Please read this leaflet carefully. It provides some information about your medicine. If you have any questions, please ask your doctor. The name of your medicine is Dysport. Its active ingredient is Clostridium botulinum type A toxin-haemagglutinin complex. Dysport also contains albumin and lactose, and is presented as a powder. For the injection, Dysport will be dissolved in Sodium Chloride for Injection.

Each pack contains 1 or 2 vials of Dysport.

Dysport is a toxin produced by Clostridium botulinum bacteria. The toxin acts on to junctions between the nerves and muscles, preventing the release of one of the chemical messengers called acetylcholine from the nerve endings which would normally cause the muscle to contract. If the messenger is prevented from being released this results in a weakened muscle and helps to reduce some of the abnormal muscle contractions. Each vial of Dysport contains 500 units of the toxin complex. These units apply to Dysport only and are not the same for other medicines containing botulinum toxin.

Dysport is manufactured by

Speywood Biopharm Limited, Ash Road,

Wrexham Industrial Estate, Wrexham LL13 9UF.

The Product Licence holder is:

Speywood Pharmaceuticals Limited,

1 Bath Road, Maidenhead, Berkshire, SL6 4UH.

Dysport is used for the treatment of blepharospasm. hemifacial spasm and spasmodic torticollis. Blepharospasm is a condition affecting the eye lid muscles causing uncontrollable blinking and closure of the eyelids. Hemifacial spasm is a condition which causes the muscles on one side of the face to contract without your control, Spasmodic torticollis is where there is turning movement of the neck leading to an unusual head and shoulder position.

You should not be given Dysport if you are having a baby. Tell your doctor if you are pregnant or think you may be pregnant or you are breast feeding your baby.

You think your symptoms have worsened or changed. Tell your doctor If you think you are allergic to any of the ingredients contained in Dysport. Tell him if you have had any unusual reactions such as skin rash or flu-like symptoms to any injections of toxin in The past. Tell your doctor if you have a history of bronchitis, pneumonia and problems with your breathing, or previous prolonged periods of muscle weakness because there are increased risks of having toxin injection for torticollis in these circumstances.

Dysport contains a small amount of albumin which has been obtained from human blood. The risk of a viral infection cannot be eliminated completely when using human blood or products made from human blood.

Your doctor will make up the injection and give the injection to you.

Your doctor will decide where to make the injections and for how long you need treatment. For blepharospasm affecting both eyes, the first injection will be approximately 120 units per eye. The medicine will be injected just under the skin at certain sites around the eye. These sites and The exact amount you need will be decided by your doctor.

You will be given injections approximately every eight weeks when the relaxing effect or, the muscles is wearing off. On your next visits the amount of Dysport given to you may be reduced to 80 or 60 units per eye. Your doctor will decide what dose to administer.

If only one of your eyes is affected by blepharospasm, your doctor will only give you injectors of Dysport around This eye.

If you have hemifacial spasm your doctor will give you injection as for blepharospasm but on the affected side only.

If you have spasmodic torticollis you will be given injections of your medicine, in a hospital which specialists in treating your condition. Your doctor will inject your medicine and he or she will be specially trained and experienced in giving Dysport injections. Your first dose of Dysport will be 500 units in total. Your doctor will divide this amount into a number of places in your neck, probably into the 2 or 3 of the neck muscles most affected by the condition. Your doctor will decide how much to give and which muscles to inject. You will be given injections approximately every 8 - 12 weeks depending on how long before the relaxing effect on the muscle wears off. Your doctor will decide when you will need your next injection and how much of the medicine will be injected.

Dysport is not recommended for use in children.

Nothing will happen if you miss an injection other than some of the spasm may return. Consult your doctor and he will decide when you need your next injection,

The relaxing effect will eventually wear off and the muscle movements will return to the way they were before treatment.

