Dysport

Dysport

Manufacturer:

Ipsen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Clostridium botulinum type A toxin-haemagglutinin complex.
Description
Each vial of powder for injection contains Clostridium botulinum type A toxin-haemagglutinin complex 500 units*; Clostridium botulinum type A toxin-haemagglutinin complex 300 units*.
* One unit (U) is defined as the median lethal intraperitoneal dose in mice.
Excipients/Inactive Ingredients: Human albumin, Lactose.
Action
Pharmacotherapeutic Group: Other muscle relaxants, peripherally acting agents. ATC code: M03AX01.
Pharmacology: Pharmacodynamics: Clostridium botulinum type A toxin-haemagglutinin complex blocks peripheral cholinergic transmission at the neuromuscular junction by a presynaptic action at a site proximal to the release of acetylcholine. The toxin acts within the nerve ending to antagonise those events that are triggered by Ca2+ which culminate in transmitter release. It does not affect postganglionic cholinergic transmission or postganglionic sympathetic transmission.
The action of toxin involves an initial binding step whereby the toxin attaches rapidly and avidly to the presynaptic nerve membrane. Secondly, there is an internalisation step in which toxin crosses the presynaptic membrane, without causing onset of paralysis. Finally the toxin inhibits the release of acetylcholine by disrupting the Ca2+ mediated acetylcholine release mechanism, thereby diminishing the endplate potential and causing paralysis.
Recovery of impulse transmission occurs gradually as new nerve terminals sprout and contact is made with the post synaptic motor endplate, a process which takes 6 - 8 weeks in the experimental animal.
Focal spasticity in adults: Upper limb: The efficacy and safety of Dysport for the treatment of upper limb spasticity was evaluated in a randomized, multi-centre, double-blind, placebo-controlled study that included 238 patients (159 Dysport and 79 placebo) with upper limb spasticity who were at least 6 months post-stroke (90%) or post-traumatic brain injury (10%). The primary targeted muscle group (PTMG) was the extrinsic finger flexors (56%), followed by the elbow (28%) and wrist flexors (16%).
The primary efficacy variable was the PTMG muscle tone at week 4, as measured by the Modified Ashworth Scale (MAS), a 5 point scale ranging from 0 (no increase in muscle tone) to 4 (affected in part[s] rigid in flexion or extension) and the first secondary endpoint was the Physician Global Assessment (PGA) of response to treatment (a 9 point scale ranging from -4 [markedly worse], through 0 [no change], to +4 [markedly improved]). The main results achieved at Week 4 and Week 12 are shown as follows: (See Table 1.)

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The Principal Target of Treatment (PTT) of the Disability Assessment Scale [DAS] was used to investigate the effect of treatment on functional impairment (passive function). Although some improvement in the mean change from baseline at Week 4 in the Dysport groups did not reach statistical significance compared to placebo, the proportion of DAS score responders (subjects achieving at least a one grade improvement) for the PTT was significantly higher at the 1000U dose as shown as follows. (See Table 2.)

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In addition, statistically significant improvements in spasticity (grade and angle) assessed by the Tardieu scale, in the active range of motion of the fingers, wrist or elbow, and in ease of applying a splint by the subject were observed, especially at the 1000U dose. However, there was no effect of treatment shown on the active function, as assessed by the Modified Frenchay Score, and on quality of life EQ5D or SF-36 questionnaires.
Lower limb affecting the ankle joint: The efficacy and safety of Dysport for the treatment of lower limb spasticity was evaluated in a pivotal randomised, multi-centre, double-blind, placebo-controlled study that included 385 post-stroke and brain injury patients (255 Dysport and 130 placebo-treated subjects) with lower limb spasticity primarily affecting the ankle joint. Two doses of Dysport were evaluated for efficacy; Dysport 1000U (N = 125), Dysport 1500U (N = 128) against Placebo (N =128). The primary target muscle group was the gastrocnemius - soleus complex (GSC). The primary end point was Modified Ashworth Scale (MAS) score assessed at the ankle joint (with the knee extended) at week 4.
Dysport was divided between the GSC and at least one other distal or proximal lower limb muscle according to clinical presentation.
When assessing the primary endpoint, MAS at the ankle with the knee extended (involving all plantar flexors), statistically significant improvement was observed for 1500U. When assessing MAS at the ankle with the knee flexed (involving all plantar flexors except the gastrocnemius), statistically significant improvement was observed for both 1000U and 1500U. (See Table 3.)

