoNT-A is limited to data from animals as no studies have been conducted in
humans. Results in animals cannot be extrapolated to humans. Distribution studies performed in rats and rabbits
demonstrate that the majority of BoNT-A remains localised at the site of the injection with limited diffusion beyond
the injection site.

5.3 Metabolism
Due to the unique properties of BoNT-A, there has also been limited research into the metabolism of BoNT-A.
No in vitro studies of hepatic metabolism have been conducted; although, preliminary assessments in animals
provide some insight [Ravichandran et al, 2006].
Results from experiments conducted using native BoNT-A using rat blood indicate that BoNT-A in blood is structurally
and functionally intact. When BoNT-A was incubated in blood, it remained intact and there was no evidence
of significant metabolism [Ravichandran et al, 2006]. Four hours after incubation, the enzymatic activity of
the toxin had not diminished and the incubated blood maintained its ability to block neuromuscular transmission
in phrenic nerve-hemidiaphragm preparations. However, there are limitations in the extrapolation of animal results
to humans.
5.4 Diffusion
An immunohistochemistry study aimed at assessing the diffusion of the toxin after injection into the tibialis anterior
of mice showed that a limited amount of toxin reached adjacent muscles and that there was no significant
difference between various BoNT-A preparations [Carli et al, 2009].
28
5 Pharmacokinetics of botulinum neurotoxin type A
References
Bagramyan K, Barash JR, Arnon SS, et al. Attomolar Detection of Botulinum Toxin Type A in Complex Biological
Matrices. PLoS ONE 2008; 3(4): e2041. doi:10.1371/journal.pone.0002041
Carli L, Montecucco C, Rossetto O. Assay of diffusion of different botulinum neurotoxin type a formulations injected
in the mouse leg. Muscle Nerve 2009; 40(3): 374-80.
Mason JT, Xu L, Sheng ZM, et al. Liposome polymerase chain reaction assay for the sub-attomolar detection
of cholera toxin and botulinum neurotoxin type A. Nature protocols 2006; 1(4): 2003-11.
Ravichandran E, Gong Y, Al Saleem FH, et al. An initial assessment of the systemic pharmacokinetics
of botulinum toxin. J Pharmacol Exp Ther 2006; 318(3): 1343-51.
Singh AK, Stanker LH, Sharma SK. Botulinum neurotoxin: where are we with detection technologies? Crit Rev
Microbiol 2013; 39(1): 43-56.
Tang-Liu DD, Aoki KR, Dolly JO, et al. Intramuscular injection of 125I-botulinum neurotoxin-complex versus
125
I-botulinum-free neurotoxin: time course of tissue distribution. Toxicon 2003; 42(5): 461-9.
29
 6 Contraindications, special warnings
and precautions for use

6.1 Contraindications Human serum albumin

Dysport® is contraindicated in individuals with known hypersensitivity to any of its components [Ipsen Biopharm Dysport® contains a small amount of human serum albumin (125µg). The risk of transmission of viral infection
Ltd, 2010]: cannot be definitively discounted when using human blood or blood derivatives.

Clostridium botulinum type A toxin haemagglutinin complex,

Haematological disorders
Human serum albumin,
As with any intramuscular injection, Dysport® should be used only when strictly necessary in patients with
Lactose monohydrate. prolonged bleeding or infection/inflammation at the proposed site of infection.

Antibody formation
6.2 Special warnings and precautions for use [Ipsen Biopharm Ltd, 2010]
Antibody formation to BoNT has been noted in rare instances in patients receiving Dysport®. In the clinical setting,
As with all botulinum neurotoxin (BoNT) preparations, there are special warnings and precautions associated
neutralising antibodies may be indicated by a substantial deterioration in response to therapy and/or the need
with the use of Dysport®.
for consistent use of increased doses. Neutralising antibodies are formed against the 150 kilodalton (kDa)
neurotoxin, which is present in all BoNT-A preparations [Dressler & Benecke, 2007].
Adverse reactions
Adverse effects may arise from the distribution of toxin effects to areas remote from the administration site. Consideration of facial features
For example, patients treated with therapeutic doses may present with excessive muscle weakness. The risk of
Detailed study of a patient’s facial anatomy is necessary before treating with Dysport® for the correction of glabellar
these undesirable effects may be reduced by using the lowest effective dose and by not exceeding the maximum
lines. In particular, facial asymmetry, ptosis, excessive dermatochalasis, scarring, and any alterations to this anatomy
recommended dose.
as a result of previous surgical interventions should be considered.

Dysphagia and breathing difficulties during treatment

Very rare cases of death related to dysphagia, pneumopathy and/or asthenia have been reported after treatment
with botulinum neurotoxin type A (BoNT-A) or -B. Patients with conditions resulting in defective neuromuscular
transmission, difficulty in swallowing or breathing are more at risk of these effects. Therefore, in these patients,
treatment should be administered by a specialist, but only if the expected benefit exceeds the risk involved.
Effects on ability to drive and use machines
Patients treated with Dysport® are potentially at risk of muscle weakness or visual disturbances. If such effects
are experienced, it may temporarily impair their ability to drive or operate machinery.

Caution is advised when administering Dysport® to patients with breathing or swallowing difficulties, who may
experience worsening of their symptoms if the toxin reaches the relevant muscles. Aspiration has been observed
in rare cases and therefore this poses a risk for patients with a chronic respiratory disorder.
Patients and their caregivers should be made aware of the necessity to seek immediate medical treatment in
case of problems with swallowing, speech or respiratory problems.
30 Pre-existing neuromuscular disorders
Precautions
The recommended dose and frequency of administration of Dysport® should not be exceeded.
To gain maximum benefit from Dysport®, precautions should be taken in the handling and administration
of the agent:
Use Dysport® to treat a single patient during a single session,
Discard any residual reconstituted product in accordance with regulations. 31

Caution should be exercised and careful supervision undertaken when administering Dysport® to patients
with evidence of clinical or sub-clinical deficiency in neuromuscular transmission (e.g., myasthenia gravis).
Dysport® should only be used from 2 years of age when treating spasticity in patients with cerebral palsy.
 6 Contraindications, special warnings and precautions for use

References

Dressler D, Benecke R. Pharmacology of therapeutic botulinum toxin preparations. Disability and rehabilitation
2007; 29: 1761-8.

Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core
Safety Information. Version 7.0.

32 33
 7 Adverse reactions and safety profile TABLE 2. Adverse events with Dysport® by indication

Indication Population Adverse event

Spasticity of the leg Adults Common: Dysphagia, leg muscle weakness,

Dysport® has a well-established safety profile, with over 20 years’ clinical experience. The estimated Dysport® post-stroke abnormal gait, accidental injury/falls
exposure is approximately 2,318,739 treatment-years across all indications. Uncommon: Urinary incontinence

Spasticity of the arm Adults Common: Dysphagia, arm muscle weakness,

post-stroke accidental injury falls
7.1 Adverse events with Dysport® are those commonly associated
with botulinum neurotoxin type A treatments Local symptomatic treatment Adults Common: Dysphagia, leg muscle weakness,
of spasticity of the leg abnormal gait, accidental injury/falls
In general, adverse events (AEs) associated with botulinum neurotoxin type A (BoNT-A) treatment reflect effects Uncommon: Urinary incontinence
related to muscle weakness and injection-site reactions.
Local symptomatic treatment Adults Common: Dysphagia, arm muscle weakness,
Safety data accumulated during a series of clinical trials show that approximately 25% of all treated patients of spasticity of the arm accidental injury/falls
experienced an AE with Dysport®.
Local symptomatic treatment Adults Common: Dysphagia, leg/arm muscle weakness,
In patients treated with Dysport , observed AEs across all indications are shown in TABLE 1 [Ipsen Biopharm Ltd,
® of spasticity affecting both abnormal gait, accidental injury/falls
2010]. the upper and lower limbs Uncommon: Urinary incontinence

Leg spasticity due to Children Common: Diarrhoea, leg muscle weakness,

TABLE 1. Observed adverse events in all patients treated with Dysport® in clinical trials cerebral palsy (aged urinary incontinence, abnormal gait,
≥2 years) accidental injury due to falls
Frequency Adverse event Local symptomatic treatment Children Common: Diarrhoea, leg muscle weakness,
of spasticity affecting (≥2 years urinary incontinence, abnormal gait,
Very common (≥1/10) None lower limb of age) accidental injury due to falls

Cervical dystonia/ Adults Very common: Dry mouth, dysphagia, muscle weakness
Common (≥1/100 to <1/10) Fatigue, flu-like syndrome, generalised weakness, Spasmodic torticollis Common: Dizziness, facial paresis, headache, blurred vision,
and pain/bruising at injection site visual acuity reduced, dysphonia, dyspnoea,
musculoskeletal pain, musculoskeletal stiffness,
Uncommon (≥1/1000 to <1/100) Itching myalgia, neck pain, pain in extremity
Uncommon: Jaw disorder, muscle atrophy
Rare (≥1/10,000 to <1/1000) Neuralgic amyotrophy, skin rashes Blepharospasm Adults Very common: Ptosis
and hemifacial spasm Common: Facial muscle weakness, diplopia, dry eyes,
Very rare (<1/10,000) None tearing, eyelid oedema
Uncommon: Facial paralysis
Rare: Ophthalmoplegia, entropion

Axillary hyperhidrosis Adults Common: Compensatory sweating

Moderate-to-severe Adults Very common: Injection-site reactions (including pain,

glabellar lines bruising, pruritus, paraesthesia, erythema, rash)*, headache
7.2 Dysport® demonstrates a distinct safety profile Common: Asthenopia, ptosis, eyelid oedema, lacrimation
34 increase, dry eye, muscle twitching, weakness of 35
For each indication, the profile of observed AEs with Dysport® is dependent on the total dose and site(s) of injection
[TABLE 2] [Ipsen Biopharm Ltd, 2010]. the muscle(s) adjacent to the area of injection, facial paresis
Uncommon: Vision blurred, diplopia, visual disturbances,
eye movement disorder, hypersensitivity, skin rash, pruritus

Very common >1/10; common >1/100, <1/10; uncommon >1/1000, <1/100; rare >1/10 000, <1/1000; very rare <1/10 000.
*These events were also seen frequently in the placebo group.
 7 Adverse reactions and safety profile

7.3 Dysport® has a well established long-term safety profile References

Dysport® has been shown to produce a consistently high level of safety over treatment periods up to 17 years in
Ipsen Biopharm Ltd. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core Safety
observational studies and over 20 years of post-marketing safety experience. In the individual indications, most
Information. Version 7.0.
AEs experienced by patients treated with Dysport® were of mild or moderate severity [Rzany et al, 2007; Keam
et al, 2011]. Keam SJ, Muir VJ & Deeks ED. Botulinum toxin A (Dysport®) in dystonias and focal spasticity. Drugs 2011; 71: 1043-58.

Long-term observational studies
In a long-term retrospective chart review, 37 patients with cervical dystonia were observed to have been treated
with Dysport® (mean 487 U over 15.9 injection cycles) for up to 17 years [Vivancos-Matellano et al, 2012]. Nine
AEs were reported in total in 8 of the 37 patients who participated in the study. The most commonly experienced
AE was dysphagia (n=7; patients who received treatment from 2 to 12 years), which was mild in severity. Dysphagia
improved with intervention within 1 to 2 weeks and did not lead to treatment discontinuation.
Mohammadi B, Balouch SA, Dengler R, et al. Long-term treatment of spasticity with botulinum toxin type A:
an analysis of 1221 treatments in 137 patients. Neurol Res 2010; 32: 309-13.
Mohammadi B, Buhr N, Bigalke H, et al. A long-term follow-up of botulinum toxin A in cervical dystonia. Neurol
Res 2009; 31: 463-6.
Rzany B, Dill-Muller D, Grablowitz D, et al. Repeated botulinum toxin A injections for the treatment of lines in
the upper face: a retrospective study of 4,103 treatments in 945 patients. Dermatol Surg 2007; 33: S18-25.

In other long-term studies of BoNT-A-treated patients with cervical dystonia (n=163) or spasticity of various Vivancos-Matellano F, Ybot-Gorrin I, Diez-Tejedor E. A 17-year experience of abobotulinumtoxinA in cervical
aetiologies (n=105) followed for up to 14 years, there were no reports of generalised AEs or severe or systemic dystonia. Int J Neurosci 2012; 122: 354-7.
side effects with Dysport® [Mohammadi et al, 2009; Mohammadi et al, 2010]. AEs experienced by patients
treated with Dysport® involved weakness of injected muscles, pain at the injection site, and dysphagia; all of which
were transient.

Post-marketing experience
Safety observations from clinical trials and observational studies are also supported by post-marketing safety data
for Dysport® reported from a variety of sources (healthcare professionals, consumers/patients, regulatory authorities
and literature reports) over the 20 years since approval. 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 [Ipsen Biopharm Ltd, 2010].

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)
[Ipsen Biopharm Ltd, 2010].

36 37
 8 Maximum recommended doses and overdose

8.1 Overview of maximum recommended doses for Dysport® [Ipsen Biopharm Ltd, 2010]
Maximum recommended doses of Dysport® for approved indications are summarised in [TABLE 1]

TABLE 1. Dosing recommendations for Dysport® [Ipsen Biopharm Ltd, 2010]

Indication Dose (U) Administration Frequency

Initial Maximum

Cervical dystonia 500* 1000 Divided dose; administered to the 2 or 3 most muscles Injections may be repeated every ~16 weeks or as
required to maintain a response, but not <12 weeks

Blepharospasm and hemifacial spasm 40 120 Per eye; divided doses into the orbicularis oculi muscle Injections should be repeated every ~12 weeks or
as required to prevent the recurrence of symptoms,
but not <12 weeks

Adult spasticity of the leg post-stroke 1500† 1500 Distributed between gastrocnemius Injections may be repeated every ~16 weeks or as
and soleus muscles; also consider tibialis posterior required to maintain a response, but not <12 weeks

Adult spasticity of the arm post-stroke 1000† 1000 Dose distributed among 5 muscles Injections may be repeated every ~16 weeks or as
(flexor digitorum profundus, flexor digitorum superficialis, required to maintain a response, but not <12 weeks
flexor carpi ulnaris, flexor carpi radialis, biceps brachii)

Adult local symptomatic treatment of spasticity 1500 1500 As for adult spasticity of the leg/arm post-stroke Injections may be repeated as required to maintain
affecting the upper and/or lower limb spasticity (up to 1000 into the upper limb) a clinical response, but not <12 weeks

Moderate to severe glabellar lines 50 50 Divided doses between 5 sites into the corrugator Treatment interval depends on individual patient
and procerus muscles response, but should not be <3 months

Paediatric lower limb spasticity 10 U/kg body weight 30 U/kg or 1000 U Divide doses between the affected spastic Injections may be repeated as required to maintain
(≥2 years of age) or 500 U (whichever is lower) (per treatment session; ower limb muscles a response, but not <12 weeks
for hemilateral injections whichever is lower)
or 20 U/kg body weight
or 1000 U (whichever is lower)
for bilateral injections† **

Paediatric dynamic equinus foot deformity 10 (one calf muscle) 30 U/kg or 1000 U Administered to the gastrocnemius muscle; also consider injections may be repeated as required
due to spasticity associated with cerebral palsy or 20 (both calf muscles) (whichever is lower) soleus and tibialis posterior to maintain a response, but not <12 weeks
(≥2 years of age) U/ kg body weight†
38 39
Axillary hyperhidrosis 100 200 Per axilla; divided doses between 10 sites; individually The time point for further applications is when
assess time of each treatment for patients the patient’s sweat secretion has returned to normal,
but not <12 weeks

†
Kg: kilogram; U: Unit. Starting dose should be lowered if there is evidence to suggest that the dose will result in excessive weakness of the target muscles.
*A lower dose may be considered if the patient is markedly underweight or in the elderly, where reduced muscle mass may exist. **If the gastrocnemius muscle is affected, administer an additional 5 U/kg into each of the two heads of the muscle.
 8 Maximum recommended doses and overdose

8.2 Overdose References

In situations of overdose with Dysport®, there may be an increased risk of the neurotoxin entering into
Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core
the bloodstream. This may result in complications associated with the effects of oral botulinum toxin poisoning
Safety Information. Version 7.0.
(e.g. dysphagia and dysphonia).

There is a possibility that excessive doses of Dysport® may induce neuromuscular paralysis. Respiratory support
may be required if paralysis of the respiratory muscles occurs. As a specific antidote is not available, antitoxin
should not be expected to be of benefit; therefore, general supportive care is recommended in such a situation.

Recommendations in the event of an overdose are detailed in FIGURE 1 [Ipsen Biopharm Ltd, 2010].

References
Figur FIGURE 1. Recommended procedure following an overdose

Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core
Safety Information. Version 7.0.

Overdose

Medically monitor
(for several weeks
if accidental injection
or oral ingestion)
Signs/symptoms:
excessive muscle
weakness or muscle
paralysis

Symptomatic
treatment
(if necessary)

40 41
 9 Toxicology

Animal studies have examined the effects of Dysport® with respect to acute and chronic toxicity and local tolerance
TABLE 1. Single- and repeat-dose toxicity studies in rats [Ipsen Biopharm Ltd, 2012]
at the injection site. Toxicology results from these animal studies, summarised in FIGURE 1, support the clinical
use of Dysport®. Toxicity study Treatment regimen Assessment interval

References
FIGURE 1. Summary of Dysport® effects in animal toxicology studies Single-dose Treated groups: 2 U or 6 U Dysport® injected 7, 30, 60, and 90 days
into the left and physiological saline
Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core
into the right gluteus muscle
Safety Information. Version 7.0.
Control group: placebo
Dysport® effects

Repeat-dose Treated groups: 1 U, 4 U or 12 U Dysport®, Every 4 weeks /

Single- and
• No potential for producing unexpected toxicity or specific target organ
effects besides known risk of botulism 6 injections into both gluteus muscles 4-week recovery period
repeat-dose
studies • Effects on injected muscles are consistent with the pharmacological
Treated group: 5 injections of 12 U Dysport ®
(5 injections treated
effect of BoNT-A, and are reversible
(rats/rabbits)
Control groups: placebo group only)

• Fertility unaffected, except at high doses inducing local muscle paralysis Repeat-dose Treated groups: 0.1 U or 2 U Dysport®, 4-week intervals /
Reproductive • Absence of teratogenic effects 3 injections into the left and physiological 13- and 26-week
and juvenile • No effect on F1 generation saline into the right gastrocnemius muscle recovery period
toxicology studies • No effects on postnatal growth or reproductive, neurological or
(rats/rabbits) neurobehavioural development in 21-day-old rats Control group: placebo
(corresponding to children of 2 years of age)
U: Unit.

