Ipsen Ltd

Adults and elderly: 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 related adverse events, including eye adverse events particularly with regard to ptosis, showed a dose relationship by an increased incidence with increasing doses of Dysport.

In the treatment of blepharospasm and hemifacial spasm, the maximum dose used must not exceed a total dose of 120 units per eye. For further information see section 5.1.

Injection of 10 units (0.05mL) should be made medially and of 10 units (0.05 mL) should be made laterally 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. 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 twelve weeks or as required to prevent recurrence of symptoms but not more frequently than every twelve 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 (0.05 mL) medially and 20 units (0.1 mL) laterally, 80 units: 20 units (0.1 mL) medially and 20 units (0.1 mL) laterally or up to 120 units: 20 units (0.1 mL) medially and 40 units (0.2 mL) laterally above and below each eye in the manner previously described. Additional sites in frontalis muscle above 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.

• In section 2, 500U changed to 500 units and list of other consitituents removed.
• In section 4.2, the following statement added to the arm spasticity and spasmodic torticollis posology - "The maximum dose administered must not exceed 1000 units."
• In section 4.4, the following wording added - "Antibody formation to botulinum toxin has been noted rarely in patients receiving Dysport. Clinically, neutralising antibodies might be detected by 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 botulinum toxin type A. The risk of a further allergic reaction must be considered in relation to the benefit of treatment."
• In section 4.6, the following wording has been added - "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 doses causing maternal toxicity (see section 5.3).
  
  Dysport should be used during pregnancy only if the benefit justifies any potential risk to the fœtus. Caution should be exercised when prescribing to pregnant women.
  
  Lactation:
  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.
• In section 4.7, the following wording replaces existing tex - "There is a potential risk of muscle weakness or visual disturbances which, if experienced, may temporarily impair the ability to drive or operate machinery.
• In section 4.9, the text has been re-arranged.
• In section 5.1, the following wording has been added - "Pharmacotherapeutic Group: Other muscle relaxants, peripherally acting agents. ATC code: M03AX01"
• In section 5.3, the following wording has been added - "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.
  In a chronic toxicity study performed in rats up to 12 units/animal, there was no indication of systemic toxicity. Effects in chronic toxicity non-clinical studies were limited to changes on 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."
• In section 6.5, 'chlorobutyl' has been chnaged to 'bromobutyl'
• In section 8, the MA number has changed to PL 034926/0001
• In section 9, the following dates have been added - Date of First Authorisation: 09 Dec 1990
  Date of Latest Renewal: 17 Dec 2002
• In section 10, the date of revision of the text has been changed to 13 September 2010 

Section 4.4 The following wording has been deleted:

Dysport should be administered with caution to patients with existing problems in swallowing or breathing as these problems can worsen if toxin spreads to the relevant muscles. Aspiration has occurred in rare cases, and is a risk when treating patients with spasmodic torticollis who have a chronic respiratory disorder.

Section 4.4 The following wording has been added:

Side effects related to spread of toxin distant from the site of administration have been reported (See section 4.8), which in some cases was associated with dysphagia, pneumonia and / or significant debility resulting in death very rarely.

Patients treated with therapeutic doses may experience exaggerated muscle weakness. Patients with underlying neurological disorders including swallowing difficulties are at increased risk of these side effects. The botulinum toxin product should be used under specialist supervision in these patients and should only be used if the benefit of treatment is considered to outweigh the risk.

Patients with a history of dysphagia and aspiration should be treated with extreme caution.

Patients and their care-givers must be warned of the necessity of immediate medical treatment in case of problems with swallowing, speech or respiratory disorders.

Section 4.8 The following wording has been added:

Side effects related to the spread of toxin distant from the site of administration have been reported (exaggerated muscle weakness, dysphagia, aspiration/aspiration pneumonia, with fatal outcome in some very rare cases). (See section 4.4).