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Spasticity assessment using the Tardieu Scale (TS) showed that there were statistically significant improvements in spasticity grade at Weeks 4 to 20 in the Dysport 1500U group and at Weeks 4 to 12 in the Dysport 1000U group. In addition it showed statistically significant differences in Angle of Catch at Week 1 and 16, favouring the higher dose of Dysport.
Based on post hoc analysis due to non-normality of PGA data, Dysport treatment was also associated with statistically significant clinical improvement at both doses as measured by the Physician Global Assessment (PGA) Score.
Numerical improvement in ankle dorsiflexion for the higher Dysport dose was seen with the change peaking at 4 weeks post administration.
Additional endpoints such as reduction in pain, using walking aids and quality of life measures did not show statistically significant improvement.
On completion of this study, 345 patients entered an open-label extension study in which re-treatment with Dysport 1000U or 1500U was determined by clinical need.
This long term follow up study confirmed a prolonged treatment effect on spasticity related outcome measures following repeated injections.
Improvements in efficacy parameters (MAS, PGA and TS) seen after 4 weeks of double blind treatment with Dysport in the lower limb were maintained over repeated treatment.
Improvements in 10-m walking speed (comfortable and maximal, with or without shoes) were observed, which increased with successive treatment cycles.
No significant improvements in lower limb pain using the SPIN scale, use of walking aids or quality of life measures were observed.
Blepharospasm: Three Dysport doses were investigated over 1 treatment cycle in a clinical study.
Efficacy was measured by the medians of differences in the Percentage of Normal Activity (PNA) values (derived from the Blepharospasm Disability Scale) between each treatment group and placebo. A dose-dependent improvement in blepharospasm was evident with Dysport dose, with all treatment groups being superior to placebo. (See Table 4.)

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For the 40 units, 80 units and 120 units Botulinum Toxin Type A treatment groups, the medians of the changes from baseline in PNA values were statistically significantly higher compared to those in placebo group at weeks 4, 8, and 12.
A statistically significant difference compared to placebo group was also observed for the 80 units and 120 units Botulinum Toxin Type A treatment groups at week 16, indicating a greater duration of response at the 80 units and 120 units doses.
The incidence of related Treatment Emergent Adverse Events (TEAEs), specifically ptosis, was higher in the Botulinum Toxin Type A treatment groups than in the placebo treatment group and was dose-dependent with greater incidence seen at higher Dysport doses. See table as follows: (See Table 5.)

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Dynamic equinus foot deformity due to focal spasticity in ambulant paediatric cerebral palsy patients, two years of age or older: A double-blind, placebo-controlled multicentre study (Study Y-55-52120-141) was conducted in children with dynamic equinus foot deformity due to spasticity in children with cerebral palsy. A total of 235 botulinum toxin naïve or non-naïve patients with a Modified Ashworth Score (MAS) of grade 2 or greater were enrolled to receive Dysport 10 units/kg/leg, Dysport 15 units/kg/leg or placebo. Forty one percent of patients were treated bilaterally resulting in a total Dysport dose of either 20 units/kg or 30 units/kg. The primary efficacy variable was the mean change from baseline in MAS in ankle plantar flexors at Week 4. Secondary efficacy variables were the mean Physicians Global Assessment (PGA) score and Mean Goal Attainment Scaling (GAS) score at Week 4. Patients were followed up for at least 12 weeks post-treatment and up to a maximum of 28 weeks. On completion of this study, patients were offered entry into an open-label extension study (Study Y-55-52120-147). (See Table 6.)

