INFORMATION FOR HEALTH PROFESSIONALS
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| Active Constituent | Per Vial |
|---|---|
| Clostridium botulinum type A toxin-haemagglutinin complex | 500U* |
| Other Constituents | |
| Albumin solution 20% | 125 mcg |
| Lactose | 2.5 mg |
One unit (U) is defined as the median lethal intraperitoneal dose in mice.
Dysport is a white lyophilised powder for reconstitution contained in Type 1 glass vials 3ml of capacity, with 13mm chlorbutyl freeze-drying closures oversealed by 13mm aluminium overseals with centre hole, crimped over.
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.
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.
Dysport is indicated for the treatment of:
Glabellar lines.
Spasticity of the arm in patients following a stroke
Dynamic equinus foot deformity due to spasticity in paediatric cerebral palsy patients, two years of age or older, only in hospital specialist centres with appropriately trained personnel.
Spasmodic torticollis in adults
Blepharospasm in adults
Hemifacial spasm in adults
The safety and effectiveness of Dysport in the treatment of arm spasticity post-stroke, spasmodic torticollis, blepharospasm, or hemifacial spasm in children have not been demonstrated.
Dysport is also indicated for the symptomatic treatment of axillary hyperhidrosis (excessive sweating).
The units of Dysport are specific to the preparation and are not interchangeable with other preparations of botulinum toxin.
The dosage is dependant on the severity of the lines and the specific muscle being treated.
For the corrugator and procerus muscles 40 to 60 units divided between injection sites as follows:
8 to 12 units in each of 5 sites, 2 in each corrugator muscle and 1 in the procerus muscle for a total dose of 60 units
Improvement of severity of glabellar lines generally occurs within 72 hours after treatment and persists for 3 to 6 months.
The exposed central portion of the rubber stopper should be cleaned with alcohol immediately prior to piercing the septum. A sterile 30-gauge needle should be used.
When treating glabellar lines, Dysport is reconstituted with 2.5ml of sodium chloride injection BP (0.9%) to yield a solution containing 10 units of Dysport per 0.05 ml. Dysport is administered by intramuscular or subcutaneous injection.
The recommended dose is 1000 units, distributed amongst the following five muscles:
flexor digitorum profundus (FDP), flexor digitorum superficialis (FDS), flexor carpi ulnaris (FCU), flexor carpi radialis (FCR) and biceps brachii (BB). The sites of injection should be guided by standard locations used for electormyography, although actual location of the injection site will be determined by palpation. All muscles except the biceps brachii will be injected at one site, whilst the biceps will be injected at two sites. The recommended distribution of dose is given below:
| BB (units) | FDP (units) | FDS (units) | FCU (units) | FCR (units) | Total Dose (units) | |
|---|---|---|---|---|---|---|
| Dysport | 300-400 | 150 | 150-250 | 150 | 150 | 1,000 |
The starting dose should be lowered if there is evidence to suggest that this
dose may result in excessive weakness of the target muscles, such as for
patients whose target muscles are small, where the BB muscle is not to be
injected or patients who are to be administered multi-level injections. Clinical
improvement may be expected within two weeks after injection. Injections may be
repeated approximately every 16 weeks, or as required to maintain response, but
not more frequently than every 8 weeks.
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.
Dysport is reconstituted with 1.0ml of sodium chloride injection B.P. (0.9%) to yield a solution containing 500 units per ml of Dysport. Dysport is administered by intramuscular injection into the five muscles detailed above when treating arm spasticity.
The initial recommended dose is 20 units/kg body weight given as a divided dose between both calf muscles. If only one calf is affected, a dose of 10 units/kg bodyweight should be used. Consideration should be given to lowering this starting dose if there is evidence to suggest that this dose may result in excessive weakness of the target muscles, such as for patients whose target muscles are small or patients who require concomitant injections to other muscle groups. Following evaluation of response to the starting dose subsequent treatment may be titrated within the range 10 units/kg and 30 units/kg divided between both legs. The maximum dose administered must not exceed 1000 units/patient.
