elative to patients treated with placebo (response rate: 37.3%; 95% CI: 1.90 to 8.30; p < 0.001, ITT population).
This fixed dose study was not designed to differentiate between female and male patients, nevertheless in a post-hoc analysis the response rates were higher in female (89.3%) compared to male (55.6%) patients, the difference being statistically significant for women only. However, in male patients response rates in Ashworth Scale after 4 weeks in XEOMIN treated patients were consistently higher in all muscle groups treated compared to placebo.
Responder rates were similar in men compared to women in the open label extension period of the pivotal study (flexible dosing was possible in this trial period) in which 145 patients were enrolled and up to 5 injection cycles were performed, as well as in the observer-blind study (EudraCT Number 2006-003036-30) in which efficacy and safety of XEOMIN in two different dilutions in 192 patients were assessed in patients with upper limb spasticity of diverse etiology.
5.2 Pharmacokinetic properties
General characteristics of the active substance
Classic kinetic and distribution studies cannot be conducted with Botulinum neurotoxin type A because the active substance is applied in such small quantities (picograms per injection), and because it binds so rapidly and irreversibly to cholinergic nerve terminals.
Native Botulinum toxin is a high molecular weight complex, which, in addition to the neurotoxin (150 kD), contains other bacterial non-toxic proteins, like haemagglutinins and non-haemagglutinins. In contrast to conventional preparations containing the Botulinum toxin type A complex, XEOMIN contains pure (150 kD) neurotoxin since it is free from complexing proteins and thus has a low foreign protein content. The foreign protein content administered is considered as one of the factors for secondary therapy failure.
Like many other proteins of its size, Botulinum neurotoxin type A has been shown to undergo retrograde axonal transport after intramuscular injection. Retrograde transsynaptic passage of active Botulinum neurotoxin type A into the central nervous system however has not been found.
Receptor-bound Botulinum neurotoxin type A is endocytosed into the nerve terminal prior to reaching its target (SNAP 25) and is eventually degraded intracellularly. Free circulating Botulinum neurotoxin type A molecules that have not bound to presynaptic cholinergic nerve terminal receptors will be phagocytosed or pinocytosed and degraded like any other free circulating protein.
Distribution of the active substance in patients
Human pharmacokinetic studies with XEOMIN have not been performed for the reasons detailed above.
5.3 Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of cardiovascular safety pharmacology.
The findings made in repeat-dose toxicity studies conducted with XEOMIN were mainly related to its pharmacodynamic action.
No evidence of local intolerability was noted. Reproductive toxicity studies with XEOMIN performed in rabbits did not show adverse effects on male or female fertility nor direct effects on embryo-foetal development. However, the administration of XEOMIN at dose levels exhibiting clear maternal toxicity at weekly to biweekly intervals increased the number of abortions in a prenatal toxicity study in rabbits. A continuous systemic exposure of the dams during the (unknown) sensitive phase of the organogenesis as a pre-requisite for the induction of teratogenic effects cannot necessarily be assumed.
No genotoxicity, carcinogenicity or pre- and postnatal development studies have been conducted with XEOMIN.
6. Pharmaceutical particulars
6.1 List of excipients
Human albumin
Sucrose
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Unopened vial:
4 years
Reconstituted solution:
Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C.
From a microbiological point of view, 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 and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Unopened vial: Do not store above 25°C.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
100 LD50 units of Clostridium Botulinum neurotoxin type A in a vial (type 1 glass) with a stopper (bromobutyl rubber) and tamper-proof seal (aluminium).
Pack sizes of 1, 2, 3, 4 or 6 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
XEOMIN is reconstituted prior to use with sodium chloride 9 mg/ml (0.9%) solution for injection. Reconstitution and dilution should be performed in accordance with good clinical practice guidelines, particularly with respect to asepsis.
It is good practice to perform vial reconstitution and syringe preparation over plastic-lined paper towels to catch any spillage. An appropriate amount of solvent (see dilution table) is drawn up into a syringe. The exposed portion of the rubber stopper of the vial is cleaned with alcohol (70%) prior to insertion of the needle. The solvent must be injected gently into the vial. The vial must be discarded, if the vacuum does not pull the solvent into the vial. Reconstituted XEOMIN is a clear, colourless solution free of particulate matter.
XEOMIN should not be used if the reconstituted solution (prepared as above) has a cloudy appearance or contains floccular or particulate matter.
Possible dilutions are indicated in the following table:
Any solution for injection that has been stored for more than 24 hours as well as any unused solution for injection should be discarded.
PROCEDURE TO FOLLOW FOR A SAFE DISPOSAL OF VIALS, SYRINGES AND MATERIALS USED
For safe disposal, unused vials should be reconstituted with a small amount of water and then autoclaved. Any used vials, syringes, and spillage etc. should be autoclaved and any residual XEOMIN should be inactivated using diluted sodium hydroxide solution (0.1 N NaOH) or diluted sodium hypochlorite solution (0.5% or 1% NaOCl).
After inactivation used vials, syringes and materials should not be emptied and must be discarded into appropriate containers and disposed of in accordance with local requirements.
RECOMMENDATIONS SHOULD ANY INCIDENT OCCUR DURING THE HANDLING OF BOTULINUM TOXIN
• Any spills of the product must be wiped up: either using absorbent material impregnated with a solution of sodium hydroxide or sodium hypochlorite (bleach) in case of the powder, or with dry, absorbent material in case of reconstituted product.
• The contaminated surfaces should be cleaned using absorbent material impregnated with a solution of sodium hydroxide or sodium hypochlorite (bleach), then dried.
• If a vial is broken, proceed as mentioned above by carefully collecting the pieces of broken glass and wiping up the product, avoiding any cuts to the skin.
• If the product comes into contact with the skin, wash the affected area with a solution of sodium hydroxide or sodium hypochlorite (bleach) then rinse abundantly with water.
• If product enters into contact with the eyes, rinse thoroughly with plenty of water or with an ophthalmic eyewash solution.
• If product enters into contact with a wound, cut or broken skin, rinse thoroughly with plenty of water and take the appropriate medical steps according to the dose injected.
These instructions for use handling and disposal should be strictly followed.
7. Marketing authorisation holder
Merz Pharmaceuticals GmbH
Eckenheimer Landstraße 100
60318 Frankfurt/Main
Germany
P.O. Box 11 13 53
60048 Frankfurt/Main
Germany
8. Marketing authorisation number(s)
PL 29978/0001
9. Date of first authorisation/renewal of the authorisation
20 December 2007
10. Date of revision of the text
16/11/2012
附：Xeomin 50 Units（https://www.medicines.org.uk/emc/medicine/24582）