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Improvement in the spasticity of the ankle plantar flexors was observed, as assessed by the Tardieu scale. The spasticity grade (Y) was statistically significantly improved compared to placebo for both the 10 units/kg/leg and 15 units/kg/leg Dysport treatment groups at Week 4 and Week 12, and the angle of catch (Xv3) was significant for the 10 units/kg/leg Dysport group at Week 12 and at both Week 4 and Week 12 for the 15 units/kg/leg Dysport group.
Both Dysport treatment groups, 10 units/kg/leg and 15 units/kg/leg, demonstrated a significant improvement from baseline in the Observational Gait Scale (OGS) overall score at Week 4 when compared to placebo and a statistically significantly higher proportion of patients were treatment responders for initial foot contact on the OGS at Week 4 and Week 12.
Parents completed the condition-specific Module for cerebral palsy for the Paediatric Quality of Life Inventory. There was a statistically significant improvement from baseline in fatigue at Week 12 in the Dysport 10 units/kg/leg and 15 units/kg/leg Dysport treatment groups compared to placebo. No other statistically significant improvements were observed in the other subscales.
On completion of this study, 216 patients entered an open-label extension study (Y-55-52120-147) where they could receive re-treatment based on clinical need. Both distal (gastrocnemius, soleus and tibialis posterior) and proximal (hamstrings and hip adductors) muscles were permitted to be injected, including multilevel injections. Efficacy was observed over repeated treatment sessions for up to 1 year as assessed by MAS, PGA and GAS.
Moderate to severe glabellar lines and lateral canthal lines: Glabellar lines: In clinical studies, 2032 patients with moderate to severe glabellar lines have been treated at the recommended dose of 50U of Botulinum Toxin Type A. Of these, 305 were treated with 50U in two pivotal Phase III double-blind placebo-controlled studies and 1200 treated with 50U in a long-term open-label repeated dose Phase III study. The remaining patients were treated in supportive and dose-ranging studies.
The median time to onset of response was 2 to 3 days following treatment, with the maximum effect observed at day thirty. In both pivotal placebo-controlled phase III studies, Botulinum Toxin Type A injections significantly reduced the severity of glabellar lines for up to 4 months. The effect was still significant after 5 months in one of the two pivotal studies.
Thirty days after injection, the assessment of the investigators showed that 90% (273/305) of patients had responded to treatment (exhibited no or mild glabellar lines at maximum frown), compared to 3% (4/153) placebo-treated patients. Five months after injection, 17% (32/190) of patients treated with Botulinum Toxin Type A were still responding to treatment compared to 1% (1/92) of placebo treated patients in the concerned study. The patients' own assessment at maximum frown after thirty days gave a response rate of 82% (251/305) for those treated with Botulinum Toxin Type A and 6% (9/153) for those treated with placebo. The proportion of patients exhibiting a two-grade improvement according to the investigator assessment at maximum frown, was 77% (79/103) in the one pivotal Phase III study where this was assessed.
A subset of 177 patients had moderate or severe glabellar lines at rest prior to treatment. Assessment by investigators of this population, thirty days after treatment, showed that 71% (125/177) of Botulinum Toxin Type A-treated patients were considered responders versus 10% (8/78) of placebo treated patients.
The long-term repeat dose open-label study showed that the median time to onset of response of 3 days was maintained across repeated dose cycles. The responder rate at maximum frown as determined by the investigator at day 30 was maintained over repeated cycles (ranging between 80% and 91% over the 5 cycles). The responder rate at rest over repeated dose cycles was also consistent with the single dose studies, with 56% to 74% of Botulinum Toxin Type A-treated patients considered by investigators to be responders thirty days after treatment.
Lateral canthal lines: In clinical studies, 308 patients with moderate to severe lateral canthal lines at maximum smile have been treated at the recommended dose of 30 units per side in double-blind studies. Of these, 252 were treated in a Phase III double-blind placebo controlled study and 56 patients were treated in a double-blind Phase II dose-ranging study.
In the phase III study, Botulinum Toxin Type A injections significantly reduced the severity of lateral canthal lines compared with placebo (p≤0.001) at 4, 8 and 12 weeks (assessed at maximum smile by the investigators). For the subjects' assessment of satisfaction with the appearance of their lateral canthal lines, there was a statistically significant difference between Botulinum Toxin Type A and placebo (p≤0.010) in favour of Botulinum Toxin Type A at 4, 8, 12 and 16 weeks.
The primary efficacy endpoint was at 4 weeks following injection: the assessment of the investigators showed that 47.2% (119/252) of patients had responded to treatment (exhibited no or mild lateral canthal lines at maximum smile), compared to 7.2% (6/83) placebo-treated patients.
In a post-hoc analysis, at the same time point, 4 weeks following injection, 75% (189/252) of Botulinum Toxin Type A treated patients had at least 1 grade improvement at maximum smile compared with only 19% (16/83) of placebo-treated subjects.
A total of 315 subjects entered the open label extension phase of the Phase III study in which they could be treated concomitantly for both lateral canthal lines and glabellar lines. Patients treated with Botulinum Toxin Type A in the double-blind and open label phases of the Phase III received a median of 3 treatments for lateral canthal lines. The median interval between injections for lateral canthal lines, which was largely determined by the protocol design, ranged from 85 to 108 days. The results showed that efficacy is maintained with repeated treatments over the period of one year.
The patient satisfaction levels at weeks 4, 16 and 52 show after the first treatment with Botulinum Toxin Type A that 165/252 subjects (65.5%) were either very satisfied or satisfied with the appearance of their LCLs.
At week 16, 4 weeks after either a second Botulinum Toxin Type A treatment for those randomised to Botulinum Toxin Type A in Part A or the first treatment for those randomised to placebo the proportion who were very satisfied or satisfied was 233/262 (89.0%). At week 52 when subjects could have had up to five cycles of Botulinum Toxin Type A treatment with the last one being at week 48 the proportion of very satisfied/satisfied subjects was 255/288 (84.7%).
No patient tested positive for toxin-neutralising antibodies after receiving repeated treatments with Botulinum Toxin Type A over one year.
Axillary hyperhidrosis: The efficacy and safety of Dysport for the treatment of Axillary Hyperhidrosis was evaluated in a multi-centre, randomised, double-blind clinical study that included 152 adult patients with Axillary Hyperhidrosis who had symptoms for greater than one year and had failed standard therapy. Patients were injected with 200U in one axilla and placebo into the other. Two weeks later patients were injected with 100U Botulinum Toxin Type A in the axilla previously injected with placebo.
At the primary end point i.e. two weeks after treatment with Botulinum Toxin Type A, efficacy was measured as PCF (Proportional Change Function of sweat production on gravimetric analysis mg/min) relative to baseline. The results are shown as follows: (See Table 7.)