Support clinical use of Dysport®
BoNT-A: botulinum neurotoxin type A.
9.1 Local and systemic tolerance of Dysport® [Ipsen Biopharm Ltd, 2012]
The local and systemic toxicity of single and repeat doses of Dysport® has been investigated in studies conducted
in male and female rats [TABLE 1].
42
Single-dose study
Administration of a single dose of Dysport® (2 U or 6 U) was not associated with adverse systemic effects compared
to placebo. A slight and temporary reduction in weight gain was seen in the first week of treatment with the
higher (6 U) dose of Dysport®. No major local reactions were recorded at the injection site with either Dysport®
dose. However, a local reduction in muscle mass was consistent with the pharmacological effect of Dysport®. There
were no histopathological changes in adjacent nerves. Total recovery was observed following administration of
the 2 U dose of Dysport®, while there were minimal changes 90 days post-administration of the 6 U dose.
Repeat-dose studies
Dose-related reductions in muscle size and/or weight were also noted in the repeat-dose studies. In the study
assessing doses up to 12 U of Dysport®, changes in muscle size were demonstrated later and occurred with less
severity in the 1 U dose group. Recovery was not observed in the 12 U dose group after the designated 4-week
recovery period. In a second study that evaluated 0.1 U and 2 U Dysport® doses, muscle weight was restored after
a 13- and 26-week recovery period, respectively. In the same study, muscle fibre size essentially recovered after
26 weeks while locomotor activity, reduced with both doses, returned to normal at 17 weeks post-treatment.
Disruption of the structure of the neuromuscular post-synaptic junction was observed 2 days post-injection,
but resumed a normal pattern 26 weeks after treatment cessation.
Overall, results from single- and repeat-dose toxicology studies of Dysport® in rats and/or rabbits were generally
43
consistent in showing:
No systemic toxicity at any investigated dose,
No signs of local irritation at injection sites at all dose levels tested.
 9 Toxicology

9.2 Reproductive toxicology of Dysport® [Ipsen Biopharm Ltd, 2012] References

Effects on fertility
Ipsen Biopharm Ltd. 2012. Dysport®. Investigator’s brochure. Version 10.0.
In rats, weekly administration of Dysport at doses up to 10 U in males and 16 U in females was not associated
®

with systemic toxicity. Also, there were no effects on fertility or implantation parameters at doses up to and
including 8 U of Dysport® (32 U total dose). In males and females, mating was impaired at the highest dose,
likely due to impaired hind limb function as well as reduced body weight gain and food consumption.

Effects on foetus and development

Dysport® doses of 1.5 and 5 U daily (18 and 60 U total dose, respectively) and 10 U intermittently (20 U total
dose) resulted in decreased body weight gain and food consumption in pregnant rats. However, foetal weights
were comparable across all groups and there were no indications of teratogenicity at any dose.

Pregnant rabbits who received Dysport® at daily doses of 10 U (140 U total dose) and 40 U intermittently
(80 U total dose) showed decreased body weight gain and body weight loss (as a result of reduced food
consumption). Those rabbits treated at 20 U daily (180 U total dose) died or were sacrificed in a moribund condition,
thus this dose was considered to exceed the maximum tolerated dose. Rates of pre-and post-implantation loss
were comparable across the surviving treated groups compared with controls. Foetal survival and weights were
not affected in treated animals, and teratogenic effects of Dysport® were not shown.

Effects on post-natal development

In the F1 offspring (21 days post-partum; comparable to children of 2 years of age) of rats who received Dysport®
at weekly doses of 1, 2.5, 5 and 10 U, there were no effects of the drug on survival, body weight, sexual maturation,
post-weaning development, mating performance or fertility. Moreover, all offspring demonstrated a normal
appearance.

Effects on juvenile animals

Given in 21-day old rats (corresponding to children of 2 years old), Dysport® given in a single dose of 1 and 3 U
did not affect postnatal growth, reproductive, neurological and neurobehavioural development.

9.3 Genotoxic and carcinogenic potential of Dysport® [Ipsen Biopharm Ltd, 2012]
The biological origin, mechanism of action and nature of Dysport® are not suggestive of a direct interaction with
DNA or any other chromosomal material. Therefore, Dysport® is not considered to have genotoxic or carcinogenic
44 45
potential. Furthermore, extensive post-marketing clinical experience has yielded no evidence of carcinogenicity.
 10 Drug interactions

As a localised treatment, Dysport® is not expected to be present in the circulation in significant quantities after
intramuscular administration. However, the effects of Dysport® may be potentiated by drugs that interfere with
neuromuscular function. Therefore, such drugs should be used with caution in patients treated with Dysport®.
References
Adler M, Macdonald DA, Sellin LC, et al. Effect of 3,4-diaminopyridine on rat extensor digitorum longus muscle
paralyzed by local injection of botulinum neurotoxin. Toxicon 1996; 34(2): 237-49.

10.1 Systemic drug interactions with botulinum neurotoxin type A
Studies to examine the theoretical potential for interactions between botulinum neurotoxin type A (BoNT-A) and
other drugs have not been performed.
Pharmacokinetic studies using iodinated BoNT-A at doses up to 25 times higher than the human recommended
dose found no evidence of unchanged toxin in the plasma of animals [Tang-Liu et al, 2003]. This is consistent
with evidence from animal data that suggests, following local administration, the amount of BoNT-A in the systemic
circulation is below detectable limits, thus posing a minimal risk of systemic drug interactions [Ipsen Biopharm
Ltd, 2012]. These observations are further supported by the absence of reports pertaining to such interactions in
the published literature.
Despite this, BoNT-A effects have been observed in areas remote to the initial site of administration [Dollery, 1998].
The process by which BoNT-A exerts these remote effects has not been fully determined.
The potential exists for systemic drug interactions if BoNT-A is distributed to remote parts of the body through
the circulation. On this basis, there is a theoretical possibility of a pharmacodynamic interaction between BoNT-A
and other drugs that:
Cull-Candy SG, Lundh H, Thesleff S. Effects of botulinum toxin on neuromuscular transmission in the rat. J Physiol
1976; 260(1): 177-203.
Dollery C. Botulinum Toxin A. In: Dollery C (ed.) Therapeutic Drugs, 2nd edition. Churchill Livingstone; 1999.
Garcia Sanchez FM, Ruiz Ruiz MD, Duarte J. Pharmacological properties and therapeutic use of botulinum toxin.
Farmacia Clinica 1992; 9(5): 44-53.
Ipsen Biopharm Ltd. 2012. Dysport®. Investigator’s brochure. Version 10.0.
Lundh H, Thesleff S. The mode of action of 4-aminopyridine and guanidine on transmitter release from motor
nerve terminals. Eur J Pharmacol 1977; 42(4): 411-2.
Santos JI, Swensen P, Glasgow LA. Potentiation of Clostridium botulinum toxin aminoglycoside antibiotics: clinical
and laboratory observations. Pediatrics 1981; 68(1): 50-4.
Tang-Liu DD, Aoki KR, Dolly JO, et al. Intramuscular injection of 125
I-botulinum neurotoxin-complex
versus I-botulinum-free neurotoxin: time course of tissue distribution. Toxicon 2003; 42(5): 461-9.
125
Wang YC, Burr DH, Korthals GJ, et al. Acute toxicity of aminoglycoside antibiotics as an aid in detecting botulism.
Appl Environ Microbiol 1984; 48(5): 951-5.

Mediate their action at neuromuscular junctions in other regions of the body,

Increase the intraneuronal concentration of calcium.

These potential interactions between BoNT-A and other drugs could result in synergistic or attenuating effects
[Cull-Candy et al, 1976; Lundh & Thesleff, 1977; Santos et al, 1981; Wang et al, 1984].

10.2 Known interactions with other agents

To date, there are no documented reports of medicinal products that influence the distribution, metabolism or
excretion of Dysport®.

Although interactions have not been observed in clinical practice, non-clinical studies have shown the potential
for BoNT-A, like Dysport® to significantly interact with:
46 Aminoglycoside antibiotics, guanidine, and gangliosides [Garcia Sanchez, 1992]. 47

Guanidine and other potassium channel blockers [Garcia Sanchez, 1992; Adler et al, 1996].

The effect of administering different botulinum neurotoxin (BoNT) serotypes at the same time or within several
months of each other remains to be determined. There is a potential for excessive neuromuscular weakness to be
exacerbated by administration of another BoNT serotype before resolution of the effects of a previous
administration.
 11 Special populations

The use of Dysport ® in children, the elderly, and pregnant women is subject to some considerations. References
These are outlined below.
Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core
Safety Information. Version 7.0.
11.1 Paediatrics [Ipsen Biopharm Ltd, 2010]
Currently, Dysport® is indicated for the treatment of dynamic equinus foot deformity due to spasticity in paediatric
cerebral palsy patients and local symptomatic treatment of spasticity affecting the lower limbs in children aged
2 years or older.

The safety and efficacy of Dysport® has not been demonstrated in children under 18 years old who have cervical
dystonia, post-stroke arm or leg spasticity, axillary hyperhidrosis, blepharospasm and hemifacial spasm.

Also, Dysport® is not recommended for the temporary treatment of moderate-to-severe glabellar lines in patients
younger than 18 years of age.

Use of Dysport® for approved indications in children should be carefully considered, and appropriate precautions
followed [TABLE 1].

TABLE 1. Considerations for Dysport® use in children [Ipsen Biopharm Ltd, 2010]

Consideration Management

Dose Consider lowering starting dose if evidence of potential for excessive

muscle weakness in target muscles (subjects with small target muscles
or requiring concomitant injection into other muscles)

Dosing recommendations Follow guidance for dosing, particularly recommended dose

and time interval between treatments

11.2 Elderly [Ipsen Biopharm Ltd, 2010]

There are no specific restrictions relating to the use of Dysport® in the elderly.

A lower starting dose may be considered when administering Dysport® for the treatment of cervical dystonia in
elderly patients as a result of the potential for reduced muscle mass.
48 49

11.3 Pregnancy and lactation [Ipsen Biopharm Ltd, 2010]

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

Data are limited on the use of Dysport® in pregnant women. Preclinical studies have not identified direct or indirect
adverse effects of Dysport® with respect to pregnancy, embryo/foetal development, parturition or postnatal
development (although maternal toxicity has been observed at high doses).

It has not been established whether Dysport® is excreted in milk, either in humans or animals. Therefore, the use
of Dysport® during lactation is currently not recommended.
 12 Size of the molecule, diffusion and spread

The techniques and practices employed to administer botulinum neurotoxin type A (BoNT-A) preparations can
affect the normal physiological movement of the toxin away from the injection site (i.e., diffusion and spread).
Several factors have been shown to affect the movement of BoNT-A from the site of administration; these include
the dose used, volume injected, as well as the injection technique. Optimisation of these treatment-related factors
is of fundamental importance in minimising diffusion and spread to achieve consistently effective therapeutic
outcomes with all BoNT-A treatments.
12.3 The diffusion profile of the various BoNT-A preparations does not differ
All complexes for BoNT-A preparations dissociate and diffuse, which means that they will have the same diffusion
characteristics at equal concentrations [Pickett, 2009].
Results from clinical and non-clinical studies confirm that the diffusion profiles of Dysport® and other BoNT-A
preparations are comparable when evaluated at equipotent doses and volumes [TABLE 1].

12.1 Key differences between ‘diffusion’ and ‘spread’ of BoNT-A TABLE 1. Studies examining diffusion profiles of BoNT-A preparations
It is imperative that the movement characteristics of BoNT-A preparations are well defined in order to establish [Hexsel et al, 2008; Wohlfarth et al, 2008; Carli et al, 2009]
and address the causes of potential adverse effects of treatment.
Study Population Method of diffusion Conclusion
‘Diffusion’ and ‘spread’ are two distinct processes that describe the movement of BoNT-A away from the site
and BoNT-A preparation measurement
of injection [Pickett, 2009; Wortzman & Pickett, 2009; Ramirez-Castaneda et al, 2013].
Non-clinical studies
Spread is physical movement of the toxin from the injection site; a fast and active process that depends,
for example, on the injection technique employed, the volume administered and other physical factors. (Carli et al, 2009) • Mice Positive staining of BoNT-A preparations showed
• Dysport®, N-CAM in muscle fibres no significant differences
Diffusion is the kinetic dispersion of the toxin beyond the original injection site; a slow and passive process
Botox®, after injection of BoNT-A in diffusion into adjacent
that occurs due to differences in concentration (Fick’s Law) such that higher concentrations will move to areas
Xeomin® muscles in the leg
of lower concentrations.
Clinical studies

12.2 Complex size does not influence the diffusion profile of BoNT-A preparations (Hexsel et al, 2008) • Healthy volunteers Size of action halos Similar action halos
(n=18) (area of muscular weakness with regard to muscular
After injection, exposure to physiological conditions causes rapid dissociation of the BoNT-A complex in all BoNT-A
• Dysport®, and anhidrosis) and sweat gland activity
complex preparations [Friday et al, 2002; Eisele et al, 2011] [FIGURE 1]. Therefore, complex size cannot affect
Botox® after injection of BoNT-A after injections of BoNT-A
migration of the toxin to areas other than the site of application [Wortzman & Pickett, 2009].
into the frontalis muscle preparations, at the same
Thus, it can be inferred that there is no relationship between complex size and the diffusion of Dysport® or other and sweat glands volume and depth
BoNT-A preparations [Pickett, 2009]. Similarly, the presence of complexing proteins does not impact on
the diffusion characteristics of the toxin molecule. (Wohlfarth et al, • Healthy volunteers Reduction in CMAP in Results suggest that
2008) (n=79) neighbouring muscles diffusion to neighbouring
FIGURE 1. Dissociation of the BoNT-A complex • Dysport®, after injection of BoNT-A muscles was similar and
Botox® into the EDB modest for BoNT-A
CP/HSA preparations
After injection, the BoNT-A
50 NT BoNT-A complex prior to injection complex rapidly dissociates 51
under
u physiological conditions BoNT-A: botulinum neurotoxin type A; CMAP: compound muscle action potential;
EDB: extensor digitorum brevis; N-CAM: neural cell adhesion molecule.

The botulinum neurotoxin component

is released to mediate its action

BoNT-A: botulinum neurotoxin type A; CP: complexing proteins; HSA: human serum albumin; NT: neurotoxin.
 12 Size of the molecule, diffusion and spread

12.4 Three factors affect diffusion and spread and need to be tailored to optimise treatment
Optimisation of Dysport® treatment is essential to minimise the risk of adverse effects in routine clinical practice.
Clinicians should be made aware that this can be achieved by modifying their skills and practices with respect to
factors known to affect diffusion and/or spread of the toxin:
Dose,
12.5 Systemic spread of BoNT-A effects
Adverse effects arising from the spread of the effects of the BoNT-A toxin to areas remote from the site of injection
have been noted [Ipsen Biopharm Ltd, 2010].
Spread-related symptoms have been reported hours to weeks after injection, and can include swallowing and
breathing difficulties that can be life-threatening [Ipsen Biopharm Ltd, 2012].

Volume of injection,
Injection technique.
Dose
It is well established that, irrespective of the BoNT-A preparation, the administered dose can influence diffusion
of the toxin [Wohlfarth et al, 2009; Brodsky et al, 2012].
Evidence supports comparability in the diffusion characteristics of BoNT-A preparations [Hexsel et al, 2008;
Wohlfarth et al, 2008; Carli et al, 2009]. However, inappropriately higher dosing when switching from other
BoNT-A preparations to Dysport® could result in greater diffusion with the latter [Wohlfarth et al, 2009]. In the
presence of unnecessarily high doses of Dysport®, excess toxin will diffuse away from the site of injection, thereby
increasing the risk of side effects [Karsai & Raulin, 2009]. Thus, appropriate dosing is key to minimising diffusion-
related adverse effects.
Clinical data
In clinical studies of Dysport®, the incidence of remote and unspecific muscle weakness was 1.9% (4/210 subjects)
and 0.5% (1/210 subjects), respectively, in patients with cervical dystonia [Ipsen Biopharm Ltd, 2012].
The median times to onset and duration of remote muscle weakness were approximately two weeks after
administration of Dysport® [Ipsen Biopharm Ltd, 2012].
Patients who experienced breathing difficulties during pivotal and key supportive studies of Dysport® demonstrated
additional risk factors predisposing to the development of these adverse effects [Ipsen Biopharm Ltd, 2012].
Importantly, no patients reported severe breathing difficulties [Ipsen Biopharm Ltd, 2012].
Post-marketing data
Post-marketing data confirm clinical trial observations of rare remote effects such as muscle weakness and
breathing difficulties with Dysport® [Ipsen Biopharm Ltd, 2012].

Injection volume Pre-existing conditions such as disorders of the neuromuscular junction, breathing difficulties and muscular
spasticity may predispose some patients to the development of remote effects and associated complications
The volume of injection affects the mechanistic spread of BoNT-A, whereby increasing or decreasing injection
following Dysport® treatment. Thus, careful consideration should be given to monitoring for remote effects of
volume increases or decreases spread [Pickett, 2009; Wortzman & Pickett, 2009]. In a prospective, randomized
Dysport® (e.g., breathing difficulties) in these patient groups as in rare cases such adverse effects may require
controlled study of 10 healthy volunteers treated for dynamic forehead lines, a five-fold increase in injection volume
supportive measures (e.g., ventilation).
produced a 50% increase in the area affected by BoNT-A [Hsu et al, 2004]. As such, injection volume should be
an important consideration during treatment.

Injection technique
Injection technique, albeit to a lesser extent than dose and injection volume, has been shown to influence
the diffusion and spread of BoNT-A preparations [Pickett, 2009; Brodsky et al, 2012].

Using a needle gauge that is too large and/or administering an injection too fast can introduce trauma to the
target tissue that reduces toxin intake to the target site and increases spread to non-target areas [Kinnett, 2004].
52 Injection technique can also affect diffusion of the BoNT-A toxin, with resulting side effects. For example, eyelid 53
ptosis is a side effect of BoNT-A treatment for glabellar lines that arises from downward diffusion of the injected
toxin to non-target muscles commonly as a result of poor technique such as rapid, forceful or excessively deep
injection [Klein, 2004].
 12 Size of the molecule, diffusion and spread

References

Brodsky MA, Swope DM, Grimes D. Diffusion of botulinum toxins. Tremor Other Hyperkinet Mov 2012;
2. pii: tre-02-85-417-1. Epub 2012 Aug 6.

Carli L, Montecucco C, Rossetto O. Assay of diffusion of different botulinum neurotoxin type a formulations injected
in the mouse leg. Muscle nerve 2009; 40: 374-80.

Eisele KH, Fink K, Vey M, et al. Studies on the dissociation of botulinum neurotoxin type A complexes. Toxicon
2011; 57: 555-65.

Friday D, Bigalke H, Frevert J. In vitro stability of botulinum toxin complex preparations at physiological pH and
temperature. Naunyn-Schmiedebergs Arch Pharmacol 2002; 365(Suppl.2): R20.

Hexsel D, Dal'Forno T, Hexsel C, et al. A randomized pilot study comparing the action halos of two commercial
preparations of botulinum toxin type A. Dermatol Surg 2008; 34: 52-9.

Hsu TS, Dover JS, Arndt KA. Effect of volume and concentration on the diffusion of botulinum exotoxin A. Arch
Dermatol 2004; 140: 1351-4.

Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core
Safety Information. Version 7.0.

Ipsen Biopharm Ltd. 2012. Dysport®. Investigator’s brochure. Version 10.0.

Karsai S, Raulin C. Current evidence on the unit equivalence of different botulinum neurotoxin A formulations
and recommendations for clinical practice in dermatology. Dermatol Surg 2009; 35: 1-8.

Kinnett D. Botulinum toxin A injections in children. Technique and dosing issues. Am J Phys Med Rehabil 2004;
83(Suppl.10): S59-64.