Administration should primarily be targeted to the gastrocnemius, although injections of the soleus and injection of the tibialis posterior should also be considered. The use of electromyography (EMG) is not routine clinical practice but may assist in identifying the most active muscles.
Clinical improvement may be expected within two weeks after injection. Injections may be repeated approximately every 16 weeks or as required to maintain response, but not more frequently than every 8 weeks.
The exposed central portion of the rubber stopper should be cleaned with alcohol immediately prior to piercing the septum. A sterile 23 or 25 gauge needle should be used.
When treating paediatric cerebral palsy spasticity, Dysport is reconstituted with 1.0ml of sodium chloride injection B.P. (0.9%) to yield a solution containing 500 units per ml of Dysport. Dysport is administered by intramuscular injection into the calf muscles when treating spasticity.
Adults and elderly: The doses recommended for torticollis are applicable to adults of all ages providing the adults are of normal weight with no evidence of low neck muscle mass. A reduced dose may be appropriate if the patient is markedly underweight or in the elderly, where reduced muscle mass may exist.
The initial recommended dose for the treatment of spasmodic torticollis is 500 units per patient given as a divided dose and administered to the two or three most active neck muscles.
For rotational torticollis distribute the 500 units by administering 350 units into the splenius capitis muscle, ipsilateral to the direction of the chin/head rotation and 150 units into the sternomastoid muscle, contralateral tot he 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. This may be followed by bilateral trapezius injections (up to 250 units per muscle) after 6 weeks, if there is insufficient response. Bilateral splenii injections may increase the risk of neck muscle weakness.
All other forms of torticollis are highly dependent on specialist knowledge and EMG to identify and treat the most active muscles. EMG should be used diagnostically for all complex forms of torticollis, for reassessment after unsuccessful injections in non complex cases, and for guiding injections into deep muscles or in overweight patients with poorly palpable neck muscles.
On subsequent administration, the doses may be adjusted according to the clinical response and side effects observed. Doses within the range of 250-1000 units are recommended, although the higher doses may be accompanied by an increase in side effects, particularly dysphagia. Doses above 1000 units are not recommended. The relief of symptoms of torticollis may be expected within a week after the injection. Injections should be repeated approximately every eight to twelve weeks or as required to prevent recurrence of symptoms.
Children: The safety and effectiveness of Dysport in the treatment of spasmodic torticollis in children have not been demonstrated.
The exposed central portion of the rubber stopper should be cleaned with alcohol immediately prior to piercing the septum. A sterile 23 or 25 gauge needle should be used.
When treating spasmodic torticollis Dysport is reconstituted with 1ml of sodium chloride injection B.P. (0.9%) to yield a solution containing 500 units per ml of Dysport. Dysport is administered by intramuscular injection as above when treating spasmodic torticollis.
Adults and elderly: In the treatment of bilateral blepharospasm the recommended initial dose is 120 units per eye.
Injection of 0.1ml (20 units) should be made medially and of 0.2ml (40 units) should be made laterally into the junction between the preseptal and orbital parts of both the upper and lower orbicularis oculi muscles of each eye.
For injections into the upper lid the needle should be directed away from its centre to avoid the levator muscle. A diagram to aid placement of these injections is provided. The relief of symptoms may be expected to begin within two to four days with maximal effect within two weeks.
Injections should be repeated approximately every eight weeks or as required to prevent recurrence of symptoms. On such subsequent administrations the dose may need to be reduced to 80 units per eye - viz -: 0.1ml (20 units) medially and 0.1ml (20 units) laterally above and below each eye in the manner previously described. The dose may be further reduced to 60 units per eye by omitting the medial lower lid injection.
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.
The exposed central portion of the rubber stopper should be cleaned with alcohol immediately prior to piercing the septum. A sterile 23 or 25 gauge needle should be used.
When treating blepharospasm and hemifacial spasm Dysport is reconstituted with 2.5ml of sodium chloride injection BP (0.9%) to yield a solution containing 200 units per ml of Dysport. Dysport is administered by subcutaneous injection medially and laterally into the junction between the preseptal and orbital parts of both the upper and lower orbicularis oculi muscles of the eyes.