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In the same study, absolute sweat production was a secondary endpoint: 200U Dysport treatment resulted in an average absolute sweat production decrease from 165 ± 112 mg/min to 24 ± 27 mg/min 2 weeks after injection, and 86.2% of patients achieved an absolute sweat rate of less than 50 mg/min. The 100U treatment resulted in an average absolute sweat production decrease from 143 ± 111 mg/min to 31 ± 48 mg/min 2 weeks after injection, and 83.4% of patients achieved an absolute sweat rate of less than 50 mg/min. The placebo treatment resulted in an average absolute sweat production decrease from 173 ± 131 mg/min to 143 ± 111 mg/min 2 weeks after injection, and 3.9% of patients achieved an absolute sweat rate of less than 50 mg/min.
Efficacy was observed for up to 48 weeks. Subsequent injections under a follow up open label study showed a similar decrease in sweating though there was some evidence that duration of effect may persist for longer in subsequent treatment cycles.
Pharmacokinetics: Pharmacokinetic studies with botulinum toxin pose problems in animals because of the high potency, the minute doses involved, the large molecular weight of the compound and the difficulty of labelling toxin to produce sufficiently high specific activity. Studies using I125 labelled toxin have shown that the receptor binding is specific and saturable, and the high density of toxin receptors is a contributory factor to the high potency. Dose and time responses in monkeys showed that at low doses there was a delay of 2 - 3 days with peak effect seen 5 - 6 days after injection. The duration of action, measured by changes of ocular alignment and muscle paralysis, varied between 2 weeks and 8 months. This pattern is also seen in man, and is attributed to the process of binding, internalisation and changes at the neuromuscular junction.
Toxicology: Pre-clinical safety data: In a chronic toxicity study performed in rats, up to 12 units/animal, there was no indication of systemic toxicity. Reproductive toxicity studies in pregnant rats and rabbits given Clostridium botulinum type A toxin-haemagglutinin complex by daily intramuscular injection, at doses of 6.6 units/kg (79 units/kg total cumulative dose) and 3.0 units/kg (42 units/kg total cumulative dose) in rats and rabbits respectively, did not result in embryo/foetal toxicity. Implantation losses at maternally toxic doses were observed at higher doses in both species. Clostridium botulinum type A toxin-haemagglutinin complex demonstrated no teratogenic activity in either rats or rabbits and no effects were observed in the pre- and postnatal study on the F1 generation in rats. Fertility of male and female rats was decreased due to reduced mating secondary to muscle paralysis at doses of 29.4 units/kg weekly in males and increased implantation loss at 20 units/kg weekly in females (see Use in Pregnancy & Lactation).
In a pivotal single dose study, juveniles showed a slight delay in sexual maturation (not observed in the repeat dose study), an effect associated with decreased body weight, but subsequent mating performance and fertility were unaffected. In a pivotal repeated dose juvenile study, rats treated weekly from the age of weaning on Postnatal Day 21 up to 13 weeks of age comparable to children of 2 years old, to young adulthood (11 administrations over 10 weeks, up to total dose of approximately 33 units/kg) do not show adverse effects on postnatal growth (including skeletal evaluation), reproductive, neurological and neurobehavioral development.
The effects in reproduction, juvenile and chronic toxicity non-clinical studies were limited to changes in injected muscles related to the mechanism of action of Clostridium botulinum type A toxin-haemagglutinin complex.
There was no ocular irritation following administration of Clostridium botulinum type A toxin-haemagglutinin complex into the eyes of rabbits.
Indications/Uses
Dysport is indicated for symptomatic treatment of focal spasticity of: Upper limbs in adults; Lower limbs in adults affecting the ankle joint due to stroke or traumatic brain injury (TBI); Dynamic equinus foot deformity in ambulant paediatric cerebral palsy patients, two years of age or older.
Dysport is indicated in adults for symptomatic treatment of: Spasmodic torticollis; Blepharospasm; Hemifacial spasm; Axillary hyperhidrosis.
Dysport is indicated for the temporary improvement in the appearance of moderate to severe: Glabellar lines (vertical lines between the eyebrows) seen at maximum frown and/or; Lateral canthal lines (crow's feet lines) seen at maximum smile in adult patients under 65 years, when the severity of these lines has an important psychological impact on the patient.
Dosage/Direction for Use
The units of Dysport are specific to the preparation and are not interchangeable with other preparations of botulinum toxin.
Training: Dysport should only be administered by appropriately trained physicians.
For instructions on reconstitution of the powder for solution for injection, handling and disposal of vials, refer to Special precautions for disposal and other handling under Cautions for Usage.
Focal spasticity in adults: Upper limb: Posology: Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, and/or adverse event history with Dysport. In clinical trials, doses of 500 Units and 1000 Units were divided among selected muscles at a given treatment session as shown as follows. No more than 1 mL should generally be administered at any single injection site. The total dose should not exceed 1000 units at a given treatment session. (See Table 8.)

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Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique, e.g. electromyography, electrical stimulation or ultrasound is recommended to target the injection sites.
Clinical improvement may be expected one week after injection and may last up to 20 weeks. Injections may be repeated every 12-16 weeks or as required to maintain response, but not more frequently than every 12 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Dysport and muscles to be injected.
Lower limb spasticity affecting the ankle joint: Posology: In clinical trials, doses of 1000U and 1500U were divided among selected muscles.
The exact dosage in initial and sequential treatment sessions should be tailored to the individual based on the size and number of muscles involved, the severity of the spasticity, also taking into account the presence of local muscle weakness and the patient's response to previous treatment. However the total dose should not exceed 1500U.
No more than 1 mL should generally be administered at any single injection site. (See Table 9.)