Klein AW. Botox for the eyes and eyebrows. Dermatol Clin 2004; 22: 145-9.

Pickett A. Dysport®: pharmacological properties and factors that influence toxin action. Toxicon 2009; 54: 683-9.

Ramirez-Castaneda J, Jankovic J, Comella C, et al. Diffusion, spread, and migration of botulinum toxin. Mov
Disord 2013; 28(13): 1775-83.

Wohlfarth K, Schwandt I, Wegner F, et al. Biological activity of two botulinum toxin type A complexes (Dysport®
and Botox®) in volunteers. A double-blind, randomized, dose-ranging study. J Neurol 2008; 255: 1932-9.

Wohlfarth K, Sycha T, Ranoux D, et al. Dose equivalence of two commercial preparations of botulinum neurotoxin
54 type A: time for a reassessment? Curr Med Res Opin 2009; 25: 1573-84. 55

Wortzman MS, Pickett A. The science and manufacturing behind botulinum neurotoxin type A-ABO in clinical use.
Aesthet Surg J 2009; 29: S34-42.
 13 Treatment failure and immunogenicity

The development of neutralising antibodies is a potential cause of treatment failure in patients treated
with botulinum neurotoxin type A (BoNT-A). If they develop, neutralising antibodies can block the activity of
the 150 kilodalton (kDa) neurotoxin, which manifests clinically as reduced therapeutic efficacy. Treatment-related
factors predicting antibody formation to BoNT-A have been identified, and can be effectively managed to fully
minimise any potential risk of neutralising antibodies to BoNT-A and consequent treatment failure.
13.1 Causes of BoNT-A treatment failure
BoNT-A therapy may fail in some patients [Dressler, 2004]. Treatment failure can be either [Anyanwu, 2007]:
Primary: non-response to initial BoNT-A treatment.
Secondary: development of resistance with repeated BoNT-A treatment.
Several causes of primary and secondary BoNT-A treatment failure have been reported [FIGURE 1] [Dressler, 2004;
Anyanwu, 2007]. The development of neutralising antibodies is one potential cause of secondary treatment failure
with BoNT-A, whereby patients have undergone several successful injection series prior to developing
immunoresistance [Dressler, 2004].
FIGURE 1. Causes of primary and secondary treatment failure with BoNT-A
[Dressler, 2004; Anyanwu, 2007]
13.2 Neutralising versus non-neutralising antibodies
Two types of antibody can form against BoNT-A: non-neutralising and neutralising [Goschel et al, 1997; Dressler
& Benecke, 2007]. Due to the rapid dissociation of complexing proteins upon injection, antibodies produced against
complexing proteins do not reduce therapeutic effect [Eisele et al, 2011; Benecke, 2012]. Only neutralising
antibodies that form against the 150 kDa neurotoxin and consequently block its biological activity have the potential
to reduce therapeutic efficacy of BoNT-A preparations.
Detection of neutralising antibodies to BoNT-A
Evaluation for the presence of neutralising antibodies is of fundamental importance in monitoring and addressing
potential waning of therapeutic response with BoNT-A preparations.
In light of this, a multi-tiered approach has been developed to detect neutralizing antibodies in patients treated
with BoNT-A [TABLE 1] using clinical- and laboratory-based tests. In this approach, patients are first screened for
the presence of binding antibodies using the relatively inexpensive radioimmunoprecipitation assay (RIPA). If the
presence of binding antibodies is confirmed, functional laboratory tests such as the hemidiaphragm assay (HDA)
or the Mouse protective assay (MPA) are then used to characterize the potentiality of antibodies to neutralize
BoNT-A preparations [Dressler, 2004; Benecke, 2012]. In addition, clinical tests of motor function (e.g. the Extensor
digitorum brevis (EDB) test, the frontalis muscle test and the sudomotor sweat test) can be used in conjunction
with these assays to quickly evaluate the potential clinical relevance of neutralising antibody development
[Benecke, 2012].

13.3 Factors predicting neutralising antibody formation to BoNT-A

Neutralising Several treatment-related factors can predispose to antibody formation with BoNT-A treatment [Greene et al,
antibodies
1994]:

Shorter injection interval – the shorter the injection interval, the earlier antibody-induced treatment failure
occurs [Dressler, 2002],
Patient selection Muscle overtactivity /
contracture / More ‘booster’ injections (2 to 3 weeks after the initial injection),
(e.g., disorder resistant to
skeletal
BoNT-A injection) Use of higher doses of BoNT-A per injection series.
abnormalities

56 57

Inappropriate Inadequate dose /

injection site decreased potency
 13 Treatment failure and immunogenicity

TABLE 1. Commonly used tests to detect neutralising antibodies in BoNT-A-treated patients [Kessler & Benecke, 1997; Palace et al, 1998; Hanna et al, 1999; Dressler, 2004; Benecke, 2012]

Test Method Confirmation Advantages Disadvantages

of neutralising antibodies

Laboratory screening tests for the detection of binding antibodies

Radioimmunoprecipitation assay (RIPA) Incubation of patient serum sample with radioactively Immunoassay where positive signals • No animals required • No differentiation between
labelled BoNT-A and ProteinG Sepharose followed indicate immunoprecipitation • Moderate costs neutralising and
by centrifugation of antibodies bound to radioactively • Semi-Quantitative non-neutralising antibodies
labelled BoNT-A (binding antibodies) • Results within hours

Laboratory functional tests for the detection of neutralizing antibodies

Mouse protection assay (MPA) Survival rate after administration of mixture Introduction of serum samples containing • Functional test that detects • Requires large numbers
of patient serum and BoNT-A to mice neutralising antibodies reduces toxic only the presence of animals
effect of BoNT-A on mice survival of neutralizing antibodies • Slow turnaround for results

Hemidiaphragm assay (HDA); mouse In-vitro test; time to paresis of murine diaphragm muscle Prolongation of time to paresis • Fewer mice required • Technically complex
diaphragm assay (MDA) after innervation with BoNT-A with and without patient • Quantitative • Low throughput
serum • Results within hours

Clinical functional tests

Extensor digitorum brevis (EDB) test Change in CMAP amplitude after injection No decrease in CMAP amplitude • High sensitivity and specificity • Not specific for NAb
of BoNT-A into the EDB with electrical stimulation • Immediate results • Not standardised
of the peroneal nerve • Functional test

Frontalis muscle test Ability to frown or contract frontalis muscles after injection No effect on frowning or contraction of • Simple and reproducible • Not specific for NAb
of BoNT-A into one side frontalis muscles • Functional test • Qualitative
• Not standardised

Sudomotor sweat test Evaluation of sweating after subcutaneous injection of BoNT-A Continued sweating • Functional test • Not specific for NAb
58 59
(visualised by iodine starch staining) • Qualitative
at the BoNT-A injection site • Not yet standardised

BoNT-A: botulinum neurotoxin type A; CMAP: compound muscle action potential; NAb: neutralising antibodies.
 13 Treatment failure and immunogenicity

13.4 Patients treated with Dysport® rarely develop neutralising antibodies The low incidence of antibody formation with Dysport® is comparable with other BoNT-A preparations:

Clinical evidence from short- and long-term studies in high-dose indications support a low incidence (≤2%) of Botox®: 1.2% to 2.2% in patients with cervical dystonia treated for 4.2 to 12 years, respectively [Brin et al,
neutralizing antibody formation with Dysport® [TABLE 2]. 2008; Mohammadi et al, 2009].

Xeomin®: 12 of 1080 subjects (1.1%) developed neutralising antibodies during the course of treatment in
the clinical development programme [Xeomin®, 2010].
TABLE 2. Low rates of neutralizing antibody formation have been reported with Dysport®

Study Patient Dysport® dose / Rate of neutralising 13.5 Reducing the risk of neutralising antibody formation
population (N) treatment duration antibody formation There are key steps to follow to minimise the risk of neutralising antibody formation and to maintain long-term
response [Kessler et al, 1999; Moore & Naumann, 2003; Jankovic, 2004]:
Short-term
Use the lowest effective dose,

(Bakheit et al, 2004) Adults, post-stroke 1000 U/ three treatment None detected Ensure dosing intervals are 12 weeks or longer,
ULS (51) cycles (up to 20 weeks each) Avoid ‘booster’ injections,

Avoid unnecessary switching of BoNT-A preparations.

(Coleman et al, 2012) Adults, cervical dystonia 500 U / 12 weeks One patient (0.7%)
(Study 1, 116;
Study 2, 136)

Long-term

(Kanovsky et al, 2009) Children, cerebral palsy 30 U/kg bodyweight / Five patients (2%)
and lower-limb spasticity up to 2 years
(214)

(Mohammadi et al, 2009) Adults, cervical dystonia 75 to 700 U/ Three patients (1.8%)
(163) up to 14 years

(Coleman et al, 2012) Adults, cervical dystonia 250 to 1000 U/ Two patients (0.8%)
(Study 1, 116; up to 94 weeks
Study 2, 136)

Kg: kilogram; U: Unit; ULS: upper limb spasticity.

60 61
 13 Treatment failure and immunogenicity

References

Anyanwu B, Hanna PA, Jankovic J. Botulinum toxin: primary and secondary resistance. In Ward AB, Barnes MP
(eds.) Clinical uses of botulinum toxins. Cambridge University Press; 2007.
Bakheit AMO, Fedorova NV, Skoromets AA, et al. The beneficial antispasticity effect of botulinum toxin type A
is maintained after repeated treatment cycles. J Neurol Neurosurg Psychiatry 2004; 75(11): 1558-61.
Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs 2012; 26(2): e1-9.
Brin MF, Comella CL, Jankovic J, et al. Long-term treatment with botulinum toxin type A in cervical dystonia
has low immunogenicity by mouse protection assay. Mov Disord 2008; 23(10): 1353-60.
Coleman C, Hubble J, Schwab J, et al. Immunoresistance in cervical dystonia patients after treatment with
abobotulinumtoxinA. Int J Neurosci 2012; 122(7): 358-62.
Mohammadi B, Buhr N, Bigalke H et al. A long-term follow-up of botulinum toxin A in cervical dystonia.
Neurol Res 2009;31(5):463-6.
Moore P, Naumann M. General and Clinical Aspects of Treatment with Botulinum Toxin. In: Moore P, Naumann M
(eds.) Handbook of Botulinum Toxin Treatment. 2 ed: Blackwell Science; 2003.
Palace J, Nairne A, Hyman N, et al. A radioimmuno-precipitation assay for antibodies to botulinum A. Neurology
1998; 50(5): 1463-6.
Xeomin® PI 2010 [http://www.xeomin.com/Prescribing-Information-Xeomin-26-Aug-2010.pdf] Last accessed
April 23rd, 2014.

Dressler D. Clinical features of antibody-induced complete secondary failure of botulinum toxin therapy. Eur Neurol
2002; 48(1): 26-9.

Dressler D. Clinical presentation and management of antibody-induced failure of botulinum toxin therapy.
Mov Disord 2004; 19 (Suppl 8): S92-S100.

Dressler D, Benecke R. Pharmacology of therapeutic botulinum toxin preparations. Disabil Rehabil 2007; 29(23):
1761-8.

Eisele KH, Fink K, Vey M, et al. Studies on the dissociation of botulinum neurotoxin type A complexes. Toxicon
2011; 57: 555-65.

Goschel H, Wohlfarth K, Frevert J, et al. Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies-
therapeutic consequences. Exp Neurol 1997; 147(1): 96-102.

Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis.
Mov Disord 1994; 9(2): 213-7.

Hanna PA, Jankovic J, Vincent A. Comparison of mouse bioassay and immunoprecipitation assay for botulinum
toxin antibodies. J Neurol Neurosurg Psychiatry 1999; 66(5): 612-6.

Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry 2004; 75(7): 951-7.

Kanovsky P, Bares M, Severa S et al. Long-term efficacy and tolerability of 4-monthly versus yearly botulinum
toxin type A treatment for lower-limb spasticity in children with cerebral palsy. Dev Med Child Neurol 2009; 51(6):
62 436-45. 63
Kessler KR, Benecke R. The EBD test-a clinical test for the detection of antibodies to botulinum toxin type A. Mov
Disord 1997; 12(1): 95-9.

Kessler KR, Skutta M, Benecke R. Long-term treatment of cervical dystonia with botulinum toxin A: efficacy,
safety, and antibody frequency. J Neurol 1999; 246(4): 265-74.
 14 Storage and retention after opening

Instructions for the use of Dysport® are summarised in TABLE 1. References

Ipsen Biopharm Ltd. 2012. Dysport®. Investigator’s brochure. Version 10.0.

TABLE 1. Storage and retention of Dysport® [Ipsen Biopharm Ltd, 2012]

Feature Instructions

Storage

Temperature • Maintain unopened vial at 2oC to 8oC

• Do not freeze

Shelf-life • XX months

Handling

After reconstitution • Use immediately (although it has been

demonstrated that the solution remains stable
for 8 hours)
• Inactivate any residual Dysport® (e.g., with dilute
hypochlorite solution [1% available chlorine])

Disposal • Dispose of Dysport® according to standard practice

14.1 Storage
Dysport® is supplied as a white lyophilised powder, which requires refrigeration at temperatures between 2 oC and
8oC, and should not be frozen [Ipsen Biopharm Ltd, 2012]. Storage of unopened vials of Dysport® under these
conditions provides assurance and guarantee of a consistent and stable product.

Dysport® can be stored for XX months.

64 65
14.2 Retention
It is recommended that Dysport® is used immediately following reconstitution, although it has been demonstrated
that Dysport® is stable in solution for 8 hours [Ipsen Biopharm Ltd, 2012].

To allow for safe handling, residual amounts of Dysport® in the vial or syringe can be inactivated with a solution
of dilute hypochlorite (1% available chlorine) prior to disposal in accordance with standard hospital practice
[Ipsen Biopharm Ltd, 2012].
 15 Approved indications

n er a ted ner a ted

be ge be ge
To un try To un try
by co by co

66 67
 15 Approved indications

n er a ted ner a ted

be ge be ge
To un try To un try
by co by co

68 69
 16 Therapeutic Indications Cervical dystonia (spasmodic torticollis)

Introduction The recommended doses are for adults of all ages, provided they are of normal weight and have no evidence of
reduced neck muscle mass, such as in the elderly. If weight or muscle mass is reduced, a lower dose may be
Cervical dystonia, previously referred to as spasmodic torticollis, is a chronic condition associated with pain and
appropriate [Ipsen Biopharm Ltd, 2010].
disability [Benecke et al, 2009]. It significantly impacts on a patient’s quality of life, and is associated with
a significant cost burden. For all complex forms of cervical dystonia, specialist knowledge and injecting technique guidance from
electromyography (EMG) findings are required to identify and administer Dysport® as a divided dose into two or
Cervical dystonia is the most common adult-onset focal dystonia and is characterised by involuntary contractions
three of the most active neck muscles. EMG should also be used for reassessment following unsuccessful injections
of the cervical muscles of the neck, resulting in twisting and repetitive movements, or abnormal postures. These
in non-complex cases, for guiding injections into deep muscles, and in overweight patients with poorly palpable
abnormal neck postures can be either sustained or intermittent [Benecke et al, 2009]. The condition generally
neck muscles [Ipsen Biopharm Ltd, 2010].
develops when a patient is in their fifties, and can be distinguished from other dystonias by the direction of
the abnormal movements: head forced forwards (anterocollis or antecollis), backwards (retrocollis), chin twisted
to shoulder (torticollis), or head tilted to one side (laterocollis) [Benecke et al, 2009]. TABLE 1. Dosing recommendations for Dysport® (U) in cervical dystonia
[Ipsen Biopharm Ltd, 2010]
The prevalence of cervical dystonia has been estimated to be 9 per 100,000, but this estimate is thought to be
conservative, because it is based on a retrospective chart review. In the US, the Dystonia Medical Research
Abnormal Total Injection site (muscle) Injection technique
Foundation estimates that 250,000 people suffer from cervical dystonia [Brashear, 2009]; however, prevalence of
movement dose (U) and dose (U)
this condition is under-reported due to misdiagnosis, late diagnosis, or patients not seeking medical treatment Intramuscular injections
[Van Zandijcke, 1995; Logroscino et al, 2003]. Torticollis 500 • 350 U into the splenius capitis muscle • Splenius capitis muscle:
• 150 U into the sternocleidomastoid muscle ipsilateral to direction of chin/head
rotation
16.1 Management of cervical dystonia
• Sternocleidomastoid muscle:
As different muscles groups are affected, it is necessary to distinguish between the different types of cervical contralateral to rotation
dystonia to establish the most effective treatment strategy.