The recommended initial dosage is 100 units per axilla. If the desired effect is not attained, up to 200 units per axilla can be administered for subsequent injections.
When treating axillary hyperhidrosis, Dysport is reconstituted with 2.5ml of sodium chloride solution (0.9%) to yield a solution containing 200 units per ml of Dysport.
The area to be injected should be determined beforehand using the iodine-starch test. Both axillae should be cleaned and disinfected. Intradermal injections at ten sites, each site receiving 10 Units are then administered.
The maximum effect should be seen by week two after injection. In the majority of cases, the recommended dose will provide adequate suppression of sweat secretion for approximately 48 weeks. The time point for further applications should be determined on an individual basis, when the patient's sweat secretion has returned to an unacceptable level, but not more often than every 12 weeks. There is some evidence for a cumulative effect of repeated doses so the time of each treatment for a given patient should be assessed individually.
Dysport is contraindicated in pregnancy.
For the treatment of spasmodic torticollis and paediatric cerebral palsy spasticity Dysport should only be injected by specialists experienced in the diagnosis and management of these conditions and who have received training on the administration of Dysport.
Careful consideration should be given before the reinjection of patients who have experienced a previous allergic reaction. The risk of a further allergic reaction must be considered in relation to the benefit of treatment.
Dysport should only be used with caution under close supervision in patients with subclinical or clinical evidence of marked defective neuro-muscular transmission. Such patients may have an increased sensitivity to agents such as Dysport which may result in excessive muscle weakness.
There has been one report of immune response after the local administration of Clostridium botulinum Type A toxin-haemagglutinin complex in accordance with the doses recommended when treating blepharospasm and hemifacial spasm. Antibody formation to botulinum toxin has also been noted in a small number of torticollis patients and in one paediatric cerebral palsy patient receiving therapy with Dysport. Clinically, this has been detected by substantial deterioration in response to therapy or a need for consistently increasing doses.
This product contains a small amount of human albumin. The risk of transmission of viral infection cannot be excluded with absolute certainly following the use of human blood or blood products.
Teratological and other reproductive studies have not been performed with Dysport. The safety of its use in pregnant or lactating women has not been demonstrated.
Not known.
Muscle weakness is the most commonly reported adverse event in clinical studies and in the literature, for this patient population. In the two pivotal studies using DYSPORT for arm spasticity post-stroke, the most frequent adverse events were focal weakness (6.7%), generalised weakness (2.2%), flu-like symptoms (5.6%), fatigue (3.3%), somnolence (1.1%) and pain at injection site (3.3%). The majority of events resolved within 2 weeks.
Dysphagia has been reported at doses in excess of 2700 units given in one dose or when given as a divided dose 12 weeks apart. No cases were reported in pivotal studies.
Adverse event incidence has been assessed by three prospective studies involving 142 patients treated with Dysport, and 75 patients treated with placebo.
Adverse events with an incidence of ≥ 5% following Dysport treatment were leg pain (8%), pharyngitis (8%), accidental injury (7 %), bronchitis (6%), and fever (6%). Those with an incidence of 1-5% were viral infection (5%), infection (4%), rhinitis (4%), convulsion (4%), upper respiratory tract infection (4%),asthenia (3%), asthma (3%), cough (3%), vomiting (3%), cold (2%), diarrhoea (2%), urinary incontinence (2%), abnormal gait (1%), gastroenteritis (1%), laryngitis (1%), and somnolence (1%).
The incidence of many of these adverse events (pharyngitis, bronchitis, fever, viral infection, rhinitis, upper respiratory tract infection, cough, vomiting, cold) was similar in placebo treated patients, and probably indicates the typical spectrum of illness in a paediatric population. Also, the incidence of convulsions was identical in placebo treated patients, and reflects one of the most frequent concomitant problems associated with cerebral palsy.