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The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Dysport and muscles to be injected.
Although actual location of the injection sites can be determined by palpation, the use of injection guiding techniques, e.g. electromyography, electrical stimulation or ultrasound are recommended to help accurately target the injection sites.
Repeat Dysport treatment should be administered every 12 to 16 weeks, or longer as necessary, based on return of clinical symptoms but no sooner than 12 weeks after the previous injection.
Upper and Lower limbs: If treatment is required in the upper and lower limbs during the same treatment session, the dose of Dysport to be injected in each limb should be tailored to the individual's need according to the relevant posology and without exceeding a total dose of 1500U.
Children: The safety and effectiveness of Dysport in the treatment of upper limb spasticity in children have not been demonstrated.
Elderly patients (≥65 years): Clinical experience has not identified differences in response between the elderly and younger adult patients. In general, elderly patients should be observed to evaluate their tolerability of Dysport, due to the greater frequency of concomitant disease and other drug therapy.
Method of administration: When treating focal spasticity affecting the upper and lower limbs in adult, Dysport is reconstituted with sodium chloride injection B.P. (0.9% w/v) to yield a solution containing either 100 units per ml, 200 units per ml or 500 units per ml of Dysport (see Special precautions for disposal and other handling under Cautions for Usage).
Dysport is administered by intramuscular injection into the muscles as described previously.
Dynamic equinus foot deformity due to focal spasticity in ambulant paediatric cerebral palsy patients, two years of age or older: Posology: Dosing in initial and sequential treatment sessions should be tailored to the individual based on the size, number and location of muscles involved, severity of spasticity, the presence of local muscle weakness, the patient's response to previous treatment, and/or adverse event history with botulinum toxins. For treatment initiation, consideration should be given to start with a lower dose.
The maximum total dose of Dysport administered per treatment session must not exceed 15 units/kg for unilateral lower limb injections or 30 units/kg for bilateral injections. In addition the total Dysport dose per treatment session must not exceed 1000 units or 30 units/kg, whichever is lower. The total dose administered should be divided between the affected spastic muscles of the lower limb(s). When possible the dose should be distributed across more than 1 injection site in any single muscle.
No more than 0.5ml of Dysport should be administered in any single injection site. See table as follows for recommended dosing: (See Table 10.)

