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BOTULINUM TOXIN TYPE A POWDER FOR SOLUTION FOR INJECTION

Active substance(s): CLOSTRIDIUM BOTULINUM TYPE A TOXIN - HAEMAGGLUTININ COMPLEX / CLOSTRIDIUM BOTULINUM TYPE A TOXIN - HAEMAGGLUTININ COMPLEX / CLOSTRIDIUM BOTULINUM TYPE A TOXIN - HAEMAGGLUTININ COMPLEX

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1

NAME OF THE MEDICINAL PRODUCT
Botulinum Toxin Type A powder for solution for injection

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
U

Per Vial

U

Active Constituent
Clostridium botulinum type A toxinhaemagglutinin complex

500U *

Other Constituents
Albumin solution

125 MCG

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

3

PHARMACEUTICAL FORM
Injection.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Botulinum Toxin Type A is indicated for focal spasticity, including the treatment of:

- arm symptoms associated with focal spasticity in conjunction with
physiotherapy;
and

- dynamic equinus foot deformity due to spasticity in ambulant paediatric
cerebral palsy patients, two years of age or older, only in hospital specialist
centres with appropriately trained personnel.

Botulinum Toxin Type A is also indicated for the following treatments:
-

4.2

Spasmodic torticollis in adults
Blepharospasm in adults
Hemifacial spasm in adults
The temporary improvement in the appearance of moderate to severe
glabellar lines (vertical lines between the eyebrows) seen at frown, in adult
patients under 65 years, when the severity of these lines has an important
psychological impact on the patient.

Posology and method of administration
The units of Botulinum Toxin Type A are specific to the preparation and are not
interchangeable with other preparations of botulinum toxin type A.
Training: Botulinum Toxin Type A should only be administered by appropriately trained
physicians.
Ipsen can facilitate training in administration of Botulinum Toxin Type A injections .
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.
Arm spasticity:
Posology
The recommended dose is 1000 units in total, distributed amongst the following five
muscles:
Biceps
brachii
(BB)

300-400
units
(0.6-0.8
mL)

Flexor
digitorum
profundus

Flexor
digitorum
superficialis

Flexor
carpi
ulnaris

Flexor
carpi
radialis

(FDP)

(FDS)

(FCU)

FCR)

150 units

150-250
units

150 units

150 units

1,000 units

(0.3 mL)

(0.3 mL)

(2.0 mL)

(0.3 mL)

Total Dose

(0.3-0.5 mL)

The sites of injection should be guided by standard locations used for
electromyography, although actual location of the injection site will be determined by
palpation. All muscles except the biceps brachii (BB) should be injected at one site,
whilst the biceps should be injected at two sites.
The 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. Data on repeated and long term treatment are limited.
Children: The safety and effectiveness of Botulinum Toxin Type A in the treatment
of arm spasticity in children have not been demonstrated.
Method of administration
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 arm spasticity, Botulinum Toxin Type A is reconstituted with 1.0 mL
of sodium chloride injection B.P. (0.9%) to yield a solution containing 500 units per
mL of .
Botulinum Toxin Type A is administered by intramuscular injection into the five
muscles detailed above when treating arm spasticity.
Paediatric cerebral palsy spasticity:

Posology
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 12 weeks.
Method of administration
When treating paediatric cerebral palsy spasticity, Botulinum Toxin Type A is
reconstituted with 1.0 mL of sodium chloride injection B.P. (0.9%) to yield a solution
containing 500 units per mL of Botulinum Toxin Type A. Botulinum Toxin Type A
is administered by intramuscular injection into the calf muscles when treating
spasticity.
Spasmodic torticollis:

Posology

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 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 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 12 weeks or as required
to prevent recurrence of symptoms.
Children: The safety and effectiveness of Botulinum Toxin Type A in the treatment
of spasmodic torticollis in children have not been demonstrated.
Method of administration
When treating spasmodic torticollis Botulinum Toxin Type A is reconstituted with
1.0 mL of sodium chloride injection B.P. (0.9%) to yield a solution containing 500
units per mL of Botulinum Toxin Type A. Botulinum Toxin Type A is administered
by intramuscular injection as above when treating spasmodic torticollis.
Blepharospasm and hemifacial spasm

Posology
Adults and elderly: 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 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. 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.
0.1 mL
0.2 mL

0.1 mL

0.2 mL

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 Botulinum Toxin Type A in the treatment
of blepharospasm and hemifacial spasm in children have not been demonstrated.

Method of administration
When treating blepharospasm and hemifacial spasm Botulinum Toxin Type A is
reconstituted with 2.5 mL of sodium chloride injection BP (0.9%) to yield a solution
containing 200 units per mL of Botulinum Toxin Type A. Botulinum Toxin Type A 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.

Glabellar Lines:
Posology and method of administration
Once reconstituted, Botulinum Toxin Type A should only be used to treat a single
patient, during a single session.
Prior to injection, the product should be reconstituted, instructions for which are
given in Section 6.6.
Remove any make-up and disinfect the skin with a local antiseptic.
Intramuscular injections should be performed at right angles to the skin using a sterile
29-30 gauge needle.