The incidence of accidental injury (falls) demonstrated the biggest difference with placebo treated patients (1%), and it is likely that these adverse events are due to over-weakening of the target muscle and/or the local spread of Dysport to other muscles involved in ambulation and balance. The reports of abnormal gait may also be the result such an effect. Another local side effect was leg pain; predominantly calf pain. Although this pain appears to be distinct from any pain experienced from the injection itself, it was also reported for 5% of placebo treatments. Asthenia and urinary incontinence were associated with higher doses of Dysport (20-30 units/kg), and may be the result of systemic spread of toxin.
Side effects may occur mainly from deep or misplaced injections temporarily paralysing other nearby muscle groups. The injections have been associated with a burning sensation which lasts for 1-2 minutes after injection.
In patients treated for torticollis, dysphagia is the most frequently reported adverse event. In a double-blind placebo controlled trial the incidence of dysphagia was 29% following treatment with 500 units of Dysport and 10% in the placebo group. This appears to be dose related and occurs most frequently following injection into the sternomastoid muscles. A soft diet may be required until symptoms resolve. In those patients severely affected, laryngoscopy has identified pooling of saliva. Aspiration may occur rarely and be of potential concern in those patients with pre-existing respiratory problems. Less frequently reported events include weakness of the neck muscles, dryness of mouth and voice changes.
A more generalised weakness and visual disturbances (including diplopia and blurred vision) have occasionally been reported. Respiratory difficulties have been noted on rare occasions in association with high doses. These side effects may be expected to resolve within two to four weeks.
Allergic reactions such as skin rashes and influenza-like symptoms have occasionally been noted.
Side effects may occur from deep or misplaced injections of Dysport, temporarily paralysing other nearby muscle groups. They may also occur from exacerbation of pre-existing eyelid abnormalities or from an initial over-correction. Ptosis is the most common unwanted effect. A few patients may also experience diplopia or symptoms from spread of the paralytic effect to mid-facial muscles. These side effects may be expected to resolve within two to four weeks. Keratitis and dry eyes due to reduced blinking have also been reported for which the use of artificial tears could be considered. Minor bruising and lid swelling may occur but are short lived. Reversible external ophthalmoplegia has been reported after excessive dosing.
The injections have been associated with a burning sensation which lasts for 1-2 minutes after injection.
Allergic reactions such as skin rashes and influenza-like symptoms have occasionally been noted.
Most adverse events associated with the use of botulinum toxin were of mild to moderate severity and all were transient. The most frequently reported treatment related adverse events were headache and blepharoptosis. Blepharoptosis may be injection technique related. Other adverse events reported, listed in decreasing order of incidence, were: injection site pain/burning/stinging (2.5%), face pain (2.2%), erythema (1.7%), local muscle weakness (1.7%), injection site oedema (1.5%), ecchymosis (1.0%), skin tightness (1.0%), parethesia (1.0%) and nausea (1.0%).
Compensatory increase in sweating in other skin areas is commonly observed.
No interactions of clinical significance have been reported.
Excessive doses may produce distant and profound neuromuscular paralysis. 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.
Unopened vials must be maintained at temperatures between 2°C and 8°C. Dysport must be stored in a refrigerator at the hospital where the injections are to be carried out and should not be given to the patient to store.
Reconstituted Dysport may be stored in a refrigerator (2-8°C) for up to 8 hours prior to use. Dysport should not be frozen.
The shelf life of the packaged product is 12 months when stored at 2-8°C. Maximum storage time of reconstituted product is 8 hours at 2-8°C.
The product does not contain an anti-microbial agent. The reconstituted product should therefore be used as soon as possible.
None known.
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). Thereafter, all items should be disposed of in accordance with standard hospital practice.
Spillage of Dysport should be wiped up with an absorbent cloth soaked in dilute hypochlorite solution.
Dysport is available in packs of 2 x 2.5 ml vials each containing 500 units Clostridium botulinum type A toxin-haemagglutinin complex.
Prescription Medicine.
Albumin and lactose.
New Zealand Medical and Scientific Ltd
PO Box 24-138
Royal Oak
Auckland
Ph (9) 259 4062
Fax (9) 259 4067
11 October 2003
DYSPORT is a registered trademark.