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Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique, e.g. electromyography, electrical stimulation or ultrasound is recommended to target the injection sites.
Repeat Dysport treatment should be administered when the effect of a previous injection has diminished, but no sooner than 12 weeks after the previous injection. A majority of patients in clinical studies were retreated between 16-22 weeks; however some patients had a longer duration of response, i.e. 28 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of Dysport and muscles to be injected.
Clinical improvement may be expected within two weeks after injection.
Method of administration: When treating spasticity associated with cerebral palsy in children, Dysport is reconstituted with sodium chloride injection B.P. (0.9% w/v) and is administered by intramuscular injection as detailed previously (see also Special precautions for disposal and other handling under Cautions for Usage).
Spasmodic torticollis: Posology: The doses recommended are applicable to adults of all ages provided the adults are of normal weight with no evidence of reduced neck muscle mass. A lower dose may be appropriate if the patient is markedly underweight or in the elderly, where a reduced muscle mass may exist.
The initial recommended initial dose for the treatment of spasmodic torticollis is 500 units per patient given as a divided dose and administered into the two or three most active neck muscles.
On subsequent administration, the doses may be adjusted according to the clinical response and side effects observed. Doses within the range of 250-1000 units are recommended, although the higher doses may be accompanied by an increase in side effects, particularly dysphagia. The maximum dose administered must not exceed 1000 units.
Injections may be repeated approximately every 16 weeks or as required to maintain a response, but not more frequently than every 12 weeks.
For rotational torticollis distribute the 500 units by administering 350 units into the splenius capitis muscle, ipsilateral to the direction of the chin/head rotation and 150 units into the sternomastoid muscle, contralateral to the rotation.
For laterocollis, distribute the 500 units by administering 350 units into the ipsilateral splenius capitis muscle and 150 units into the ipsilateral sternomastoid muscle. In cases associated with shoulder elevation the ipsilateral trapezoid or levator scapulae muscles may also require treatment, according to visible hypertrophy of the muscle or electromyographic (EMG) findings. Where injections of three muscles are required, distribute the 500 units as follows, 300 units splenius capitis, 100 units sternomastoid and 100 units to the third muscle.
For retrocollis distribute the 500 units by administering 250 units into each of the splenius capitis muscles. Bilateral splenii injections may increase the risk of neck muscle weakness.
All other forms of torticollis are highly dependent on specialist knowledge and EMG to identify and treat the most active muscles. EMG should be used diagnostically for all complex forms of torticollis, for reassessment after unsuccessful injections in non complex cases, and for guiding injections into deep muscles or in overweight patients with poorly palpable neck muscles.
Children: The safety and effectiveness of Dysport in the treatment of spasmodic torticollis in children have not been demonstrated.
Method of administration: When treating spasmodic torticollis, Dysport is reconstituted with sodium chloride injection B.P. (0.9% w/v) to yield a solution containing 500 units per ml of Dysport (see Special precautions for disposal and other handling under Cautions for Usage).
Dysport is administered by intramuscular injection as described previously.
Blepharospasm and hemifacial spasm: Posology: In a dose ranging clinical trial on the use of Dysport for the treatment of benign essential blepharospasm, a dose of 40 units per eye was significantly effective. Doses of 80 units and 120 units per eye resulted in a longer duration of effect. However, the incidence of local adverse events, specifically ptosis, was dose related. In the treatment of blepharospasm and hemifacial spasm, the maximum dose used must not exceed a total dose of 120 units per eye.
An injection of 10 units (0.05ml) medially and 10 units (0.05ml) laterally should be made into the junction between the preseptal and orbital parts of both the upper (3 and 4) and lower orbicularis oculi muscles (5 and 6) of each eye. In order to reduce the risk of ptosis, injections near the levator palpebrae superioris should be avoided.
For injections into the upper lid the needle should be directed away from its centre to avoid the levator muscle. The relief of symptoms may be expected to begin within two to four days with maximal effect within two weeks. Injections should be repeated approximately every 12 weeks or as required to prevent recurrence of symptoms but not more frequently than every 12 weeks.
On such subsequent administrations, if the response from the initial treatment is considered insufficient, the dose per eye may need to be increased to: 60 units: 10 units (0.05mL) medially and 20 units (0.1mL) laterally; 80 units: 20 units (0.1mL) medially and 20 units (0.1mL) laterally; or up to 120 units: 20 units (0.1mL) medially and 40 units (0.2mL) laterally above and below each eye in the manner previously described. Additional sites in the frontalis muscle above the brow (1 and 2) may also be injected if spasms here interfere with vision.
In cases of unilateral blepharospasm the injections should be confined to the affected eye. Patients with hemifacial spasm should be treated as for unilateral blepharospasm. The doses recommended are applicable to adults of all ages including the elderly.
Children: The safety and effectiveness of Dysport in the treatment of blepharospasm and hemifacial spasm in children have not been demonstrated.
Method of administration: When treating blepharospasm and hemifacial spasm, Dysport is reconstituted with sodium chloride injection BP (0.9% w/v) to yield a solution containing 200 units per ml of Dysport (see Special precautions for disposal and other handling under Cautions for Usage).
Dysport is administered by subcutaneous injection medially and laterally into the junction between the preseptal and orbital parts of both the upper and lower orbicularis oculi muscles of the eyes as described previously.
Moderate to severe glabellar lines and/or lateral canthal lines: Posology: The treatment interval depends on the individual patient's response after assessment. Treatment interval with Dysport should not be more frequent than every three months.
Remove any make-up and disinfect the skin with a local antiseptic.
Intramuscular injections should be performed using a sterile 29-40 gauge needle. The recommended injection points for glabellar lines and lateral canthal lines are described as follows: Glabellar lines: The recommended dose is 50 units (0.25 ml of reconstituted solution) of Dysport to be divided into 5 injection sites, 10 units (0.05 ml of reconstituted solution) are to be administered intramuscularly, at right angles to the skin, into each of the 5 sites: 2 injections into each corrugator muscle and one into the procerus muscle near the nasofrontal angle.
The anatomical landmarks can be more readily identified if observed and palpated at maximum frown. Before injection, place the thumb or index finger firmly below the orbital rim in order to prevent extravasation below the orbital rim. The needle should be pointed upwards and medially during the injection.
In order to reduce the risk of ptosis: avoid injections near the levator palpebrae superioris muscle, particularly in patients with larger brow-depressor complexes (depressor supercilii); Injections into the corrugators muscle must be made into the central part of that muscle, at least 1 cm above orbital rim.
In clinical studies, an optimal effect, in glabellar lines, was demonstrated for up to 4 months after injection. Some patients were still responders at 5 months (see Pharmacology: Pharmacodynamics under Actions).
Lateral canthal lines: The recommended dose per side is 30 units (60 units for both sides, 0.30ml of reconstituted solution) of Dysport, to be divided into 3 injection sites; 10 units (0.05ml of reconstituted solution) are to be administered intramuscularly into each injection point.
Injection should be lateral (20-30° angle) to the skin and very superficial. All injection points should be at the external part of the orbicularis oculi muscle and sufficiently far from the orbital rim (approximately 1-2cm). The anatomical landmarks can be more readily identified if observed and palpated at maximal smile. Care must be taken to avoid injecting the zygomaticus major/minor muscles to avoid lateral mouth drop and asymmetrical smile.
General information: In the event of treatment failure or diminished effect following repeat injections, alternative treatment methods should be employed. In case of treatment failure after the first treatment session, the following approaches may be considered: Analysis of the causes of failure, e.g. incorrect muscles injected, inappropriate injection technique, and formation of toxin-neutralizing antibodies; Re-evaluation of the relevance of treatment with Dysport.
The efficacy and safety, of repeat injections of Dysport, has been evaluated in glabellar lines up to 24 months and up to 8 repeat treatment cycles and for lateral canthal lines up to 12 months and up to 5 repeat treatment cycles.
Children: The safety and effectiveness of Dysport in treating moderate to severe glabellar lines and lateral canthal lines in individuals under 18 years of age have not been demonstrated.
Method of administration: For moderate to severe glabellar lines or lateral canthal lines, Dysport is reconstituted with sodium chloride injection BP (0.9% w/v) to yield a solution containing 200 units per ml of Dysport (see Special precautions for disposal and other handling under Cautions for Usage). Dysport is administered by intramuscular injection as described previously.