The recommended dose is 50 Speywood units (0.25 ml of reconstituted solution) of
Botulinum Toxin Type A to be divided into 5 injection sites, 10 Speywood units
(0.05 ml of reconstituted solution) are to be administered intramuscularly into each of
the 5 sites: 2 injections into each corrugator muscle and one into the procerus muscle
near the nasofrontal angle as shown below:

The anatomical landmarks can be more readily identified if observed and palpated at
maximal 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 upward 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 in the
corrugator muscle must be made into the central part of that muscle, at least 1 cm
above the orbital rim.
The treatment interval depends on the individual patient’s response after assessment.
In clinical studies, an optimal effect was demonstrated for up to 4 months after
injection. Some patients were still responders at 5 months. Treatment interval should
not be more frequent than every three months.
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, injection
technique, and formation of toxin-neutralising antibodies;



Re-evaluation of the relevance of treatment with botulinum toxin A

Use in children
The safety and effectiveness of Botulinum Toxin Type A in treating glabellar lines in
individuals under 18 years of age have not been demonstrated.

4.3

Contraindications
Botulinum Toxin Type A is contraindicated:
In individuals with known hypersensitivity to any components of Botulinum Toxin
Type A or to any of the excipients of the formulation.

In the presence of infection at the proposed injection sites;
In the presence of myasthenia gravis, Eaton Lambert syndrome or Amyotrophic
lateral sclerosis.

4.4

Special warnings and precautions for use
Botulinum Toxin Type A should only be used with caution and under close
supervision in patients with subclinical or clinical evidence of marked defective
neuro-muscular transmission (e.g. myasthenia gravis). Such patients may have an
increased sensitivity to agents such as Botulinum Toxin Type A which may result in
excessive muscle weakness with therapeutic doses. Patients with underlying
neurological disorders are at increased risk of this side effect.
Patients with a history of dysphagia and aspiration should be treated with extreme
caution. Swallowing or breathing disorders can worsen due to the spread of toxin
distant from the site of administration. Aspiration has occurred in rare cases and this
is a risk when treating patients who have a chronic respiratory disorder. Botulinum
Toxin Type A should be used under specialist supervision in all such patients and
should only be used if the benefit of treatment is considered to outweigh the risk.
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 and their care-givers must be warned of the necessity of immediate medical
treatment in case of problems with swallowing, speech or respiratory disorders.
Antibody formation to botulinum toxin has been noted rarely in patients receiving
Botulinum Toxin Type A. Clinically, neutralising antibodies have been detected by a
substantial deterioration in response to therapy and /or a need for consistently
increasing doses.
For the treatment of cerebral palsy in children, Botulinum Toxin Type A should only
be used in children over 2 years of age.
The recommended posology and frequency of administration for must not be
exceeded (see section 4.2).
Botulinum Toxin Type A should only be used to treat a single patient, during a single
session. Specific precautions must be taken for the preparation and administration of
the product (see section 4.2) and for the inactivation and disposal of any unused
reconstituted solution (see section 6.6).
When treating glabellar lines, it is essential to study the patient’s facial anatomy prior
to administering. 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 or atrophy.
The effect of administering different botulinum neurotoxins during the course of
treatment with Botulinum Toxin Type A is unknown and must be avoided.
As with any intramuscular injection, Botulinum Toxin Type A should be used only
where strictly necessary in patients with prolonged bleeding times.

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.

4.5

Interaction with other medicinal products and other forms of interaction
The effects of botulinum toxin may be enhanced by drugs interfering directly or
indirectly with the neuromuscular function ( e.g. aminoglycosides, curare-like nondepolarising blockers) and such drugs should be used with caution in patients treated
with botulinum toxin.

4.6

Pregnancy and lactation
Teratological and other reproductive studies have not been performed with Botulinum
Toxin Type A. The safety of its use in pregnant or lactating women has not been
demonstrated.
Botulinum Toxin Type A should not be used in pregnant or lactating women, unless
clearly necessary.

4.7

Effects on ability to drive and use machines
Botulinum Toxin Type A may impair the ability to drive or operate machinery in case
of adverse reactions such as muscle weakness and eye disorders (diplopia, blurred
vision, eyelid ptosis).

4.8

Undesirable effects
Very common >1/10: Common >1/100, <1/10: Uncommon >1/1000, <1/100:
Rare >1/10 000, < 1/1000: Very rare <1/10 000.
Side effects related to 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).
General
In the clinical trial programme, approximately 28% of the patients treated with
Dysport experienced an adverse event.