Treatment with botulinum neurotoxin type A (BoNT-A) is established as first-line treatment of cervical dystonia
Laterocollisa 500 • 350 U into the splenius capitis muscle Intramuscular injections
[Simpson et al, 2008], and has shown to be effective in 85% of treated patients [Comella & Thompson, 2006;
• 150 U into the sternocleidomastoid muscle • Splenius capitis muscle:
Swope & Barbano, 2008]. BoNT-A provides relief by lessening or eliminating muscle contractions, reducing pain,
ipsilateral to direction of tilt
and improving control over voluntary head and neck movements [Comella & Thompson, 2006; Swope & Barbano,
• Sternocleidomastoid muscle:
2008].
ipsilateral to tilt
The American Academy of Neurology (AAN) evidence-based treatment guidelines for cervical dystonia (seven
Class 1 studies: three of the four botulinum neurotoxin (BoNT) studies used Dysport®), recommend that BoNT Retrocollisb 500 • 250 U into each of the splenius capitis Intramuscular injections
should be offered as a treatment option to patients with cervical dystonia (Level A), and that BoNT is probably muscles
more efficacious and better tolerated than treatment with trihexyphenidyl [Simpson et al, 2008]. More recently,
Other forms 500 EMG recommended to identify
the European Federation of Neurological Societies (EFNS) guidelines now also recommend BoNT-A as first-line
of torticollis and treat the most active muscles
treatment for primary cervical dystonia [Albanese et al, 2011].
(including
70 anterocollis) 71

16.2 Dysport® for the treatment of cervical dystonia: initial dosing

EMG: electromyography; U: Unit.
Dysport® initial dosing recommendations for the treatment of cervical dystonia is 500 U given as a divided dose a
If shoulder elevation is present (visible hypertrophy or EMG findings), the ipsilateral trapezoid or levator scapulae muscles may
and administered into two or three of the most active neck muscles [TABLE 1], most often the sternocleidomastoid also need treatment (injection of 3 muscles: 300 U splenius capitis, 100 U sternocleidomastoid, and 100 U into third muscle).
b
Bilateral splenii injections may increase the risk of neck muscle weakness.
(sternomastoid), splenius capitis, trapezius or angular muscles [Ipsen Biopharm Ltd, 2010].
 16 Therapeutic Indications Cervical dystonia (spasmodic torticollis)

16.3 Dysport® for the treatment of cervical dystonia: TABLE 2. Proven efficacy versus placebo in RCTs
dose modification for subsequent treatment
Subsequent doses of Dysport® can be adjusted according to clinical response and side effects. Doses of between Study Design Patients Results
250–1000 U are recommended, although higher doses may lead to an increase in side effects, particularly dysphagia. Primary endpoints Secondary endpoints
The maximum dose administered should not exceed 1000 U. Injections can be repeated approximately every Prospective, 68 patients Significant improvement Significantly more pain-
(Wissel
16 weeks, or as required to maintain a response, but not less than every 12 weeks [Ipsen Biopharm Ltd, 2010]. et al, randomised, with in mean Tsui score from free patients at week 4,
2001) double-blind, moderate-to- baseline to week 4, mean Dysport® 49% vs. placebo
placebo-controlled, severe CD, change Dysport® 4.6 vs. 33% (p=0.02)
16.4 Dysport® clinical trials efficacy in cervical dystonia parallel-group study majority had placebo 2.0 (p=0.001),
Three key double-blind, placebo-controlled studies provide evidence for Dysport® as an effective treatment for (Dysport® 500 U IM received prior week 8, Dysport® 3.4 vs.
cervical dystonia [TABLE 2; FIGURE 1]. Together with open-label extensions [Hauser et al, 2013], an open-label for 8 weeks) BoNT placebo 1.4 (p=0.002)
cohort study [TABLE 3] [Hefter et al, 2011; Hefter et al, 2013], and three active comparator studies [TABLE 4] Open-label phase to treatment
[Brans et al, 1996; Odergren et al, 1998; Ranoux et al, 2002], these data validate the effectiveness, and week 10 (for week 4
maintenance of clinical effect of Dysport®. non-responders)

Key findings from the clinical trials programme support the following conclusions about the use of Dysport®: (Truong Randomised, 80 patients, High responder rate at Median duration of
et al, double-blind, majority week 4 (TWSTRS): Dysport® response:
Dysport® as an effective and safe treatment for cervical dystonia, placebo-controlled women and 78% vs. placebo 56% 18.5 weeks
2005)
Dysport® results in a reduction of symptoms for up to 12–16 weeks, outpatient study had received Significant improvement in Significant 25.57%
(Dysport® 500 U IM prior BoNT TWSTRS total score from reduction in VAS pain
Dysport® results in sustained symptom control and a significant reduction of disease-associated pain and for 12 weeks), treatment baseline to week 4, mean score from baseline to
improved quality of life. 16 US centres change Dysport® 9.9 vs. week 4, Dysport®13.4 mm
placebo 3.8 (p=0.013) vs. placebo
FIGURE 1. Dysport® significantly reduces disease severity, disability and pain in cervical dystonia Significant improvement in 1.9 mm (p≤0.02), and
[Truong et al, 2005]
TWSTRS total score sustained week 8 (15.22%
at week 8 vs. placebo reduction; p=0.025)
50
Dysport®
(p=0.007), and week 12
Placebo
(p=0.03) [FIGURE 1]

45 (Truong Randomised, 116 patients, Significant improvement Significant reduction

TWSTRS-Total mean scores

et al, double-blind, majority had in TWSTRS total score from in VAS pain score from
2010) placebo-controlled received prior baseline to week 4, baseline to Week 4,
study (Dysport® BoNT mean change Dysport® Dysport® 26.5 mm vs.
40 500 U IM for treatment 15.6 vs. placebo 6.4 placebo 10.8 mm, and up
-22% 12 weeks), 16 US (p<0.001) to Week 12, Dysport®
72 and 4 Russian centres Significant improvement 7.9 mm vs. placebo 73
Open-label in TWSTRS total score 4.5 mm
35
extension phase sustained at weeks 8 vs. Dysport® results in a greater
(4 additional placebo (p<0.001), ability to perform daily
Dysport® treatments) and week 12 (p<0.019) activities (e.g. work,
30 driving)
Baseline Week 4 Week 8 Week 12
BoNT: botulinum neurotoxin; CD: cervical dystonia; IM: intramuscular; RCT: randomised controlled trial;
p-values from ANCOVA based on change from baseline
TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale; US: United States of America; VAS: Visual Analogue Scale.

Mean change from baseline in TWSTRS total score

TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale.
 16 Therapeutic Indications Cervical dystonia (spasmodic torticollis)

Three active comparator studies have shown Dysport® to be more efficacious than trihexyphenidyl, with a longer
TABLE 3. Proven efficacy in open-label trials
mean duration of action compared to Botox® [TABLE 4]:

Study Design Patients Results

TABLE 4. Proven efficacy versus active comparators in RCT
(Hauser et al, Two open-label 218 patients Improved TWSTRS from baseline in all
2012) extension studies who entered treatment cycles in both studies (-10.8 to -16.2).
Study Design Patients Results
(Dysport® 500 U IM the extension Increase in dose above 500 U was not
Primary endpoints Secondary endpoints
for one cycle then phase of the associated with incremental improvement
dose adjustment— studies (Brans Prospective, 66 patients Significant improvement Improvement in Tsui score
titration in 250 U et al, randomised, in TWSTRS disability score at week 12
increments to 1996) double-blind, from baseline to week 12 (5 points vs. 0 points),
a minimum of 250 U placebo-controlled for Dysport® (2 points) p=0.0009
and a maximum study (Dysport® vs. vs. trihexyphenidyl
of 1000 U) oral trihexyphenidyl (0 points); p=0.0097
for 12 weeks)
(Hefter et al, Prospective open- 516 patients Significant improvements in CDQ-24 scores at
2011; Hefter et label QoL study with de novo weeks 4 and 12 (p<0.001). Changes did not (Odergren Randomised, 73 patients Primary endpoints:
al, 2013) (Dysport® 500 U IM) CD significantly differ between torticollis et al, double-blind, No significant differences in post-treatment Tsui score
in German and and laterocollis groups or between patients 1998) parallel-group, run-in at weeks 2, 4, 8 and 12
Austrian outpatient with or without depression study (Dysport® vs. No significant difference in mean time to re-treatment:
clinics Botox® for 12 84 days (Dysport®) vs. 81 days (Botox®)
Significant reductions in activities of daily living
weeks)
scores, pain and pain duration (p<0.001). Pain
relief reported by 66% and 74.1% of patients (Ranoux Randomised, 54 patients Significantly better effect Significantly better effect
at weeks 4 and 12 et al, double-blind, cross- on impairment and pain on impairment and pain
2002) over study (Dysport® with Dysport® groups vs. with Dysport® groups vs.
CD: cervical dystonia; CDQ-24: Craniocervical Dystonia Questionnaire; IM: intramuscular; QoL: quality of life;
TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale; U: unit. vs. Botox for 1 month) Botox®: week 4 Tsui Botox®: week 4 TWSTRS
scores, 4.27, 4.92 vs. 3.25 scores, 4.41, 5.37 vs. 2.59
(p=0.02, p=0.01, (p=0.04, p=0.02,
respectively) respectively)
Mean duration of action
25 days longer for
Dysport® vs. Botox®
74 (p=0.02) 75

RCT: randomised controlled trial; TWSTRS: Toronto Western Spasmodic Torticollis Rating Scale.
 16 Therapeutic Indications Cervical dystonia (spasmodic torticollis)

16.5 Dysport® clinical trials safety in cervical dystonia There is no increase in the incidence of AEs or cumulative events with repeated dosing of Dysport® over multiple
treatment cycles. This has been demonstrated in a large, randomised, double-blind, placebo-controlled study with
Dysport® has a well-established safety profile; side effects are generally mild and transient, and are those
open-label extension; dysphagia and muscle weakness occurred in both study phases at rates consistent with
commonly associated with BoNT-A treatments [Truong et al, 2005; Truong et al, 2010].
the known safety profile of Dysport® [Truong et al., 2010].
The most commonly reported adverse events (AEs) in clinical trials were muscular weakness, dysphagia, dry mouth,
The long-term (1–17 years) safety profile of Dysport® has also been established in real-world clinical practice
injection-site discomfort or pain, fatigue, headache, neck and musculoskeletal pain [Wissel et al, 2001; Truong
[Mohammadi et al, 2009; Vivancos-Matellano et al, 2012].
et al, 2005; Truong et al, 2010]. Treatment-emergent AEs (TEAEs) in a large, randomised, double-blind, placebo-
controlled study, typical of Dysport®’s safety profile, were similar to placebo (47% vs. 44%) [TABLE 5] [Truong et
al, 2010]. The most common TEAE with Dysport® was dysphagia during both the double-blind and extension 16.6 Dysport® in real-world clinical practice
treatment [Truong et al, 2010]. However, dysphagia did not appear to be dose or treatment cycle-related during
Two large, retrospective long-term studies [Mohammadi et al, 2009; Vivancos-Matellano et al, 2012], an
extension treatment: for the 500 U, 750 U and 1000 U doses, dysphagia was reported in 15%, 17% and 14%
outcomes registry [Polukhin et al, 2013], and one long-term follow up of a longitudinal cohort [Haussermann et
of patients, respectively, and dysphagia during cycles 1, 2, 3 and 4 was reported by 12%, 13%, 6% and 10%
al, 2004] have established the effectiveness and safety of Dysport® in treating cervical dystonia in clinical practice.
of patients, respectively [Truong et al, 2010].
A retrospective analysis of long-term results of 3052 BoNT-A treatments in 207 patients from a movement disorder
clinic database confirmed the efficacy and safety of BoNT-A in patients with cervical dystonia for up to 14 years
TABLE 5. Dysport® is well tolerated in the treatment of cervical dystonia [Truong et al, 2010]
[Mohammadi et al, 2009]:

Adverse event Double-blind Open-label extension 163 patients were treated with Dysport® (treatment time 7.3 ± 3.1 years).
n (%) treatment by treatment cycle* Mean latency to response was 7.6 ± 3.5 days, and mean duration of treatment effect was 11± 1.6 weeks.
Dysport® Placebo Cycle 1 Cycle 2 Cycle 3 Cycle 4 Dysport® treatment had a moderate-to-marked benefit over the long-term: patients mean severity and
(N=55) (N=61) (N=108) (N=100) (N=96) (N=88) functioning score was 2.5±0.3 using a clinical global improvement (CGI) scale of 0 (no effect), 1 (slight effect),
2 (moderate effect), 3 (marked improvement).
All 26 (47) 27 (44) 51 (47) 36 (36) 25 (26) 25 (28)
No severe of systemic side effects were observed. Side effects included muscle weakness (5% of treatment
Dysphagia 5 (9) 0 13 (12) 13 (13) 6 (6) 9 (10) sessions), dysphagia (8% of treatment sessions), and pain at injection site (9% of treatment sessions).

Injection-site pain 3 (5) 2 (3) - - - - The long-term safety profile of Dysport® did not differ from that of Botox®.

A retrospective, long-term chart review of 37 patients with cervical dystonia followed up for 7 years (range 1–17
Influenza - - 1 (1) 0 2 (2) 0
years) reported long-term efficacy and safety of Dysport® in clinical practice [Vivancos-Matellano et al, 2012]:

Urinary tract Nearly half of all patients had been diagnosed with cervical dystonia for over 10 years.
- - 1 (1) 3 (3) 1 (1) 1 (1)
infection
97% of patients maintained a response from treatment initiation to the end of the evaluation period (70%
of patients were taking concomitant oral medication).
Upper respiratory
2 (4) 2 (3) 0 1 (1) 0 2 (2)
tract infection Dysport® was generally well tolerated; dysphagia was reported in 18.9% of patients, but this did not lead to
76 discontinuation. 77
Muscular
- - 9 (8) 6 (6) 4 (4) 2 (2)
weakness

Neck pain 3 (5) 3 (5) 5 (5) 2 (2) 1 (1) 2 (2)

Headache 2 (4) 2 (3) 3 (3) 2 (2) 0 1 (1)

Adverse event reported at a rate of <5%; *Adverse events that occurred within 30 days of treatment
 16 Therapeutic Indications Cervical dystonia (spasmodic torticollis)

FIGURE 2. Dysport® treatment algorithm based on presence of secondary components

of cervical dystonia and SCM involvement [Hefter et al, 2011]
An open-label, one-year observational study (ANCHOR-CD registry) included 344 adult patients with cervical
dystonia at 41 sites the US (median Dysport® dose for treatment Cycle 1 was 500 U) [Polukhin et al, 2013]: Patient

Improvement was reported for all TWSTRS domains (severity, disability and pain). Main type
Torticollis of CD? Laterocollis
Patients in a long-term, longitudinal cohort study of 100 consecutive patients with cervical dystonia followed up
for 10–12 years after initial treatment with Dysport® reported long-term sustained relief of symptoms Secondary Secondary
components present? components present?
[Haussermann et al, 2004]:

Using a global subjective rating scale of –4 (very bad effect in all treatment sessions) to +4 (very good effect No secondary Plus Shoulder No secondary Plus Shoulder
Plus Tremor Plus Tremor
in all treatment sessions), patients scored 1.93±1.18, indicating a pronounced effect (complete remission n=1, component elevation component elevation

significant improvement n=5). SCM SCM SCM SCM SCM SCM

hypertrophy? hypertrophy? hypertrophy? hypertrophy? hypertrophy? hypertrophy?
57 patients continued Dysport® up to 12 years, 33 patients stopped treatment (mainly due to side effects of
therapy, n=11).
yes None yes None yes None yes None yes None yes None
Segmental or multisegmental spread of dystonia developed in one third of patients. /mild /mild /mild /mild /mild /mild
Units CL IL CL IL CL IL CL IL CL IL CL IL CL IL CL IL CL IL CL IL CL IL CL IL
34 patients reported an AE on at least one treatment visit. The most common AEs were weakness of cervical SCM (at least 2 120 80 120 80 120 80 120 60 120 60 120 60
injection points)
muscles (n=13), mild dysphagia for solid food (n=12), general weakness (n=5), and dysphagia for fluids (n=3). M. levator scapulae
and/or Mm. scalenii
80 80 60 60 140 140 60 60
(at least 2 injection points
with at least 1deeper)
M. splenius capitis and/or 380 420 300 340 80 300 80 340 320 380 240 300 80 240 80 300
M.trapezius superior
and/or M. semispinalis
16.7 Hints for optimising outcomes in treating cervical dystonia (at least 4 injection points)
yes
For other types of cervical dystonia, including anterocollis (antecollis) and retrocollis, specialist knowledge and
CD: cervical dystonia; CL: controlateral to movement direction; IL: ipsilateral to movement direction; M: muscle;
EMG are recommended to identify and treat the most active muscles. SCM: sternocleidomastoid muscle.

The Dysport® maximum dose administered must not exceed 1000 U. Plus shoulder elevation: ¼ 2 Tsui score, subscore C;
Plus tremor: Tsui score 4, subscore D;
Dosing with Dysport® can be optimised for patients with torticollis or laterocollis, with or without hypertrophy Sternocleidomastoid muscle hypertrophy: yes (marked) or none/mild (light/no) hypertrophy.
of the sternocleidomastoid muscle (SCM), and secondary components of cervical dystonia (shoulder
elevation/tremor) using a treatment algorithm to guide dose selection [FIGURE 2] [Hefter et al, 2011].

Conclusions
16.8 Dysport® cost-effectiveness in cervical dystonia
There are a number of costs associated with managing cervical dystonia; for example the costs of healthcare
professional visits and drug-related costs, which are influenced by frequency of administration of treatment and
duration of effect. The annual per-patient cost of treating cervical dystonia in France was estimated as €1,042; this
increased by €156 when the additional cost of BoNT-A treatment was taken into account [Burbaud et al, 2011].
78 An important factor to consider in the cost-effectiveness of BoNT-A preparations is the difference between a unit
of Dysport® and a unit of Botox®. Dysport® is a comparatively cost-effective treatment for cervical dystonia; more
patients can be treated with Dysport® for a given overall cost than with Botox®. In the US ANCHOR-CD registry
study the cost per treatment cycle was $1090.60 for Botox® compared with $705.30 for Dysport®, representing
a 35% cost saving when using Dysport® [Trosch et al, 2013].
AAN evidence-based treatment guidelines for cervical dystonia recommend that BoNT should be offered as
a treatment option to patients with cervical dystonia.
Key findings from the clinical trials programme and real-world clinical practice support the use of Dysport® as an
effective, long-term treatment for cervical dystonia, reducing symptoms, disability and disease-associated pain.
Dysport® has a well-established, long-term safety profile; side effects are generally mild and transient, and are 79
those commonly associated with BoNT-A treatments.
There is no increase in the incidence of AEs or cumulative events with repeated dosing of Dysport® over multiple
treatment cycles.
Dysport® has a significantly longer duration of action compared with Botox®.

Compared with other treatment options, Dysport® is a cost-effective treatment for cervical dystonia.
 16 Therapeutic Indications Cervical dystonia (spasmodic torticollis)

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Hauser RA, Truong D, Hubble J, et al. AbobotulinumtoxinA (Dysport®) dosing in cervical dystonia: an exploratory Truong D, Duane DD, Jankovic J, et al. Efficacy and safety of botulinum type A toxin (Dysport®) in cervical dystonia:
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botulinum toxin A. Mov Disord 2004; 19: 303-8. 1995; 95: 210-15.

Hefter H, Kupsch A, Mungersdorf M, et al. A botulinum toxin A treatment algorithm for de novo management Vivancos-Matellano F, Ybot-Gorrin I, Diez-Tejedor E. A 17-year experience of abobotulinumtoxinA in cervical
of torticollis and laterocollis. BMJ Open 2011; 1: e000196. dystonia. Int J Neurosci 2012; 122: 354-7.

Hefter H, Benecke R, Erbguth F, et al. An open-label cohort study of the improvement of quality of life and pain
in de novo cervical dystonia patients after injections with 500 U botulinum toxin A (Dysport®). BMJ Open 2013; 3:
e001853.
Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core
Safety Information. Version 7.0.
Wissel J, Kanovsky P, Ruzicka E, et al. Efficacy and safety of a standardised 500 unit dose of Dysport (clostridium
botulinum toxin type A haemaglutinin complex) in a heterogeneous cervical dystonia population: results of a
prospective, multicentre, randomised, double-blind, placebo-controlled, parallel group study. J Neurol 2001; 248:
1073-8.

Logroscino G, Livrea P, Anaclerio D, et al. Agreement among neurologists on the clinical diagnosis of dystonia at
different body sites. J Neurol Neurosurg Psychiatry 2003; 74: 348-50.

Mohammadi B, Buhr N, Bigalke H, et al. A long-term follow-up of botulinum toxin A in cervical dystonia. Neurol
Res 2009; 31: 463-6.

80 Odergren T, Hjaltason H, Kaakkola S, et al. A double blind, randomised, parallel group study to investigate 81
the dose equivalence of Dysport® and Botox® in the treatment of cervical dystonia. J Neurol Neurosurg Psychiatry
1998; 64: 6-12.