Axillary hyperhidrosis: Posology: The recommended initial dose is 100 units per axilla (armpit). If the desired effect is not achieved, up to 200 units per axilla may be administered in subsequent injections. The maximum dose administered should not exceed 200 unit per axilla. The injection site must be determined in advance by using the iodine starch test. Both armpits must be cleaned thoroughly and disinfected. Then intradermal injections should be administered in ten sites, whereby each site receives 10 units, thus 100 units per armpit. The timescale for further application should be determined on an individual basis, dependent on when the sweat secretion on the patient has returned to previous levels, but not more frequently than every 12 weeks. There are indications of a cumulative effect with repeated dosages, so that the timescale of each treatment of a particular patient should be individually determined.
Children: The safety and effectiveness of Dysport in treating axillary hyperhidrosis in children has not been demonstrated.
Method of administration: When treating axillary hyperhidrosis, Dysport is reconstituted with 2.5ml of sodium chloride solution (0.9% w/v) to yield a solution containing 200 units per ml of Dysport. In treating axillary hyperhidrosis, Dysport is administered by intradermal injections on ten sites.
Treatment of Upper Limb Spasticity in Pediatric Patients: The safety and effectiveness of Dysport in the treatment of upper limb spasticity in pediatric patients has not been demonstrated.
Method of administration: When treating lower limb spasticity in pediatric patients, two years of age and older, Dysport is reconstituted with sodium chloride injection B.P. (0.9% w/v) and is administered by intramuscular injection as detailed previously (see also Special precautions for disposal and other handling under Cautions for Usage).
Overdosage
Excessive doses may produce distant and profound neuromuscular paralysis. Overdose could lead to an increased risk of the neurotoxin entering the bloodstream and may cause complications associated with the effects of oral botulinum poisoning (e.g. dysphagia and dysphonia). Respiratory support may be required where excessive doses cause paralysis of respiratory muscles. There is no specific antidote; antitoxin should not be expected to be beneficial and general supportive care is advised. In the event of overdose the patient should be medically monitored for any signs and/or symptoms of excessive muscle weakness or muscle paralysis. Symptomatic treatment should be instigated if necessary.
Symptoms of overdose may not present immediately following injection. Should accidental injection or oral ingestion occur the patient should be medically supervised for several weeks for signs and/or symptoms of excessive muscle weakness or muscle paralysis.
Contraindications
Known hypersensitivity to the active substance or to any excipients listed in Description.
Special Precautions
Side effects related to spread of toxin distant from the site of administration have been reported (see Adverse Reactions) which, in some cases, was associated with dysphagia, pneumonia and/or significant debility resulting, very rarely, in death. Patients treated with therapeutic doses may present with excessive muscle weakness. The risk of occurrence of such undesirable effects may be reduced by using the lowest effective possible dose and by not exceeding the maximum recommended dose.
Dysport should only be used with caution under close supervision in patients with subclinical or clinical evidence of marked defective neuro-muscular transmission (eg myasthenia gravis). Such patients may have an increased sensitivity to agents such as Dysport, which may result in excessive muscle weakness with therapeutic doses. Patients with underlying neurological disorders are at increased risk of this side effect.
Caution should be exercised when treating adult patients especially the elderly, with focal spasticity affecting the lower limbs, who may be at increased risk of fall. In placebo-controlled clinical studies, where patients were treated for lower limb spasticity, 6.3% and 3.7% of patients experienced a fall in the Dysport and placebo groups, respectively.
Very rare cases of death, occasionally in the context of dysphagia, pneumopathy (including but not limited to dyspnea, respiratory failure, respiratory arrest) and/or in patients with significant asthenia have been reported following treatment with botulinum toxin A or B. Patients with disorders resulting in defective neuromuscular transmission, difficulty in swallowing or breathing are more at risk of experiencing these effects. In these patients, treatment must be administered under the control of a specialist and only if the benefit of treatment outweighs the risk.
Dysport should be administered with caution to patients with pre-existing swallowing or breathing problems as these can worsen following the distribution of the effect of toxin into the relevant muscles. Aspiration has occurred in rare cases and is a risk when treating patients who have a chronic respiratory disorder.
The recommended posology and frequency of administration for Dysport must not be exceeded (see Dosage & Administration).
Patients and their care-givers must be warned of the necessity to seek immediate medical treatment in case of swallowing, speech or respiratory problems.
For the treatment of spasticity associated with cerebral palsy in children, Dysport should only be used in children of 2 years of age or over.
Dysport should not be used to treat spasticity in patients who have developed a fixed contracture.
As with any intramuscular injection, Dysport should only be used where strictly necessary in patients with prolonged bleeding times, infection or inflammation at the proposed site(s) of injection.
Dysport should only be used to treat a single patient, during a single session. Specific precautions must be taken during the preparation and administration of the product (see Dosage & Administration) and for the inactivation and disposal of any unused reconstituted solution (see Special precautions for disposal and other handling under Cautions for Usage).
Antibody formation to botulinum toxin has been noted rarely in patients receiving Dysport. Clinically, neutralizing antibodies might be suspected by a substantial deterioration in response to therapy and/or the need for consistent use of increased doses.
Careful consideration should be given before the injection of patients who have experienced a previous allergic reaction to a product containing Dysport. The risk of a further allergic reaction must be considered in relation to the benefit of treatment.
When treating glabellar lines, it is essential to study the patient's facial anatomy prior to administration. Facial asymmetry, ptosis, excessive dermatochalasis, scarring and any alterations to this anatomy as a result of previous surgical interventions should be taken into consideration. Caution should be taken when the targeted muscle shows excessive weakness of atrophy.
The safety and effectiveness of Dysport injected into proximal muscles of the lower limb for the treatment of spasticity in pediatric patients has not been established.
Effects on ability to drive and use machines: There is a potential risk of muscle weakness or visual disturbances which, if experienced, may temporarily impair the ability to drive or operate machinery.
Use in Children: For the treatment of spasticity associated with cerebral palsy in children, Dysport should only be used in children of 2 years of age or over. Post-marketing reports of possible distant spread of toxin have been very rarely reported in paediatric patients with comorbidities, predominantly with cerebral palsy. In general, the dose used in these cases was in excess of that recommended (see Adverse Reactions).
There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in children with severe cerebral palsy after treatment with botulinum toxin, including following off-label use (e.g. neck area). Extreme caution should be exercised when treating paediatric patients who have significant neurologic debility, dysphagia, or have a recent history of aspiration pneumonia or lung disease. Treatment in patients with poor underlying health status should be administered only if the potential benefit to the individual patient is considered to outweigh the risks.
Use In Pregnancy & Lactation
Pregnancy: There are limited data from the use of Clostridium botulinum type A toxin-haemagglutinin complex in pregnant women. Studies in animals have shown reproductive toxicity at high doses causing maternal toxicity (see Pharmacology: Toxicology: Pre-clinical safety data under Actions).
Dysport should be used during pregnancy only if the benefit justifies any potential risk to the foetus. Caution should be exercised when prescribing to pregnant women.
Breast-feeding: It is not known whether Clostridium botulinum type A toxin-haemagglutinin complex is excreted in human milk. The excretion of Clostridium botulinum type A toxin-haemagglutinin complex in milk has not been studied in animals. The use of Clostridium botulinum type A toxin-haemagglutinin complex during lactation cannot be recommended.
Fertility: Studies in male and female rats have shown effects on fertility (see Pharmacology: Toxicology: Pre-clinical safety data under Actions).
Adverse Reactions
General: The frequency of adverse reactions reported in placebo-controlled trials after a single administration is defined as follows: Very common >1/10; Common >1/100, <1/10; Uncommon >1/1000, <1/100; Rare >1/10 000, < 1/1000.
Side effects related to spread of toxin distant from the site of administration have been reported such as dry mouth, exaggerated muscle weakness, dysphagia, aspiration/aspiration pneumonia, with fatal outcome in some very rare cases (see Precautions). Hypersensitivity reactions have also been reported post-marketing.
The following adverse reactions were seen in patients treated across a variety of indications including blepharospasm, hemifacial spasm, torticollis and spasticity associated with either cerebral palsy or stroke/TBI and axillary hyperhidrosis: (See Table 11.)