The following adverse reaction were seen in patients treated across variety of
indications including blepharospasm, hemifacial spasm, torticollis and
spasticity associated with either cerebral palsy or stroke:
Nervous system disorders
Rare: Neuralgic amyotrophy

Skin and subcutaneous tissue disorders
Uncommon: Itching
Rare: Skin rashes

General disorders and administration site conditions
Common: Generalised weakness, fatigue, flu-like syndrome, pain / bruising
at injection site.
In addition, the following adverse reactions specific to individual indication were
reported:

Arm spasticity
Gastrointestinal disorders
Common: Dysphagia

Musculoskeletal and connective tissue disorders
Common: Arm muscle weakness

Injury, poisoning and procedural complications
Common: Accidental injury/falls

Paediatric cerebral palsy spasticity
Gastrointestinal disorders
Common: Diarrhoea, vomiting

Musculoskeletal and connective tissue disorders
Common: Leg muscle weakness

Renal and urinary disorders
Common: Urinary incontinence

General disorders and administration site conditions
Common: Abnormal gait

Injury, poisoning and procedural complications
Common: Accidental injury due to falling
Accidental injury due to falling and abnormal gait may have been due to the overweakening of the target muscle and / or the local spread of Botulinum Toxin Type A
to other muscles involved in ambulation and balance.

Spasmodic torticollis
Nervous system disorders
Common: Dysphonia
Uncommon: Headache

Eye disorders
Uncommon: Diplopia, blurred vision

Respiratory, thoracic and mediastinal disorders
Rare: Respiratory disorders

Gastrointestinal disorders
Very common: Dysphagia
Uncommon: Dry mouth

Musculoskeletal and connective tissue disorders
Common: Neck muscle weakness
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
Nervous system disorders
Common: Facial muscle weakness

Uncommon: Facial nerve paresis
Eye disorders
Very common: Ptosis
Common: Diplopia, dry eyes, tearing
Rare: Ophthalmoplegia

Skin and subcutaneous tissue disorders
Common: Eyelid oedema

Rare: Entropion
Side effects may occur due to deep or misplaced injections of Botulinum
Toxin Type A temporarily paralysing other nearby muscle groups.
Glabellar Lines

Nervous system disorders

Eye disorders

Skin and subcutaneous
tissue disorders

General disorders and
administration site
conditions
Immune system disorders

Very Common
Headache
Common
Facial paresis (predominantly describes brow
paresis)
Uncommon
Dizziness
Common
Asthenopia, Ptosis, Eyelid oedema, Lacrimation
increase, Dry eye, Muscle twitching (twitching of
muscles around the eyes)
Uncommon
Visual disturbances, Vision blurred, Diplopia
Rare
Eye movement disorder
Uncommon
Pruritus, Rash
Rare
Urticaria
Very Common
Injection site reactions (e.g. erythema, oedema,
irritation, rash, pruritus, paraesthesia, pain,
discomfort, stinging and bruising)
Uncommon
Hypersensitivity

Post-marketing experience
The profile of adverse reactions reported to the Company during postmarketing use reflects the pharmacology of the product and those seen during
clinical trials. In addition, hypersensitivity reactions have been reported.

4.9

Overdose
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. 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. deglutition
and dysphonia).
Symptomatic treatment should be instituted if necessary. In the event of an overdose
the patient should be medically monitored for several weeks for symptoms of
systemic weakness or muscle paralysis.

5

PHARMACOLOGICAL PROPERTIES

5.1

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.

5.2

Pharmacokinetic properties
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.

5.3

Preclinical safety data
There is no further pre-clinical information relevant to the prescribing physician that
has not been included in other sections of the Summary of Product Characteristics.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Albumin and Lactose.

6.2

Incompatibilities
None known.

6.3

Shelf life
The shelf life of the packaged product is 24 months at 2-8ºC.
The product may be stored for up to 8 hours at 2-8ºC following reconstitution.
Since the product does not contain an antimicrobial agent, from a microbiological
point of view, it is recommended that the product should be used immediately
following reconstitution.

6.4

Special precautions for storage
Unopened vials must be maintained at temperatures between 2°C and 8°C. Botulinum
Toxin Type A 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 Botulinum Toxin Type A may be stored in a refrigerator (2-8ºC) for up
to 8 hours prior to use. Botulinum Toxin Type A should not be frozen.

6.5

Nature and contents of container
Nature of container/closure:
Type 1 glass vials 3 mL capacity. 13 mm chlorbutyl freeze-drying closures oversealed
by 13 mm aluminium overseals with centre hole, crimped over.
Contents of container:
A white lyophilised powder for reconstitution.

6.6

Special precautions for disposal
Immediately after treatment of the patient, any residual Botulinum Toxin Type A
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 Botulinum Toxin Type A should be wiped up with an absorbent cloth
soaked in dilute hypochlorite solution.

7

MARKETING AUTHORISATION HOLDER
Ipsen Limited
190 Bath Road, Slough
Berkshire, SL1 3XE

8

MARKETING AUTHORISATION NUMBER(S)
PL 06958/0028

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
First Authorisation: 04 May 2006

10

DATE OF REVISION OF THE TEXT
22/07/2010

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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