Polukhin E, Jozefczyk PB, Truong D, et al. ANCHOR-CD (AbobotulinumtoxinA Neurotoxin: Clinical and Health
Economics Outcomes Registry in Cervical Dystonia): A multicenter, observational study of Dysport
(abobotulinumtoxinA) in cervical dystonia: Baseline data and cycle one efficacy data. Poster presented at
the American Academy of Physical Medicine and Rehabilitation Annual Assembly, National Harbor, Maryland,
3–6 October 2013.
 16 Therapeutic Indications Blepharospasm

Introduction 16.4 Dysport® clinical trials efficacy in blepharospasm

Blepharospasm is a focal cranial dystonia characterised by excessive, involuntary contractions and spasms of the
eyelid muscles that can cause sustained eyelid closure, twitching or repetitive movements [Simpson et al, 2008].
In the most common primary form (benign essential blepharospasm), the orbicularis oculi muscle surrounding the
eye is affected. Adjacent muscles in the eyebrow, paranasal and labial regions may also be involved. In severe
forms, blepharospasm can be associated with depression, anxiety and social isolation [Hall et al, 2006]. Hemifacial
spasm caused by muscle spasms from the facial nerve may occur in association with blepharospasm.
A large phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study has established
the efficacy and well tolerated safety profile of Dysport® (40 U, 80 U, 120 U) in treating bilateral benign essential
blepharospasm [TABLE 1; FIGURE 1] [Truong et al, 2008].
Key findings from this study support the following conclusions about the use of Dysport® [Truong et al, 2008]:
Dysport® reduces the frequency and intensity of facial spasms,

Dysport® improves functional impairment and sustains this improvement,

16.1 Management of blepharospasm High level of patient satisfaction with Dysport®.

Blepharospasm was one of the first focal dystonias to be successfully treated with botulinum neurotoxin (BoNT),
demonstrating a marked improvement in 90% of patients [Jankovic, 2002]. Since then BoNT has also been shown TABLE 1. Proven efficacy in RCT
to be efficacious in other dystonias and facial spasticity [Keam et al, 2011].
Study Design Patients Results
BoNT is considered to be the treatment of choice for this lifelong condition [Ross et al, 2011]. The American
Academy of Neurology (AAN) evidence-based treatment guidelines for blepharospasm and hemifacial spasm Multicentre, 120 patients
(Truong et al, Significant decrease in functional disability
recommend that BoNT should be offered as a treatment option to patients with blepharospasm (Level B) [Simpson phase II, (blepharospasm)
2008) at Week 4 (median difference in percentage
et al, 2008]. European Federation of Neurological Societies (EFNS) guidelines recommend BoNT type-A (BoNT-A) double-blind, of normal activity on BDS between
as first-line treatment for blepharospasm [Albanese et al, 2011]. randomised, Dysport® and placebo):
Dysport® has shown to be an effective treatment for blepharospasm, significantly reducing functional disability, placebo-controlled, 40 U (-30%, p=0.006), 80 U (-40%,
with the potential to improve a patient’s quality of life [Truong et al, 2008]. (Dysport® 40, 80, p=0.001), 120 U (-50%, p=0.001)
120 U per eye Sustained improvement in reduction of
for 16 weeks) functional disability for Dysport® 80 U and
16.2 Dysport® for the treatment of blepharospasm: initial dosing 120 U at weeks 8, 12 and 16 (p=0.001), and
Dysport® dosing recommendations for the treatment of benign essential blepharospasm is 40 U per eye given as weeks 8 and 12 for Dysport® 40 U (p=0.001)
a divided (medial and lateral) dose and administered into the junction between the preseptal and orbital parts of Patients reported a high level of satisfaction
both the upper (taking care to direct the needle away from the levator muscle) and lower orbicularis muscles of with Dysport®: 40 U (87%), 80 U (97%),
each eye, for a total of four injection points per eye [FIGURE 1]. A dose of 80 U per eye results in a longer duration 120 U (94%) vs placebo (25%)
of effect, but the incidence of local adverse effects, in particular ptosis, is dose related. The maximum dose should
BDS: Blepharospasm Disability Scale; RCT: randomised controlled trial; U: Unit.
not exceed 120 U for each eye [Ipsen Biopharm Ltd, 2010].

16.3 Dysport® for the treatment of blepharospasm: dose modification

for subsequent treatment
82 83
Subsequent doses of Dysport® can be adjusted according to clinical response. If initial treatment is considered
insufficient, the dose per eye can be increased to either: 60 U (10 U administered medially and 20 U administered
laterally), 80 U (20 U administered medially and 20 U administered laterally), or 120 U (20 U administered medially
and 40 U administered laterally) into the junction between the preseptal and orbital parts of both the upper and
lower orbicularis muscles of each eye. To reduce the risk of ptosis, injections near the levator palpebrae superioris
should be avoided.

If spasms interfere with vision, two additional sites in the frontalis muscle above the brow may also be injected.
In cases of unilateral blepharospasm, injections should just be carried out to the affected eye muscles. Injections
should not be repeated more frequently than once every 12 weeks [Ipsen Biopharm Ltd, 2010].
 16 Therapeutic Indications Blepharospasm

FIGURE 1. Dysport® significantly reduces functional disability [Truong et al, 2008] TABLE 2. Proven efficacy in combined indication trials

Study Design Patients Results

70 (Sampaio et al, Single-blind, parallel 91 patients For patients with BLP and HFS: mean
1997) randomised, Dysport® (n=48), duration of effect was 13.3±5.9 weeks
Week 4 comparison Botox® (n=43) (Dysport®) vs 11.2±5.8 weeks (Botox®).
(active treatment compared with placebo)

60
Week 8
(BLP: Dysport®100 U, (BLP and HFS) Proportion of patients requiring a booster
Week 12
50 Botox® 25 U; HFS: treatment: Dysport®, 11 patients (23%)
Difference in median PNA

Week 16
Dysport® 70 U, vs Botox®, 5 patients (12%)
40 Botox® 17.5 U)

30 (Rollnik et al, 2-year, open-label, 115 patients For patients with BLP:
ns 2000) non-controlled, pilot BLP(n=28), HFS mean duration of beneficial effects
20 study (low-dose (n=21), cervical was 9.9±5.3 weeks Patient-rated CGI
Dysport® dystonia (n=66) (scale 0–4) was 2.4±1.2
10 25 U, EMG control)

(Tsai et al, Phase IV, prospective, 48 patients For patients with BLP and HFS, therapeutic
0
Dysport® 40 Units/eye Dysport® 80 Units/eye Dysport® 120 Units/eye 2005) one-arm, (idiopathic BLP efficacy of Dysport® was evident from 1.5
non-comparative, and HFS) to 15 days (mean 6.1±2.9 days).
open study Maximum effect: 12.2±5.0 days
PNA: percentage of normal activity; ns: non-significant; *p=0.006; **p≤0.001.
over 12 weeks Decrease in DSS from baseline (1.84),
to week 6 (0.71), week 8 (0.50),
week 10 (0.54), week 12 (0.67). Dysport®
significantly improved reading, working,
One prospective 3-month study in 23 patients with essential blepharospasm found Dysport® (mean dose 38 ± 5.6 U) driving, watching TV, house work, outing alone
to be effective at reducing spasm as well as improving dry eye symptoms and lacrimal secretion [Park et al, 2013].
EMG: electromyography; BLP: blepharospasm; HFS: hemifacial spasm; CGI: Clinical Global Improvement;
Three further studies, including a low-dose study [Rollnik et al, 2000], a comparator study [Sampaio et al, 1997], DSS: Disease Severity Score; U: Unit.

and a Phase IV study [Tsai et al, 2005], investigating the use of Dysport® in both blepharospam and hemifacial
spasm provide further evidence for Dysport® as an effective treatment in blepharospam [TABLE 2].

84 85
 16 Therapeutic Indications Blepharospasm

16.5 Dysport® clinical trials safety in blepharospasm 16.6 Dysport® in real-world clinical practice
Dysport® has an established safety and tolerability profile; side effects are generally mild and transient, and A large, retrospective, long-term study has established the effectiveness and safety of Dysport® in treating
are those commonly associated with BoNT-A treatments [Truong et al, 2008]. blepharospasm. During this 15-year, comparator study, clinical charts reviewed from 128 patients with
blepharospam who had received treatment with BoNT (332 treatments with Dysport®, 1009 treatments with
Results from the phase II, randomised, double-blind, placebo-controlled trial have shown that Dysport® is a
Botox®) reported long-lasting efficacy in clinical practice [Bentivoglio et al, 2009]:
generally well tolerated treatment for blepharospasm with most adverse events mild to moderate in severity.
Treatment-emergent adverse events (TEAEs) were dose-related. The most common TEAEs with Dysport® were Mean latency of clinical effect: 5.0 ± 5.7 days (Dysport®) versus 4.5 ± 4.6 days (Botox®).
eyelid ptosis, blurred vision, lagophthalmos, diplopia, increased lacrimation and aggravated dry eyes [TABLE 3]
Mean duration of clinical improvement: 80.1 ± 36.3 days (Dysport®) versus 66.2±39.8 days (Botox®), p<0.01.
[Truong et al, 2008].
Mean efficacy of treatment (6-point scale, 0=no efficacy, 6=remission): 3.85 ± 1.2 (Dysport®) versus
3.51 ± 1.4 (Botox®), p<0.01.
TABLE 3. Dysport® is well tolerated in the treatment of blepharospasm [Truong et al, 2008]
Doses of both Dysport® and Botox® were significantly increased over time.
Adverse event Placebo Dysport® (units/eye)
n (%) n (%)
16.7 Hints for optimising outcomes in treating blepharospasm [Ipsen Biopharm Ltd, 2010]
40 U 80 U 120 U To reduce the risk of ptosis, avoid injections near the levator palpebrae muscle .
(N=28) (N=30) (N=31) (N=31) The Dysport® maximum dose administered must not exceed 120 U per eye.

Dysport® recommended doses are applicable to adults of all ages including the elderly.
Eyelid ptosis 1 (4) 4 (13) 12 (39) 18 (58)
Injections may need to be repeated every 12 weeks to maintain efficacy, but should not be repeated more
Blurred vision 1 (4) 7 (23) 6 (19) 13 (42) frequently than once every 12 weeks.

Lagophthalmos 0 3 (10) 2 (6) 7 (23)

Conclusions
Diplopia 0 3 (10) 5 (16) 5 (16) AAN and EFNS evidence-based treatment guidelines recommend that BoNT-A should be offered as a treatment
option to patients with blepharospasm.
Increased lacrimation 1 (4) 5 (17) 3 (10) 2 (6) Key clinical trials findings and real-world clinical practice support the use of Dysport® as an effective, long-term
treatment for blepharospasm, significantly reducing functional disability and sustaining this reduction.
Aggravated dry eyes 0 1 (3) 4 (13) 0
Dysport® has a well-established, long-term safety profile; side effects are generally mild and transient, and are
those commonly associated with BoNT-A treatments.
Treatment-emergent adverse events occurring in more than 10% of patients in at least one treatment group (safety population).
There is a high level of patient satisfaction with Dysport® in blepharospasm.
U: Unit.

86 87

The long-term (1–15 years) safety and tolerability profile of Dysport® has also been established in real-world clinical
practice [Bentivoglio et al, 2009].
 16 Therapeutic Indications Blepharospasm

References

Albanese A, Asmuc F, Bhatia KP, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J
Neurol 2011; 18: 5-18.

Bentivoglio AR, Fasano A, Ialongo T, et al. Fifteen-year experience in treating blepharospasm with Botox® or
Dysport®: same toxin, two drugs. Neurotox Res 2009; 15: 224-31.

Hall TA, McGwin G, Jr., Searcey K, et al. Health-related quality of life and psychosocial characteristics of patients
with benign essential blepharospasm. Arch Ophthalmol 2006; 124: 116-9.

Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core
Safety Information. Version 7.0.

Jankovic J. Blepharospasm. Paper presented at the 20th Annual International Conference and Scientific Symposium
of the Benign Essential Blepharospasm Research Foundation Houston, TX, 2002.

Keam SJ, Muir VJ, Deeks ED. Botulinum toxin A (Dysport®) in dystonias and focal spasticity. Drugs 2011; 71:
1043-58.

Park DI, Shin HM, Lee SY, et al. Tear production and drainage after botulinum toxin A injection in patients with
essential blepharospasm. Acta Ophthalmol 2013; 91: e108-12.

Rollnik JD, Matzke M, Wohlfarth K, et al. Low-dose treatment of cervical dystonia, blepharospasm and facial
hemispasm with albumin-diluted botulinum toxin type A under EMG guidance. An open label study. Eur Neurol
2000; 43: 9-12.

Ross AH, Elston JS, Marion MH, et al. Review and update of involuntary facial movement disorders presenting
in the ophthalmological setting. Survey Ophthalmol 2011; 56: 54-67.

Sampaio C, Ferreira JJ, Simoes F, et al. DYSBOT: a single-blind, randomized parallel study to determine whether
any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type A—
Dysport® and Botox®-assuming a ratio of 4:1. Mov Disord 1997; 12: 1013-8.

Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement
disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of
the American Academy of Neurology. Neurology 2008; 70: 1699-706.

Truong D, Comella C, Fernandez HH et al. Efficacy and safety of purified botulinum toxin type A (Dysport®) for
the treatment of benign essential blepharospasm: a randomized, placebo-controlled, phase II trial. Parkinsonism
88 Relat Disord 2008; 14: 407-14. 89

Tsai CP, Chiu MC, Yen DJ, et al. Quantitative assessment of efficacy of dysport® (botulinum toxin type A) in the treatment
of idiopathic blepharospasm and hemifacial spasm. Acta Neurol Taiwan 2005; 14: 61-8.
 16 Therapeutic Indications Hemifacial spasm

Introduction 16.4 Dysport® clinical trials efficacy in hemifacial spasm

Hemifacial spasm is a focal cranial dystonia characterised by unilateral intermittent clonic or tonic contraction of
the muscles responsible for facial expression. These muscles are supplied by the facial nerve, and the most likely
cause of hemifacial spasm is a blood vessel compressing the root of this nerve [Jitpimolmard et al, 1998].
Hemifacial spasm can occur in association with blepharospasm, as similar muscle groups (e.g. the orbicularis oculi
muscle) surrounding the eye are involved. Hemifacial spasm can be associated with ipsilateral pain – spasms can
spread to other areas of the body, and have negative impact on a patient’s quality of life, and physical and mental
well-being [Ross et al, 2011; Setthawatcharawanich et al, 2011].
A long-term (up to 7 years), prospective, descriptive study of 175 consecutive cases has established the efficacy
and well tolerated safety profile of Dysport® in treating hemifacial spasm [TABLE 1; FIGURE 1] [Jitpimolmard et
al, 1998].
Key findings from this study support the following conclusions about the use of Dysport® [Jitpimolmard et al,
1998]:
Dysport® reduces the frequency and intensity of facial spasms,

Dysport® improves functional impairment and sustains this improvement,

16.1 Management of hemifacial spasm High level of patient satisfaction with Dysport®.

Botulinum neurotoxin type A (BoNT-A) is efficacious in [Keam et al, 2011] and considered to be a treatment of
choice for hemifacial spasm, with a 97% response rate for this lifelong condition [Jitpimolmard et al, 1998]. TABLE 1. Proven long-term efficacy

The American Academy of Neurology (AAN) evidence-based treatment guidelines for blepharospasm and
Study Design Patients Results
hemifacial spasm recommend that botulinum neurotoxin (BoNT) should be offered as a treatment option to patients
with hemifacial spasm (Level C) [Simpson et al, 2008]. European Federation of Neurological Societies (EFNS)
(Jitpimolmard Long-term, 175 patients Median duration of symptoms before
guidelines similarly recommend BoNT-A as first-line treatment for hemifacial spasm [Albanese et al, 2011].
et al, 1998) prospective, (hemifacial treatment 4 (0.25–25) years
Dysport® has shown to be an effective treatment for hemifacial spasm [Jitpimolmard et al, 1998], with the descriptive study, spasm) Total of 855 treatments analysed in
potential to improve a patient’s quality of life [Kongsengdao & Kritalukkul, 2012]. of consecutive cases 158 patients over 7 years; median 4 (1–19)
(Dysport® treatments per patient
28–220 U) Response rate, 97%; 597 treatments (70%)
16.2 Dysport® for the treatment of hemifacial spasm: initial dosing
rated as 75–100% improvement
Dysport® dosing recommendations for the treatment of hemifacial spasm are the same as for unilateral Adjusted mean peak of improvement,
blepharospasm. A total of 40 U per eye is given as a divided (medial and lateral) dose and administered into 77.2 (95% CI: 74.7–79.4)
the junction between the preseptal and orbital parts of both the upper (taking care to direct the needle away Adjusted duration of improvement,
from the levator muscle) and lower orbicularis muscles of each eye, for a total of four injection points per eye. 3.4 (95% CI: 3.2–3.6), range 0–18 months
A dose of 80 U per eye results in a longer duration of effect, but the incidence of local adverse effects, in particular A total of 26 treatments (3%) were considered
ptosis, is dose related. The maximum dose should not exceed 120 U for each eye [Ipsen Biopharm Ltd, 2010]. unsuccessful (peak improvement <20%)

CI: confidence interval ; U: Unit.

16.3 Dysport® for the treatment of hemifacial spasm: dose modification
for subsequent treatment
90 Subsequent doses of Dysport® can be adjusted according to clinical response. If initial treatment is considered 91
insufficient, the dose per eye can be increased to either: 60 U (10 U administered medially and 20 U administered
laterally), 80 U (20 U administered medially and 20 U administered laterally), or 120 U (20 U administered medially
and 40 U administered laterally) into the junction between the preseptal and orbital parts of both the upper and
lower orbicularis muscles of each eye.

If spasms interfere with vision, two additional sites in the frontalis muscle above the brow may also be injected.
Injections should not be repeated more frequently than once every 12 weeks [Ipsen Biopharm Ltd, 2010].
 16 Therapeutic Indications Hemifacial spasm

FIGURE 1. Long-term improvement of functional disability with Dysport® TABLE 2. Proven efficacy in combined indication trials
[Jitpimolmard et al., 1998]
Study Design Patients Results

100 (Sampaio et al, Single-blind, 91 patients For patients with BLP and HFS: mean
(155) (120) (95) (82) (73) (61) (54) (43) (36) (29) (22) (21) 1997) parallel randomised, Dysport® (n=48), duration of effect was 13.3±5.9 weeks
90
comparison Botox® (n=43) (Dysport®) vs. 11.2±5.8 weeks (Botox®).
80 (Dysport® 70 U (BLP and HFS) Proportion of patients requiring a booster
divided into 7 treatment: Dysport®, 11 patients (23%) vs.
70
injections vs. Botox® Botox®, 5 patients (12%)
Peak improvement (%)

60 17.5 U divided into

7 injections)
50

(Rollnik et al, 2-year, open-label, 115 patients For patients with HFS: mean duration
40
2000) non-controlled, pilot BLP (n=28), of beneficial effects was 13.1±6.4 weeks
30 study (low-dose HFS (n=21), Patient-rated CGI (scale 0–4) was 3.0±1.0
Dysport® 20 U (divided cervical dystonia
20
into 4 injections), (n=66)
10 EMG control)

0 (Tsai et al, Phase IV, prospective, 48 patients For patients with BLP and HFS, therapeutic
0 1 2 3 4 5 6 7 8 9 10 11 12
2005) one-arm, (idiopathic BLP efficacy of Dysport® was evident from 1.5
Treatment (n) non-comparative, and HFS) to 15 days (mean 6.1±2.9 days).
open study over Maximum effect: 12.2±5.0 days
Mean (95% confidence interval) of peak improvement (patient numbers are in brackets). 12 weeks Decrease in DSS from baseline (1.84),
(Dysport 90 U to week 6 (0.71), week 8 (0.50), week 10 (0.54),
divided into 4 week 12 (0.67). Dysport® significantly
injections for BLP & improved reading, working, driving,
Three studies, investigating the use of Dysport® in both blepharospam and hemifacial spasm, including a low-dose
6 injections for HFS) watching TV, house work, outing alone
study [Rollnik et al, 2000], a comparator study [Sampaio et al, 1997], and a Phase IV study [Tsai et al, 2005]
provide further evidence for Dysport® as an effective treatment in hemifacial spasm [TABLE 2].
BLP: blepharospasm; CGI: Clinical Global Improvement; DSS: Disease Severity Score; EMG: electromyography;
A further three active comparator studies, established Dysport® as a treatment of choice in hemifacial spasm HFS: hemifacial spasm.