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Frequency of specific adverse reactions by indication: In addition, the following adverse reactions specific to individual indications were reported: Focal spasticity affecting the upper limbs: (See Table 12.)

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Focal spasticity affecting the lower limbs: (See Table 13.)

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Dynamic equinus foot deformity due to focal spasticity in ambulant paediatric cerebral palsy patients, two years of age or older: (See Table 14.)

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Spasmodic torticollis: (See Table 15.)

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Dysphagia appeared to be dose related and occurred most frequently following injection into the sternomastoid muscle. A soft diet may be required until symptoms resolve. These side effects may be expected to resolve within two to four weeks.
Blepharospasm and hemifacial spasm: (See Table 16.)

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Side effects may occur due to deep or misplaced injections of Dysport temporarily paralysing other nearby muscle groups.
Moderate to Severe Glabellar lines: (See Table 17.)

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Moderate to severe lateral canthal lines: (See Table 18.)

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Axillary hyperhidrosis: The following adverse events were observed in patients treated with Dysport for hyperhidrosis. (See Table 19.)

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Drug Interactions
The effects of botulinum toxin may be potentiated by drugs interfering either directly or indirectly with neuromuscular function (e.g. aminoglycosides, curare-like non-depolarising blockers, muscle relaxants) and such drugs should be used with caution in patients treated with botulinum toxin due to the potential for undesirable effects.
Caution For Usage
Special precautions for disposal and other handling: When preparing and handling Dysport solutions, the use of gloves is recommended. If Dysport dry powder or reconstituted solution should come into contact with the skin or mucous membranes, they should be washed thoroughly with water.
Instructions for reconstitution: The exposed central portion of the rubber stopper should be cleaned with alcohol immediately prior to piercing the septum. A sterile 23 or 25 gauge needle should be used.
Each vial is for single use only.
Reconstitution instructions are specific for each of the 300 U vial and the 500 U vial. These volumes yield concentrations specific for the use for each indication. (See Table 20.)

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For pediatric cerebral palsy spasticity, which is dosed using unit per body weight, further dilution may be required to achieve the final volume for injection.
Appearance of product after reconstitution: A clear, colorless solution, free from particulate matter.
Disposal: Immediately after treatment of the patient, any residual Dysport which may be present in either vial or syringe should be inactivated with dilute hypochlorite solution (1% available chlorine).
Spillage of Dysport should be wiped up with an absorbent cloth soaked in dilute hypochlorite solution.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Storage
Unopened vial: Store in a refrigerator (2°C - 8°C).
Do not freeze.
Reconstituted solution: For storage conditions after reconstitution of the medicinal product, see Shelf life as follows.
Shelf life: Unopened vial: 2 years.
Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C.
From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
MIMS Class
ATC Classification
M03AX01 - botulinum toxin ; Belongs to the class of other agents used as peripherally-acting muscle relaxants.
Presentation/Packing
Powd for inj (vial) 300 U x 1's. 500 U x 1's.
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