Along with its desired effects your medicine may cause unwanted effects because of a weakening of muscles near the injected muscle. After Dysport treatment, you may experience a temporary change in the muscles near to where the injection was given. It is possible that you may also see some bruising or swelling around the site where the Injection was given or feel a burning sensation lasting 1-2 minutes at the time the injection is given. If the treatment is given around the eye, you may notice slight eyelid droop, dry eyes or some difficulty seeing clearly. If the injection is given into The neck muscles you may notice that swallowing certain foods becomes difficult, your neck feels weaker, your mourn feels dry, or there is a change to the tone of your voice. Very rarely you may notice that you feel a little tired or your breathing feels a bit difficult. These effects, if they occur, are noticeable a few days after injection and usually wear off within 2 - 4 weeks. After Dysport treatment you may experience an allergic reaction such as skin rates or flu-like symptoms. If any side effect becomes troublesome or causes concern, you should tell your doctor. You should tell your doctor immediately if you have any breathing difficulties, very dry eyes, or if you have any difficulties in swallowing, particularly if the swallowing difficulties prevent you from eating and cause you to lose weight.

Your medicine will be stored in a refrigerator (2° C - 8° C) at the hospital where the injections are carried out. This medicine should not be given to you to store.

Do not use after the expiry date shown on the box.

February 1997

PL 6958/0005

Dysport.

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

Injection.

For the treatment of blepharospasm, hemifacial spasm and spasmodic torticollis.

In the treatment of bilateral blepharospasm the recommended initial dose is 120 units per eye. Injection of 0.1 ml (20 units) should be made medially and of 0.2 ml (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 or 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 -: 0.1 ml (20 units) medially and 0.1 ml (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.

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/bead 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. 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 muscle. 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.

The safety and effectiveness of Dysport in children has 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. When treating spasmodic torticollis Dysport is reconstituted with 1 ml of sodium chloride injection BP (0.9%) to yield a solution containing 500 units per ml or Dysport. Dysport is administered by intramuscular injection as above when treating spasmodic torticollis.

Dysport is contraindicated in pregnancy.

For the treatment of spasmodic torticollis, Dysport should only be injected by specialists experienced in the diagnosis and management of this condition 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 neuromuscular transmission. Such patients may have an increased sensitivity to agents such as Dysport which may res4jlt in excessive rustle weakness.

Training: Speywood will facilitate training in administration of Dysport injections. There are no reports of any 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 been noted in a small number of patients receiving Therapy with Dysport for torticollis. 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 certainty following The use of human blood or blood products.

No interactions of clinical significance have been reported.

Teratological and other reproductive studies have riot been performed with Dysport. The safety of its use in pregnant or lactating women has not been demonstrated.

None known.

Undesirable effects when treating blepharospasm and hemifacial spasm

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 shod lived. Reversible external ophthalmoplegia has been reported after excessive dosing.

The injections have bean associated with a burning sensation which lasts for I - 2 minutes after injection.

Allergic reactions such as skin rashes and influenza-like symptoms have occasionally been noted undesirable effects when treating spasmodic torticollis.

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 I - 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 20% following treatment with 5CC units of Dysport and 10% in the placebo group. This appears to be dose related and occurs most frequently following injection into the sternomastoid muscle. 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 preexisting 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 bean 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.

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.

Pharmacological Properties

Pharmacodynamic properties 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 mar, and is attributed to the process of binding, internalisation and changes at the neuromuscular junction.

Pharmaceutical Particulars

Albumin and Lactose.

None known.

The shelf life of the packaged product is 12 months.

The reconstituted product should be used within one hour of reconstitution.

Unopened vials must be maintained at temperatures between 2oC and 8oC. Dysport must be stored in a refrigerator at the hospital where the injections are to be carried out end should not be given to the patent to store. Dysport should not be frozen.

Type I glass vials 3 ml capacity. 13mm chlorbutyl freeze-drying closures oversealed by 13mm aluminium overseals with centre hole, crimped over.

A while lyophilised powder for reconstitution..

Instruction for use/handling

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.

1 Bath Road, Maidenhead

Berkshire, SL6 4UH

February 1997

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