[TABLE 3] [Bentivoglio et al, 2009; Kollewe et al, 2010; Kongsengdao & Kritalukkul, 2012].

92 93
 16 Therapeutic Indications Hemifacial spasm

16.5 Dysport® clinical trials safety in hemifacial spasm

TABLE 3. Proven efficacy versus active comparators
Dysport® has a well-established safety profile; side effects are generally mild and transient, and are those
Study Design Patients Results commonly associated with BoNT-A treatments [Jitpimolmard et al, 1998; Bentivoglio et al, 2009; Kollewe et al,
2010].
(Bentivoglio Long-term outcome 108 patients Total number of Dysport® and Botox® Results from two long-term studies have shown that Dysport® is a generally well tolerated treatment for hemifacial
et al, 2009) study over 10 years treatments was 665 spasm [Jitpimolmard et al, 1998], with incidence of side effects (19.7%) comparable with Botox® (16.7%)
(Dysport® vs. Botox®). Mean latency of clinical effect: Dysport® 4.9±4.6 (Bentivoglio et al, 2009). The most common treatment-emergent adverse event (TEAE) with Dysport® was eyelid
Mean dose per days vs. Botox® 5.4±5.3 days (p>0.05) ptosis (8.7% of treatments) [Bentivoglio et al, 2009] [TABLE 5]. Common adverse events were similar in another
session: 11.2 ± 4.9 Mean duration of clinical improvement was long-term study [Kollewe et al, 2010].
U Botox® (1–50); higher with Dysport® 105.9± 54.2 days vs.
46.5 ± 18.9 U Dysport® Botox® 85.4±41.6 days (p<0.01)
(8–130) Fewer treatment failures with Dysport® 4.6% vs. TABLE 5. Dysport® is well tolerated in the treatment of hemifacial spasm
Botox®6.5% (p<0.05) [Bentivoglio et al, 2009]
Botox® doses increased significantly over time
(p<0.001 vs. baseline), Dysport® doses Adverse event n a
Percentage
remained unchanged Ptosis 15 8.7
Duration of clinical benefit increased slightly with Lacrimation 3 1.7
Botox® (p<0.01), but remained constant for Dysport®
Irritation of conjunctiva 1 0.6

(Kollewe et al, Long-term study 97 patients No significant difference between Dysport®- vs. Haematoma 3 1.7
2010) over 6 years Botox®-treated patients. Blurred vision 2 1.2
(Dysport®51±24 U vs. Latency of effect: Dysport®5.9 days, Botox®
Lagophtalmos 8 4.6
Botox® 22±10 U) 6.1days
Duration of effect Dysport®12.2 weeks, Botox® Diplopia 4 2.3
12.1 weeks Dry eye 2 1.2
CGI Dysport®2.6, Botox® 2.6 Palpebral oedema 1 0.6
Mean ratio of dosages in Botox® and Dysport®
Other 1 0.6
patients was 1:2.56
a
Percentage out of 173 treatments.
(Kongsengdao 24-week, double- 26 patients Hemifacial spasm total intensity score, duration
& Kritalukkul, blind, randomised, of facial muscle spasm per day, and duration of
2012) cross-over, comparison functional impairment per day was significantly
to evaluate QoL after lower for Dysport® vs. Neuronox®(p<0.001) 16.6 Hints for optimising outcomes in treating hemifacial spasm [Ipsen Biopharm Ltd, 2010]
94 treatment (Dysport® Mean HFS-30, AIMS (p=0.02) and CES-D To reduce the risk of ptosis, avoid injections near the levator palpebrae muscle. 95
60 U (divided into 4 questionnaire (p<0.001) were reduced for both
The Dysport® maximum dose administered must not exceed 120 U per eye.
injections) treatments over the course of treatment
vs. Neuronox® 19.2 U Dysport® recommended doses are applicable to adults of all ages including the elderly.
(divided into
Injections may need to be repeated every 12 weeks to maintain efficacy, but should not be repeated more
4 injections))
frequently than once every 12 weeks.

AIMS: Abnormal Involuntary Movement Scale; CES-D: Center for Epidemiological Studies Depression;
CGI: Clinical Global Improvement; HFS-30: QoL assessment hemifacial spasm 30; QoL: quality of life.
 16 Therapeutic Indications Hemifacial spasm

Conclusions References
The EFNS and AAN evidence-based treatment guidelines recommend that BoNT should be offered
Albanese A, Asmuc F, Bhatia KP, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur
as a treatment option to patients with hemifacial spasm.
J Neurol 2011; 18: 5-18.
Long-term clinical trials findings support the use of Dysport® as an effective, long-term treatment
Bentivoglio AR, Fasano A, Ialongo T, et al. Outcome predictors, efficacy and safety of Botox and Dysport®
for hemifacial spasm, significantly reducing functional disability and improving quality of life.
in the long-term treatment of hemifacial spasm. Eur J Neurol 2009; 16: 392-8.
Dysport® has a well established, long-term safety and tolerability profile; side effects are generally mild and
Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company Core
transient, and are those commonly associated with BoNT-A treatments.
Safety Information. Version 7.0.

Jitpimolmard S, Tiamkao S & Laopaiboon M. Long term results of botulinum toxin type A (Dysport®) in
the treatment of hemifacial spasm: a report of 175 cases. J Neurol Neurosurg Psychiatry 1998; 64: 751-7.

Keam SJ, Muir VJ, Deeks ED. Botulinum toxin A (Dysport®) in dystonias and focal spasticity. Drugs 2011; 71: 1043-58.

Kollewe K, Mohammadi B, Dengler R, et al. Hemifacial spasm andreinnervation synkinesias: long-term treatment
with either Botox® or Dysport®. J Neural Transm 2010; 117: 759-63.

Kongsengdao S, Kritalukkul S. Quality of life in hemifacial spasm patient after treatment with botulinum toxin
A; a 24-week, double-blind, randomized, cross-over comparison of Dysport and Neuronox study. J Med Ass Thailand
2012; 95 (Suppl 3): S48-54.

Rollnik JD, Matzke M, Wohlfarth K, et al. Low-dose treatment of cervical dystonia, blepharospasm and facial
hemispasm with albumin-diluted botulinum toxin type A under EMG guidance. An open label study. Eur Neurol
2000; 43: 9-12.

Ross AH, Elston JS, Marion MH, et al. Review and update of involuntary facial movement disorders presenting
in the ophthalmological setting. Survey of ophthalmology 2011; 56: 54-67.

Sampaio C, Ferreira JJ, Simoes F, et al. DYSBOT: a single-blind, randomized parallel study to determine whether
any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type A-
Dysport® and Botox®-assuming a ratio of 4:1. Mov Disord 1997; 12: 1013-8.

Setthawatcharawanich S, Sathirapanya P, Limapichat K, et al. Factors associated with quality of life in hemifacial
spasm and blepharospasm during long-term treatment with botulinum toxin. Qual Life Res 2011; 20: 1519-23.

Simpson DM, Blitzer A, Brashear A, et al. Assessment: Botulinum neurotoxin for the treatment of movement
disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of
the American Academy of Neurology. Neurology 2008; 70: 1699-706.
96 97
Tsai CP, Chiu MC, Yen DJ, et al. Quantitative assessment of efficacy of dysport® (botulinum toxin type A) in
the treatment of idiopathic blepharospasm and hemifacial spasm. Acta Neurol Taiwan 2005; 14: 61-8.
 16 Therapeutic Indications Adult spasticity

Introduction
Spasticity is a chronic condition with potentially harmful, distressing and disabling consequences [Ward, 2008;
Royal College of Physicians et al, 2009]. The burden of disability associated with spasticity can exert an immense
impact on patient quality of life [Doan et al, 2012], as well as greater dependability on the caregiver and increased
societal costs [Royal College of Physicians et al, 2009; Doan et al, 2012].
16.2 Dysport® for the treatment of adult spasticity: initial dosing, dose modification for
subsequent treatment
Recommended doses of Dysport are applicable to adults (regardless of age) with spasticity. However, a lower dose
may be advisable if target muscles are small or concomitant treatment of other muscle groups is intended [Ipsen
Biopharm Ltd, 2010]. Identification of the site of injection may be guided by the use of electromyography (EMG).

Spasticity is characterised by involuntary muscle overactivity that commonly results from damage to the brain or
Dosing for adult upper limb spasticity
spinal cord seen with clinical conditions or trauma such as stroke, brain injury, spinal cord injury, multiple sclerosis
(MS) and cerebral palsy [Ward, 2008; Royal College of Physicians et al, 2009]. The underlying pathophysiology For the treatment of upper-limb spasticity, Dysport® should be initially administered at a recommended dose of
of spasticity is complex, but overactive muscle contraction (neurogenic component) and stiffening and shortening 1000 U, given as a divided dose at multiple injection sites depending on the affected limb [TABLE 1]
of the muscle and other soft tissues (biomechanical component) are the two main contributory factors to movement [Ipsen Biopharm Ltd, 2010].
resistance in the limbs after damage to the brain or spinal cord [Royal College of Physicians et al, 2009].

It is difficult to estimate the overall incidence and/or prevalence of spasticity as this depends on the underlying TABLE 1. Dosing recommendations for Dysport® (U) in the treatment of upper-limb spasticity
cause of the lesion [McGuire, 2011]. However, it has been estimated that approximately one-third of patients
who experience stroke, 65% with severe MS, and 75% with physical disability after severe traumatic brain injury Spasticity Indication Total dose (U) Injection site (muscle) and dose (U)
will develop spasticity that necessitates treatment [Royal College of Physicians et al, 2009].
Adult spasticity 1000 Dose distributed among five muscles:
of the arm flexor digitorum profundus (150 U), flexor digitorum superficialis
16.1 Management of adult spasticity
post-stroke (150 to 250), flexor carpi ulnaris (150 U), flexor carpi radialis
Key treatment goals in the management of spasticity are to maintain muscle length and enable normal positioning (150 U), and biceps brachii (300 to 400 U)
of the limbs to prevent secondary soft tissue shortening [Royal College of Physicians et al, 2009]. In this respect,
physical treatments alone may be inadequate (particularly in moderate-to-severe spasticity), and therefore early U: Unit.
intervention with pharmacological agents is advised [Royal College of Physicians et al, 2009].

The integral role of botulinum neurotoxin (BoNT) in spasticity treatment is recognised by guidelines from around
the world [Simpson et al, 2008; Royal College of Physicians et al, 2009; Wissel et al, 2009]. The American
For subsequent treatment, maximum Dysport® dose should not exceed 1000 U [Ipsen Biopharm Ltd, 2010].
Academy of Neurology (AAN) conducted an evidence-based review of 14 Class I (defined as a randomised
Injections may be repeated approximately every 16 weeks, or as required to maintain a response, but not more
controlled clinical trial with masked or objective outcome assessment in a representative population) studies of
frequently than every 12 weeks [Ipsen Biopharm Ltd, 2010].
BoNT treatments, of which eight studies evaluated Dysport® [Simpson et al, 2008]. In establishing their
recommendations, the AAN concluded that BoNT is a safe treatment option and effective for improving muscle
tone and function in patients with spasticity [Simpson et al, 2008].

Botulinum neurotoxin type A (BoNT-A) is an acknowledged mainstay pharmacological treatment for the
management of spasticity [Simpson et al, 2008; Royal College of Physicians et al, 2009]. The therapeutic use of
98 BoNT-A represents the first-line therapy for several hyperkinetic movement disorders [Charles & Gill, 2010]. Aside 99
from improved muscle tone, patients suffering from spasticity who are treated with BoNT-A may expect
to experience improvement in function, increased ease of care and comfort, prevention of musculoskeletal
complications, and general cosmesis [Anwar & Barnes, 2005; Simon & Yelnik, 2010; Lam et al, 2012; Turner-
Stokes et al, 2013a; Turner-Stokes et al, 2013b].
 16 Therapeutic Indications Adult spasticity

Dosing for adult lower limb spasticity 16.3 Dysport® clinical trials efficacy in adult spasticity
For the treatment of lower-limb spasticity, Dysport® should be initially administered at a recommended dose of
1500 U, given as a divided dose at multiple injection sites depending on the affected limb [TABLE 2] Dysport® clinical trials efficacy in adult upper-limb spasticity
[Ipsen Biopharm Ltd, 2010]. The proven efficacy of Dysport® in upper-limb spasticity is based on a robust evidence-base. Seven placebo-
controlled or single-arm studies were included in the Dysport® clinical programme for upper limb spasticity
[TABLE 3], including two pivotal randomised, double-blind, placebo-controlled studies [Bakheit et al, 2000;
TABLE 2. Dosing recommendations for Dysport® (U) in the treatment of lower-limb spasticity Bakheit et al, 2001]. One active comparator, placebo-controlled study also examined Dysport® in combination
with electrical stimulation versus either agent alone [TABLE 4].
Spasticity Indication Total dose (U) Injection site (muscle) and dose (U)

Adult spasticity 1500 Distributed between gastrocnemius and soleus muscles;

of the leg also consider tibialis posterior
post-stroke

U: Unit.

For subsequent treatment, maximum Dysport® doses should not exceed 1500 U [Ipsen Biopharm Ltd, 2010].
Injections may be repeated approximately every 16 weeks, or as required to maintain a response, but not more
frequently than every 12 weeks [Ipsen Biopharm Ltd, 2010].

100 101

TABLE 3. Proven efficacy in upper limb spasticity
Study
(Bakheit et al, 2000)
(Bhakta et al, 2000)
(Smith et al, 2000)
(Bakheit et al, 2001)
(Bakheit et al, 2004)
(Suputtitada & Suwanwela,
2005)
102 (McCrory et al, 2009)
AQoL: Assessment of Quality of Life; ARA: Action Research Arm Test; BoNT: botulinum neurotoxin; GAS: Goal Attainment Scale;
IM: intramuscular; MAS: Modified Ashworth Scale; ROM: range of movement; U: Unit; UK: United Kingdom; VAS: visual analogue scale.
*Formal statistical analysis was not conducted.
Design
Randomised, double-blind,
placebo-controlled dose-ranging study
(Dysport® 500, 1000 or 1500 U IM;
16 weeks), 11 European centres
Randomised, double-blind,
placebo-controlled study (1000 U IM;
12 weeks), 1 UK centre
Randomised, double-blind,
placebo-controlled, dose-ranging study
(500, 1000 or 1500 U IM; 12 weeks),
1 UK centre
Randomised, double-blind,
placebo-controlled study
(Dysport® 1000 U IM; 16 weeks),
7 European centres
Prospective, open-label, repeat-dose study
(1000 U IM for ≥3 treatment cycles),
2 UK and 3 Russian centres
Prospective, randomised, double-blind,
placebo-controlled, dose-ranging study
(350, 500 or 1000 U IM; 6 months),
single-centre (Thailand)
Randomised, double-blind,
placebo-controlled study
(750 to 1000 U IM initially; retreatment
with 500 to 1000 U IM; for 6 months),
6 Australian centres
Secondary analysis of goal attainment
(Turner-Stokes et al., 2010)
Patients
83 patients with moderate-to-severe
post-stroke hemiplegic arm;
BoNT treatment-naïve
40 patients with post-stroke
chronic hemiparesis,
BoNT treatment-naïve
21 patients with post-stroke or
traumatic brain injury
hemiparesis; significant disabling
spasticity
59 patients with post-stroke
hemiplegic arm; received prior
BoNT treatment
(but not within last 6 months)
51 patients with post-stroke
(hemiplegic) severe/moderately
severe spasticity; no BoNT
treatment within 120 days
50 patients with spasticity
of various aetiologies
96 patients with post-stroke
(hemiplegic) severe/moderately
severe spasticity; no BoNT
treatment within 120 days
Results
Primary endpoints
Significant improvement in MAS score at week 4 all
doses 78.9%–95.5% vs. 68.4% (placebo) of patients
with change; p≤0.02
Benefit sustained up to 16 weeks
Disability significantly improved at week 6, –0.5 vs.
–0.1 (placebo) (p=0.016); week 12, –0.5 vs. –0.2
(p=0.055)
Significant reduction in median MAS score at week 6
combined Dysport® doses, fingers –2 vs. 2 (placebo)
and wrist –2 vs. 0; p<0.01
Increase in wrist passive ROM at week 6, 14o vs. 4o; p=0.05
Significant improvement in MAS score at week 4;
patients with change, 81.5% vs. 68.7% (placebo);
p=0.004
Benefit sustained in the wrist (p=0.004) and finger
joints (p=0.001) up to 16 weeks
Improvement in MAS score in 100% of patients at
cycle 1; maintained for 3 cycles (98% of patients)
Significant decrease in MAS score at week 8 with all
Dysport® doses; p<0.05
No significant differences in AQoL
16 Therapeutic Indications Adult spasticity
Secondary endpoints
Improvement in ROM, all doses
Dose-dependent improvement in functional activities
at week 4*
Significant improvement in carer burden at week 6:
–1.0 vs. 0 (placebo) (p=0.005);
week 12: –1.0 vs. 0 (p=0.027)
Finger flexor spasticity significantly improved at week
6: –1.5 vs. 0 (placebo) (p<0.001); week 12:
–1.0 vs. 0 (p=0.006)
Significant increase in global assessment of benefit at
week 6, 15 versus 2 (placebo) patients; p<0.02
Significant increase in passive ROM (elbow) at week
16; p=0.036
Greater patient satisfaction (‘much improved’ or ‘some
improvement’), 92.3% vs. 50% (placebo); p=0.007
Reduction in disability rating and carer burden scale
scores (mean decrease 0.31 and 0.34); maintained for
3 cycles
Treatment goals achieved by 58% of patients after
3 cycles
90% (patients) and 95% (investigators) reported overall
treatment benefit
Significant increase in arm function (ARA) at week 8
and 24 with 500 U Dysport®; p<0.05
Significant reduction in mean VAS pain score at week 8
Significant reduction in MAS score at week 20, –1.8 vs. 103
–0.2 (placebo), p<0.001
No significant differences in pain, mood, disability or
carer burden
Significant improvement in GAS, 7.0 vs. 1.8 (placebo);
p<0.01
GAS correlated with spasticity reduction (r=0.36;
p=0.001) and global benefit (r=0.46; p<0.001)
 16 Therapeutic Indications Adult spasticity

An active comparator study demonstrated that Dysport® in combination with electrical stimulation versus either
TABLE 5. Proven efficacy in lower limb spasticity
agent alone was associated with significant efficacy in patients with upper limb spasticity [TABLE 4].

Study Design Patients Results

TABLE 4. Proven efficacy versus active comparators in upper limb spasticity Primary endpoints Secondary endpoints

(Burbaud Randomised, 23 hemiparetic Significant Significant improvement in

Study Design Patients Results double-blind, patients with improvement in Ashworth scale scores at week
et al,
1996) placebo- ankle plantar subjective spasticity 4, ankle extensors 2.4 vs. 3.7
(Hesse et al, Randomised, double-blind, 24 patients Greater reduction in MAS score, elbow joint
controlled, flexor and foot score, 1.5 vs. 0.2 pre-treatment, invertors 1.8 vs.
1998) placebo-controlled study (–1.17 vs. +0.16 to –0.83 [other groups]; crossover study invertor (placebo); p=0.0014 2.8, active ankle dorsiflexion
(Dysport® 1000 U plus between-group, p=0.011) (1000 U IM; spasticity 3.3 vs. 2.2; all p≤0.0002
electrical stimulation vs. Significant improvement in daily activity 120 days),
Maintained until day 120
electrical stimulation and (cleaning the palm); p=0.004 single-centre
(except ankle dorsiflexion)
placebo or Dysport® 1000 U or (France)
Improvement in limb position at rest; ns Improved gait velocity, 29.4 vs.
placebo alone for 12 weeks)
25.1 (pre-treatment) cm/s (ns)

MAS: Modified Ashworth Scale; ns: not significant; U: Unit.

(Hyman Double-blind, 74 patients Significant increase in Significantly longer benefit,
et al, dose-ranging, with definite or knee-to-knee distance 99–119 vs. 56 (placebo) days;
2000) placebo- probable MS at week 4; p=0.02 p<0.05
In addition to seminal studies from the clinical programme, the efficacy of Dysport® in spasticity is supported by controlled, parallel and disabling
group study (500, hip adductor
a wealth of clinical evidence [Keam et al, 2011; Rosales et al, 2012; Esquenazi et al, 2013]. In upper limb
1000, or 1500 U spasticity
spasticity, Dysport® has demonstrated significant benefit in reducing post-stroke spasticity alone [Das & Park, 1989; IM; 12 weeks)
Memin, 1994; Woldag & Hummelsheim, 2003] and when combined with rehabilitation [Rosales et al, 2012].
Open-label and randomised, controlled studies have also revealed significant improvements with Dysport® on (Pittock Randomised, 234 patients, Significantly increased Significant increase in stepping
other outcome measures of upper limb spasticity such as associated reactions, disability, pain, functional et al, double-blind, post-stroke 2-min walking distance rate at week 12, 66.8–70.0 vs.
2003) placebo-controlled hemiparesis from baseline at week 69.6 (placebo) steps/min;
activities, and self-care [Hesse et al, 1992; Konstanzer et al, 1993; Finsterer et al, 1997; Lani et al, 1998;
dose-ranging with spastic 12. Differences were within-group p<0.05
Maurri et al, 1998; Bakheit & Sawyer, 2002; Bhakta et al, 2008; Lam et al, 2012]. One randomised placebo- study (500, 1000, equinovarus non-significant Significantly improved calf
controlled trial in patients with severe upper limb spasticity and experiencing difficulty in basic upper limb care or 1500 U IM; 12 deformity of between groups spasticity (1500 U significant at
also showed that treatment with Dysport® significantly reduced carer burden for up to 16-weeks post-injection weeks), ankle, no including placebo all time points, all p<0.02; 500
[Lam et al, 2012]. multinational BoNT-A & 1000 U significant at week 4,
treatment p<0.01) and limb pain (all doses
Pivotal findings from clinical studies lend support to the following conclusions regarding treatment with Dysport® within 6 at all time points; p<0.05)
for upper limb spasticity: months
Patient and investigator-reported
Dysport® is an effective and safe treatment for upper- limb spasticity. greater overall benefit
• Dysport® significantly reduces muscle tone in elbow, wrist, and fingers at doses of 500 and 1000 U and in
(Gusev Randomised, 106 patients 29% of patients More patients improved by
the forearm at a dose of 1000 U. placebo-controlled with definite (each group) improved
et al, ≥1 point on MAS score leg
• More Dysport®-treated patients showed improvement in muscle tone at week 4 (upper limb spasticity) versus placebo. 2008) study (1000 to or probable MS ≥1 grade in key adductor muscle at Week 8,
1500 U IM; 12 and leg adductor functional outcome
104 p=0.067 105
Dysport® treatment provides a reduction in symptoms for up to 16 weeks in upper limb spasticity. weeks) spasticity, no at Week 4 (ns)
BoNT-A for lower Significant bilateral reduction in
• 16 weeks after Dysport® injections, muscle tone is still reduced in elbow, wrist and fingers.
limb spasticity leg pain up to Week 12, p≤0.027
Dysport® achieves a high level of patient satisfaction. in previous
12 weeks
• Up to 92% of patients with upper limb spasticity are satisfied with Dysport®.
BoNT-A: botulinum neurotoxin type A; cm: centimetre; IM: intramuscular; MAS: Modified Ashworth Scale;
MS: multiple sclerosis; ns: non-significant; s: second; U: Unit.
Dysport clinical trials efficacy in adult lower-limb spasticity
®

The Dysport® clinical programme in lower limb spasticity included four placebo-controlled studies [TABLE 5]. Among
these two were seminal randomised, double-blind, placebo-controlled studies [Hyman et al, 2000; Pittock et al, 2003].

In addition to seminal studies from the clinical programme, the efficacy of Dysport® in lower limb spasticity is
supported by a wealth of clinical evidence [Keam et al, 2011]. In open-label studies of patients with lower limb
spasticity, single- and repeat-dose Dysport® treatment significantly improved spasticity, joint position, and pain
[Dengler et al, 1992; Benecke, 1994; Pauri et al, 2000].
16.4 Dysport® clinical trials safety in adult spasticity
16.5
Dysport® clinical trials safety in adult upper-limb spasticity
The safety and tolerability profile of Dysport® is well established in patients with upper-limb spasticity.
Across clinical trials of Dysport® in patients with upper-limb spasticity, commonly experienced adverse events (AEs)
were dysphagia and arm muscle weakness, abnormal gait, and accidental injury or falls [Ipsen Biopharm Ltd,
2010]. Notably, dysphagia was reported at Dysport® doses in excess of 2700 U when administered as a single or
divided dose [Ipsen Biopharm Ltd, 2010].
In key placebo-controlled trials of patients with upper-limb spasticity, the incidence of AEs was generally
comparable between Dysport® and placebo [Bakheit et al, 2000; Bakheit et al, 2001]. The overall frequency of
AEs did not demonstrate a relationship with Dysport® dose [Bakheit et al, 2000; Bakheit et al, 2001]. In a study
of patients with upper limb spasticity (N=82), common AEs in the overall population were epileptic seizures (n=5),
accidental injury (n=5), and urinary and respiratory tract infections (n=6) [Bakheit et al, 2000]. Hypertonia of
injected and/or non-injected muscles (22%), weakness of non-injected muscles (14%), and fatigue (7%) were
commonly reported AEs in a key lower limb spasticity trial [Hyman et al, 2000]. In these studies, common AEs
were generally mild to moderate in severity.
Consistent with the general safety profile of Dysport® (across clinical indications) [Ipsen Biopharm Ltd, 2010],
skin rashes, flu-like symptoms, fatigue, tiredness and pain in the arm following injection were less frequently
reported AEs that were considered possibly related to single-dose treatment in patients with upper limb post-
stroke spasticity [Bakheit et al, 2000; Bakheit et al, 2001]. Repeated treatment has also been shown to be well
tolerated in upper limb spasticity, with no cumulative effect of dosing with Dysport® over multiple treatment cycles
[Bakheit et al, 2004].
Dysport® clinical trials safety in adult lower-limb spasticity
The safety and tolerability profile of Dysport® is well established in patients with lower -limb spasticity.
106 Across clinical trials of Dysport® in patients with lower-limb spasticity, commonly experienced AEs were dysphagia,
leg muscle weakness, abnormal gait, and accidental injury or falls [Ipsen Biopharm Ltd, 2010]. Notably, dysphagia
was reported at Dysport® doses in excess of 2700 U when administered as a single or divided dose [Ipsen
Biopharm Ltd, 2010].
In key placebo-controlled trials of patients with lower-limb spasticity, the incidence of AEs was generally comparable
between Dysport® and placebo [Hyman et al, 2000; Pittock et al, 2003]. The overall frequency of AEs did not
demonstrate a relationship with Dysport® dose [Pittock et al, 2003]. Hypertonia of injected and/or non-injected
16 Therapeutic Indications Adult spasticity
muscles (22%), weakness of non-injected muscles (14%), and fatigue (7%) were commonly reported AEs in a
key lower limb spasticity trial [Hyman et al, 2000]. In these studies, common AEs were generally mild to moderate
in severity.
The safety and tolerability of Dysport® in upper and/or lower limb spasticity has also been established over the
longer term (12 years) in studies conducted in real-world clinical practice [Mohammadi et al, 2010].
Dysport® in real-world clinical practice
Dysport® for adult upper limb spasticity in real-world clinical practice
Two studies provide confirmation that beneficial effects observed with Dysport® in the upper-limb spasticity clinical
programme extend to real-world practice [Mohammadi et al, 2010; Turner-Stokes et al, 2013b].
One retrospective long-term study included 137 patients, aged 15 to 86 years (mean age 52 ± 17 years), with
spasticity of various aetiologies who received 1221 BoNT-A treatments (at least 8 consecutive treatments) for up
to 12 years [Mohammadi et al, 2010]:
Of the 105 patients who were treated with Dysport® (7.5 years, range 2 to 12 years), 16 patients were treated
in the upper limb only.
Mean latency between injection and response to Dysport® was 6.8 ± 3.8 days (overall), 6.8 ± 3.6 days (upper
limb spasticity patients only).
Dysport® treatment effect was observed for a mean duration of 11.3 ± 2.7 weeks (overall), or 11.6 ± 3.1 weeks
(upper limb spasticity patients only).
There were no severe or systemic side effects. Reported side effects were transient and included weakness
of injected limb (2.3% or 1.1% of treatment sessions) and pain at injection site (1.7% of treatment sessions).
The long-term safety profile of Dysport® did not differ from that of Botox®.
One prospective, multicentre, observational study of patients with post-stroke upper limb spasticity included 456
patients who received one cycle of BoNT-A treatment under routine practice conditions [Turner-Stokes et al, 2013a;
Turner-Stokes et al, 2013b]. The primary outcome was achievement of the patient’s primary goal using goal
attainment scale (GAS) and the majority of patients (n=321, 70%) received treatment with Dysport®.
Overall, 363 (79.6%) patients achieved (or overachieved) their primary goal and 355 (75.4%) mainly in terms
of passive and active functions and pain reduction. 107
Similarly, 355 (75.4%) patients achieved their secondary goal.
GAS T-scores were correlated with global assessment of benefits (patient and investigator rated) as well as
reductions in spasticity.
Baseline and mean change from baseline in GAS T-scores were similar between BoNT-A preparations.
 16 Therapeutic Indications Adult spasticity

Dysport® for adult lower limb spasticity in real-world clinical practice
The same study also provides confirmation that beneficial effects observed with Dysport® in the lower-limb
spasticity clinical programme extend to real-world practice [Mohammadi et al, 2010]:
Of the 105 patients who were treated with Dysport® (7.5 years, range 2 to 12 years), 44 patients were treated
in the lower limb only.
Mean latency between injection and response to Dysport® in lower limb spasticity patients was 7.3 ± 3.8 days.
Dysport® treatment effect in lower limb spasticity was observed for a mean duration of 11.5 ± 2.9 weeks.
Conclusions
Evidence-based clinical practice guidelines advocate BoNT-A as a mainstay treatment option for patients
with spasticity.
Dysport® provides consistent clinical performance in the treatment of spasticity, as shown in numerous clinical
trials and real-life studies.
Key findings from clinical studies lend support to Dysport® as an efficacious long-term treatment for spasticity,
with benefits extending to overall patient function in addition to improvements in muscle tone.

There were no severe or systemic side effects. Reported side effects were transient and included weakness of Dysport® has a well-established safety and tolerability profile, based on up to 12 years of published clinical
injected limb (2.3% or 1.1% of treatment sessions) and pain at injection site (1.7% of treatment sessions). experience in spasticity.

The long-term safety profile of Dysport® did not differ from that of Botox®. Dysport® achieves a high level of satisfaction in patients with spasticity.

Dysport® is a highly cost-effective treatment for spasticity.

16.6 Hints for optimising outcomes in treating adult spasticity

As part of the integrated multidisciplinary approach for spasticity, a tailored treatment is needed in spasticity
[Anwar & Barnes, 2005; Simon & Yelnik, 2010].

Dysport® dose can be adjusted according to clinical response and side effects; but should not exceed the
maximum dose per indication.

Injection technique guidance (EMG) may aid the identification and treatment of the most active muscles.

16.7 Dysport® cost-effectiveness in adult spasticity

The direct costs of treating post-stroke spasticity are four-fold greater than for stroke patients without spasticity,
and increase with the severity of spasticity (higher MAS scores) [Lundstrom et al, 2010]. However, BoNT-A
treatment has the potential to reduce costs by changing the pattern of resource utilisation and reducing the need
for ongoing care of patients with spasticity [Esquanizi, 2006; Royal College of Physicians et al, 2009]. Indeed,
cost-effectiveness analyses show that combining physiotherapy with BoNT-A treatment can reduce the cost of
treatment by at least 20% compared with physiotherapy alone [Ravasio et al, 2013].

In addition, Dysport® specifically has been shown to be a cost-effective alternative for upper-limb spasticity.
In one analysis, the annual drug costs for Dysport® was estimated to be £924 (1000 U) compared with £1,385 for
Xeomin® (307 U) and £1,062 with Botox® (221 U), resulting in a cost saving with Dysport® of £461 versus Xeomin®
108 and £138 versus Botox® [Scottish Medicines Consortium, 2012]. 109

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112 113
 16 Therapeutic Indications Paediatric spasticity (cerebral palsy)

Introduction 16.2 Dysport® for the treatment of spasticity in paediatric cerebral palsy: initial dosing
Cerebral palsy is a disorder of neurodevelopment that affects movement and posture [Bax et al, 2005]. Estimates In children (≥2 years of age) with cerebral palsy and dynamic equinus foot deformity due to spasticity, Dysport®
suggest that 1.5 to 3 children per 1000 children aged between 3 and 10 years suffer from cerebral palsy worldwide should be administered at an initial recommended dose of 20 U/kg of body weight (10 U/kg bodyweight if one
[Odding et al, 2006; Paneth et al, 2006]. calf muscle is affected), administered as a divided dose [TABLE 1] [Ipsen Biopharm Ltd, 2010]. A lower dose
may be needed if target muscles are small or there is a requirement for concomitant treatment of other muscle
Spasticity is observed in a subset of children with cerebral palsy, and is characterised by hypertonia of a variety of
groups [Ipsen Biopharm Ltd, 2010].
muscles [Delgado et al, 2010; Molenaers et al, 2010]. It is important to treat spasticity in the developing child,
because it can lead to fixed contractures and joint instability, which may further impair the child’s motor Electromyography (EMG), although not part of routine clinical practice, may be used to guide the identification
performance [Simpson et al, 2008] and may eventually require orthopaedic surgery [Molenaers et al, 2010]. of active muscles [Ipsen Biopharm Ltd, 2010]. Likewise, sonoelastography assists with precise, guided injection
A common pattern of spasticity noted in cerebral palsy is equinus foot deformity, which arises from spasticity of in lower-limb spasticity, with proven therapeutic results [Vasilescu et al, 2010].
the muscles that control ankle movement (especially the gastrocnemius and soleus muscles) and results in a
distinctive gait [Keam et al, 2011].
TABLE 1. Dosing recommendations for Dysport® (U) in the treatment of paediatric cerebral palsy
Pain is a commonly reported symptom among children with moderate-to-severe cerebral palsy [Parkinson et al,
2010]. Ultimately, spasticity and the resulting pain confer a marked detrimental effect on health-related quality Indication Total dose (U) Injection site (muscle)
of life in children and adolescents with cerebral palsy [Akodu et al, 2012; Ramstad et al, 2012]. While historically and dose (U)
acknowledged as a non-progressive disorder, more recent reports in adults with cerebral palsy suggest worsening
or non-improvement of symptoms, such as pain, fatigue, imbalance and weakness, over time [Hirsh et al, 2010]. Paediatric dynamic equinus foot 20 U/kg Divided doses into both calf muscles
deformity due to spasticity associated body weight* (primarily the gastrocnemius muscle;
with cerebral palsy (≥2 years of age) also consider soleus and tibialis posterior)
16.1 Management of spasticity in paediatric cerebral palsy
Treatment of spasticity in children with cerebral palsy aims to reduce muscle pain and spasm, improve posture,
Kg: kilogram; U: Unit.
minimise contractures and deformities, and improve mobility, dexterity and ease of care [Delgado et al, 2010]. *10 U/kg bodyweight if one calf muscle is affected.
Moreover, delaying surgery in younger children is considered crucial because the results of early surgical
interventions are unpredictable with a relatively high risk of failure and relapse. While they form the basis of most
therapy programs, conservative approaches (e.g. physical therapy and use of orthoses) when used alone do not
prevent the development of fixed contractures. Thus concomitant treatment with botulinum neurotoxin A (BoNT-A) 16.3 Dysport® for the treatment of spasticity in paediatric cerebral palsy:
to reduce muscle tone and thereby optimise conservative treatment has become widely accepted [Molenaers et al, dose modification for subsequent treatment
2010].
After the evaluation of initial response, subsequent Dysport® treatment may be adjusted between doses of
The introduction of BoNT-A treatment represented a major advance in the management of cerebral palsy 10 U/kg and 30 U/kg body weight divided between both legs. However, doses should not exceed a maximum
[Molenaers et al, 2010]. In recognition of this, there have been concerted efforts to develop evidence-based of 30 U/kg body weight or 1000 U (whichever is lower) [Ipsen Biopharm Ltd, 2010]. Injections may be repeated
clinical practice guidelines for the appropriate management of spasticity with BoNT-A in paediatric cerebral palsy approximately every 16 weeks, or as required to maintain a response, but not less than every 12 weeks [Ipsen
[Simpson et al, 2008; Delgado et al, 2010; Heinen et al, 2010]. The American Academy of Neurology (AAN) Biopharm Ltd, 2010].
performed a review of evidence relating to pharmacological treatments for spasticity in children and adolescents
114 115
(up to 19 years of age) with cerebral palsy [Delgado et al, 2010]. The review identified 15 Class I (defined as a
randomised controlled clinical trial with masked or objective outcome assessment in a representative population)
16.4 Dysport clinical trials efficacy in spasticity in paediatric cerebral palsy
®

studies of BoNT-A treatments, six of which were conducted with Dysport® [Delgado et al, 2010]. Based on The efficacy of Dysport® in children with cerebral palsy is based on a large body of evidence.
this evidence, the AAN recommended that BoNT-A should be offered as an effective and generally safe treatment The Dysport® clinical programme in children with cerebral palsy comprised five placebo-controlled or single-arm
for localised/segmental spasticity in children and adolescents with cerebral palsy (highest graded recommendation) studies [TABLE 2; FIGURE 1], including two key randomised, double blind, placebo-controlled studies [Ubhi et al, 2000;
[Delgado et al, 2010]. Baker et al, 2002]. Efficacy was also demonstrated in an open-label trial [TABLE 3] [Deleplanque et al, 2002].

TABLE 2. Proven efficacy in RCT
Study
(Ubhi et al, 2000)
(Baker et al, 2002)
(Kanovsky et al, 2004)
(Mall et al, 2006)
116 (Kanovsky et al, 2009)
BoNT-A: botulinum neurotoxin type A; CP: cerebral palsy; IM: intramuscular; Kg: kilogram; MAS: Modified Ashworth Scale;
MPAD: maximum passive ankle dorsiflexion; OR: odds ratio; RCT: randomised controlled trial; U: Unit; VGA: video gait analysis.
Design
Randomised, double-blind, placebo-controlled,
parallel-group study (Dysport® 15 U/kg
[hemiplegics] or 25 U/kg [diplegics] body
weight IM; 12 weeks), 1 UK centre
Randomised, double-blind, placebo-controlled,
dose-ranging study (Dysport® 10, 20,
and 30 U/kg body weight IM; 16 weeks),
12 European centres
Randomised, double-blind, placebo-controlled
study (Dysport® 30 U/kg body weight IM;
16 weeks; up to 36 weeks in responders),
5 European centres
Randomised, double-blind study
(Dysport® 30 U/kg body weight IM; 12 weeks),
multicentre
Randomised, single-blind, repeat-dose study
(Dysport® 30 U/kg body weight every 4 months
or yearly; 2 years),
18 European centres
Patients
40 patients (aged 2 to 16 years) with
diplegic or hemiplegic CP and dynamic
equinus spasticity; no prior BoNT
treatment or surgery
125 patients (aged 2 to 9 years)
with diplegic CP and dynamic equinus
spasticity; no BoNT-A treatment
within 90 days before study;
no surgery
52 patients (aged 2 to 7 years) with
diplegic CP and dynamic equinus
spasticity; no BoNT-A treatment
in prior 9 months; no surgery
61 patients (aged 18 months
to 10 years) with CP and bilateral
adductor spasticity, no prior surgery
or Dysport® treatment
within previous 9 months
215 patients (aged 1 to 8 years)
with diplegic CP, no prior surgery
or BoNT-A treatment within
previous 9 months
16
Results
Primary endpoints
Significantly improved initial foot contact (VGA
score) at week 6: 48% vs. 17% (placebo) of patients
(p=0.02); week 12: 50% vs. 11% (p=0.003)
Dysport® significantly decreased dynamic
component of gastrocnemius shortening at week 4;
p≤0.05 [FIGURE 1]
Maintained until week 16 in the 20 U/kg group;
p<0.001 [FIGURE 1]
Improved gross motor function with both groups
at weeks 4, 8 and 16
Significant improvement in knee-to-knee distance
(fast catch) at week 12, p=0.01
Median MPAD at month 28 was 12o and 11o
n the 4-monthly and yearly groups, respectively
Therapeutic Indications Paediatric spasticity (cerebral palsy)
Secondary endpoints
Clinically significant improvement in gross motor
function at week 12, 37% vs. 7% (placebo)
of patients; p=0.04
Dysport® 30 U/kg significantly increased ankle
dorsiflexion knee extended (difference vs. placebo
4.6o; p=0.043) and flexed (6.3o; p=0.019) at week 4
Significantly higher subjective functional benefit at
week 4 with Dysport® 30 U/kg, parent-rated 53.3%
vs. 22.6% (placebo) of patients; p=0.009
Three-quarters of parents/investigators reported
overall treatment benefit
Improved initial foot contact at week 16, 38% of
treated legs vs. 20% (placebo)
Significantly less worsened foot contact at week 16,
6% of treated legs vs. 24% (placebo); p=0.004
Significant reduction in Ashworth scale score for
adductor muscles at week 12; p=0.045
Significant improvement in goal attainment at week 12;
p=0.045
Good response more likely at month 25 117
with 4-monthly vs. annual dosing,
OR 1.82 (assessor) and OR 1.84 (parent); p≤0.034
 16 Therapeutic Indications Paediatric spasticity (cerebral palsy)

FIGURE 1. Significant reduction in dynamic component of gastrocnemius shortening up A number of additional studies contribute to the clinical trial evidence supporting the efficacy of Dysport® in children
to 16 weeks [Baker et al, 2002] with cerebral palsy. Regardless of study design (open-label, randomised, or retrospective), single- or repeat-dose,
Dysport® has demonstrated clinical efficacy in improving gastrocnemius muscle length, muscle tone, gait, dynamic
Week 4 Week 8 Week 16 range of movement, and functional disability in children with lower limb spasticity associated with cerebral palsy
0
[Cosgrove et al, 1994; Denislic & Meh, 1995; Watanabe et al, 1998; Eames et al, 1999; Metaxiotis et al, 2002;
-0.2 Polak et al, 2002; Hu et al, 2009; Colovic et al, 2012]. BoNT-A treatment in children with cerebral palsy provides
component of gastrocnemius shortening (%)

a reduction in passive motion resistance values and improves functional motor status [Colovic et al, 2012]. Moreover,
Mean change from baseline in dynamic

-0.4
a randomised, single blind comparator study of 20 children with dynamic equinus spasticity associated with cerebral
-0.6 palsy showed that Dysport® improved gait analysis for longer (up to 12 weeks) than serial casting [Corry et al,
1998].
-0.8

-1 Key results from Dysport® clinical trials in children with cerebral palsy support the following conclusions:

-1.2 Dysport® is effective and safe in the treatment of children with cerebral palsy.

-1.4 • Dysport® significantly reduces spasticity.

-1.6 • Dysport® significantly improves the dynamic component of gastrocnemius muscle and initial foot contact at
weeks 4 and 6, respectively.
-1.8
• Dysport® improves motor function in 81% of patients.
-2
Dysport® 10U Dysport® 20U Dysport® 30U PL Dysport® reduces symptoms for up to 16 weeks.

• Sustained improvement in initial foot contact and the dynamic component of cerebral palsy until weeks 12
PL: placebo. and 16, respectively.
Versus placebo: *p <0.05; **p <0.01; ***p <0.001
Dysport® achieves high response and treatment benefit.

• Significantly higher subjective functional benefit at week 4.

• Overall treatment benefit reported by 75% of parents and investigators.

TABLE 3. Proven efficacy in an open-label trial

Study Design Patients Results 16.5 Dysport® clinical trials safety in spasticity in paediatric cerebral palsy
Primary endpoints Secondary endpoints Dysport® has a well-established safety and tolerability profile in children with cerebral palsy.

(Deleplanque Open-label 11 patients Decrease in MAS score Relief from lower limb Across clinical trials of Dysport® in children with spasticity associated with cerebral palsy, common adverse events
et al, 2002) study (20 (mean age 5 (≥1 point) in 20 of 21 hips pain in 27.2% (3 of 11) (AEs) were diarrhoea, leg muscle weakness, urinary incontinence, abnormal gait and accidental injury due to falling
118 U/kg body years 9 at 1 month [Ipsen Biopharm Ltd, 2010]. Events of accidental injury due to falls and abnormal gait may reflect over-weakening 119
Motor function
weight; months) with of the target muscle and/or the local spread of Dysport® to other muscles involved in ambulation and balance
improvement in 81.8%
12 months), quadriplegic CP [Ipsen Biopharm Ltd, 2010].
(9 of 11)
single-centre Results from key placebo-controlled trials in paediatric cerebral palsy reveal that the incidence and profile of AEs
is similar between Dysport® and placebo [Baker et al, 2002; Kanovsky et al, 2004]. Furthermore, most AEs were
CP: cerebral palsy; Kg: kilogram; MAS: Modified Ashworth Scale; U: Unit. mild and generally self-limiting [Ubhi et al, 2000; Baker et al, 2002; Kanovsky et al, 2004]. Among 52 children
with cerebral palsy and dynamic equinus spasticity who received single-dose treatment, 80% and 79% of AEs in
 16 Therapeutic Indications Paediatric spasticity (cerebral palsy)

the Dysport® and placebo groups, respectively, resolved within 2 weeks of onset [Kanovsky et al, 2004].
In a large, placebo-controlled, dose-ranging (Dysport® 10, 20, or 30 U/kg) study, the treatment-related AEs most
frequently observed were falls (n=6 of 123 events), pain (n=6), and asthenia (n=4) [Baker et al, 2002].
The frequency of repeat dosing with Dysport® over multiple treatment cycles has not been observed to have
a cumulative effect on the incidence of overall AEs or individual AE profile [Kanovsky et al, 2009].
16.6 Dysport® in real-world clinical practice
The effectiveness and safety of Dysport®, demonstrated across clinical studies of children with cerebral palsy, is
supported by findings from real-world clinical practice [Bakheit et al, 2001; Papavasiliou et al, 2013].
16.7 Hints for optimising outcomes in treating spasticity in paediatric cerebral palsy
Treatment of spasticity associated with paediatric cerebral palsy requires appropriate selection of pharmacological
treatments. Recommendations for the use of BoNT-A treatments such as Dysport® in children with cerebral palsy
are based on the highest graded evidence [Delgado et al, 2010].
Dysport® dose can be adjusted depending on clinical response, but maximum dose administered must
not exceed 30 U/kg of body weight or 1000 U (whichever is lower).
Injection technique guidance (EMG or ultrasound) may aid the identification and treatment of the most active
muscles.

In a retrospective analysis of case records, results were obtained for 758 children with muscle spasticity (429 males
Conclusions
and 329 females; mean age of 7.2 years; 94% had cerebral palsy) who received a total of 1594 treatments with
Evidence-based clinical practice guidelines recommend Dysport® as an effective treatment option
Dysport® in five European clinics [Bakheit et al, 2001]:
for children with focal spasticity associated with cerebral palsy.
Mean Dysport® dose per treatment session was 22.9 U/kg of body weight (47% had one treatment, 28% two
Clinical and real-world data support the consistent clinical performance of Dysport® in the treatment
treatments, and 25% three or more).
of spasticity associated with paediatric cerebral palsy.
82% of treatments were associated with a good response.
Treatment with Dysport® leads to clinically relevant benefits in children with cerebral palsy, from significant
Functional goals (for example, improvement of foot contact pattern, balance, and walking distance) were reductions in spasticity to improvements in function and relief from lower limb pain.
achieved moderately in 94% and fully in 3% of patients.
Dysport® has a well-established safety and tolerability profile in children with cerebral palsy.
Adverse events were reported in 107 of 1594 (7%) treatments. Focal muscle weakness was observed in 1% of
Dysport® achieves a high overall treatment benefit according to parent and investigator opinion.
treatments while urinary incontinence, pain at the site of injection, fatigue, somnolence, flu-like symptoms,
fever, and purpuric skin rash were reported in less than 1% of treatments. Of 758 patients, there were 6 and
7 reports of generalised muscle weakness and falls, respectively. Treatment with Dysport® doses >1000 U was
associated with a five-fold higher likelihood of an AE than treatment with lower Dysport® doses (250 U or less;
p<0.001).

Another retrospective study of 454 patients who had 1515 BoNT-A sessions, data on AEs were available in
356 patients and 1382 sessions [Papavasiliou et al, 2013].

51 non-fatal adverse events were reported (3.3% of the total injections number, 8.7% of the patients).
In 5 cases AEs children were attributed to sedation.

Of reactions attributed to BoNT-A, 23 involved excessive reduction of muscle tone; others included local pain,
restlessness, lethargy with pallor, disturbance in swallowing and speech production, seizures, strabismus,
120 excessive sweating, constipation, vomiting, a flu-like syndrome and emerging hypertonus in adjacent muscles. 121

The incidence of AEs was associated with Gross Motor Function Classification System (GMFCS) level and with
the presence of epilepsy but not with BoNT-A dose.
 16 Therapeutic Indications Paediatric spasticity (cerebral palsy)

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(an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American
Eames NWA, Baker R, Hill N, et al. The effect of botulinum toxin A on gastrocnemius length: magnitude and
Academy of Neurology. Neurology 2008; 70(19): 1691-8.
duration of response. Dev Med Child Neurol 1999; 41(4): 226-32.
Ubhi T, Bhakta BB, Ives HL, et al. Randomised double blind placebo controlled trial of the effect of botulinum
Heinen F, Desloovere K, Schroeder AS, et al. The updated European Consensus 2009 on the use of Botulinum
toxin on walking in cerebral palsy. Arch Dis Child 2000; 83(6): 481-7.
toxin for children with cerebral palsy. Eur J Paediatr Neurol 2010; 14(1): 45-66.
Vasilescu D, Vasilescu D, Dudea S, et al. Sonoelastography contribution in cerebral palsy spasticity treatment
Hirsh AT, Gallegos JC, Gertz KJ, et al. Symptom burden in individuals with cerebral palsy. J Rehabil Res Dev 2010;
122 assessment, preliminary report: a systematic review of the literature apropos of seven patients. Med Ultrason 123
47(9): 863-76.
2010; 12(4): 306-10.
Hu GC, Chuang YC, Liu JP, et al. Botulinum toxin (Dysport®) treatment of the spastic gastrocnemius muscle in
Watanabe Y, Bakheit AMO, McLellan DL. A study of the effectiveness of botulinum toxin type A (Dysport®) in
children with cerebral palsy: a randomized trial comparing two injection volumes. Clin Rehabil 2009; 23(1): 64-71.
the management of muscle spasticity. Disabil Rehabil 1998; 20(2): 62-5.
Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company
Core Safety Information. Version 7.0.

Kanovsky P, Bares M, Severa S, et al. Functional benefit of botulinum toxin (Dysport®) in the treatment of dynamic
equinus cerebral palsy spasticity: a prospective, multicentre, double-blind, placebo-controlled study. Ces A Slov
Neurol Neurochir 2004; 67/100(1): 16-23.
 17 Reconstitution and injection technique

17.1 Reconstitution 17.2 Injection technique

Accurate and safe reconstitution and administration of Dysport® can be achieved by following these key steps Dysport® is administered by intramuscular, intradermal or subcutaneous injection – the site of injection is dependent
[Ipsen Biopharm Ltd, 2012]: on the indication [TABLE 2] [note: not all indications for Dysport® have been approved in this region; for further
information on indications licensed in your region, see ‘Approved indications’ and sections dedicated to individual
Before using Dysport®, ensure that the packaging integrity has not been compromised. Dysport® should not be
therapeutic indications].
used after the expiration date printed on the vial.
Injections may be repeated approximately every 12 or 16 weeks in the case of most clinical indications [TABLE 2].
Using an appropriately sized sterile syringe and needle, and employing aseptic techniques, draw up the required
Alternatively, in all patients, Dysport® may be used as needed to maintain response, but not more frequently than
volume of sterile 0.9% sodium chloride injection BP.
every 12 weeks [Ipsen Biopharm Ltd, 2010].
Insert the needle into the Dysport® vial – the partial vacuum will begin to pull the saline into the vial. Any
Although not routine clinical practice, electromyography (EMG) may assist in locating the most active muscles prior
remaining required saline should be expressed into the vial manually. Do not use the vial if no vacuum
to administration of Dysport® in patients with spasticity (post-stroke and paediatric) and some forms of cervical
is observed.
dystonia [Ipsen Biopharm Ltd, 2010].
Gently rotate the vial with the syringe still attached do not shake until the white substance is fully dissolved.
Avoid any air bubbles that could lead to protein denaturation.

Reconstituted Dysport® should be a clear, colourless solution that is free of particulate matter; otherwise, it
should not be injected.

Using the sterile syringe, slowly draw the reconstituted Dysport® solution from the bottom corner of the vial. Do
not invert the vial.

Reconstitution instructions are specific for each of the 300 and 500 U vials. Prior to administration, each 300 U and
500 U vial of lyophilised Dysport® is reconstituted with sodium chloride injection BP (0.9% wv) to yield a final
concentration that is specific for the use in each indication [TABLE 1] [Ipsen Biopharm Ltd, 2012].

TABLE 1. Dilution of Dysport®

Vial size (U) Diluent Concentration (U/mL)

300 1.5 mL 0.9% sodium chloride injection BP 200

300 0.6 mL 0.9% sodium chloride injection BP 500

124 125

500 2.5 mL 0.9% sodium chloride injection BP 200

500 1.0 mL 0.9% sodium chloride injection BP 500

mL: millilitre; U: Unit.

 17 Reconstitution and injection technique

TABLE 2. Reconstitution and site of administration of Dysport® in key indications

[Ipsen Biopharm Ltd, 2010]

Indication Dose when Injection site Injection

reconstituted frequency References
(per mL)
Ipsen Biopharm Ltd. 2010. Botulinum Toxin Type A-Hemagglutinin Complex (Dysport®, Azzalure®). Company
Cervical 500 U • Rotational torticollis: splenius capitis and sternomastoid ~16 weeks
Core Safety Information. Version 7.0.
dystonia (sternocleidomastoid); ipsilateral and contralateral,
respectively, to direction of chin/head rotation) muscles Ipsen Biopharm Ltd. 2012. Dysport®. Prescribing information.
• Laterocollis: ipsilateral splenius capitis and Ipsen Biopharm Ltd. 2012. Dysport®. Investigator’s brochure. Version 10.0.
sternomastoid muscles; also trapezoid or levator
scapulae muscles for shoulder elevation
• Retrocollis: splenius capitis muscles
• Other forms: dependent on specialist knowledge and
EMG to locate active muscles

Blepharospasm 200 U • Upper and lower orbicularis oculi muscles and ~12 weeks
and hemifacial frontalis muscle if spasms interfere with vision; avoid
spasm the levator palpebrae superioris

Adult spasticity 500 U • Arm: five muscles (flexor digitorum profundus, flexor ~16 weeks
post-stroke or digitorum superficialis, flexor carpi ulnaris, flexor
local carpi radialis, biceps brachii (BB); injected into one
symptomatic site except for BB (two sites)
treatment • Leg: gastrocnemius and soleus muscles; also consider
tibialis posterior muscle

Moderate-to- 200 U • Five sites (10 U each) into the corrugator (central Depends
severe part) and procerus muscles; avoid the levator on individual
glabellar lines palpebrae superioris patient
• Remove makeup and disinfect skin before response
administration

Paediatric 500 U • Dynamic equinus foot deformity: gastrocnemius ~16 weeks

spasticity* muscle; also consider soleus and tibialis posterior (dynamic
muscles equinus foot
• Local symptomatic treatment: gastrocnemius muscle; deformity) /
initial 5 U/kg BW dose into the two heads of the muscle as required to
maintain
126 response (local 127
symptomatic
treatment)

Axillary 200 U • Ten sites per axilla Individual

hyperhidrosis • Determine area using iodine-starch test; disinfect basis
axillae before administration

BB: biceps brachii: EMG: electromyography; Kg: kilogram; U: Unit.

*Paediatric dynamic equinus foot deformity due to spasticity associated with cerebral palsy (≥2 years of age) and paediatric lower limb
spasticity (≥2 years of age).
 18 Site of injection / Recommended dose per muscle

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 18 Site of injection / Recommended dose per muscle

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 19 Local labeling

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 17 Local labeling

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134 135
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