Summary of Product Characteristics: 4.1 Therapeutic Indications

SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
BOTOX
50 Allergan Units
Powder for solution for injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Botulinum toxin* type A, 50 Allergan Units/vial.

*
from Clostridium botulinum
Botulinum toxin units are not interchangeable from one product to another.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for solution for injection.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
BOTOX is indicated for:
Neurologic disorders:
• treatment of focal spasticity, including:

Ø dynamic equinus foot deformity due to spasticity in ambulant paediatric cerebral
palsy patients, two years of age or older
Ø wrist and hand disability due to upper limb spasticity associated with stroke in adults
Ø ankle disability due to lower limb spasticity associated with stroke in adults
• symptomatic relief of blepharospasm, hemifacial spasm and idiopathic cervical
dystonia (spasmodic torticollis)
• prophylaxis of headaches in adults with chronic migraine (headaches on at least 15 days
per month of which at least 8 days are with migraine)
Bladder disorders:
• management of bladder dysfunctions in adult patients who are not adequately managed
with anticholinergics
Ø overactive bladder with symptoms of urinary incontinence, urgency and frequency
Ø neurogenic detrusor overactivity with urinary incontinence due to subcervical
spinal cord injury (traumatic or non-traumatic), or multiple sclerosis
Skin and skin appendage disorder:
• management of severe hyperhidrosis of the axillae, which does not respond to topical
treatment with antiperspirants or antihidrotics
• temporary improvement in the appearance of the following facial lines, when the severity
of these lines has an important psychological impact in adult patients:
Ø moderate to severe vertical lines between the eyebrows seen at maximum frown
(glabellar lines)
Ø moderate to severe lateral canthal lines (crow’s feet lines) seen at maximum smile
Ø moderate to severe crow’s feet lines seen at maximum smile and glabellar lines seen
at maximum frown when treated simultaneously.
4.2 Posology and method of administration
Posology
Botulinum toxin units are not interchangeable from one product to another. Doses
recommended in Allergan Units are different from other botulinum toxin preparations.
Elderly patients
Dosages for elderly patients are the same as for younger adults. Initial dosing should begin at
the lowest recommended dose for the specific indication. Elderly patients with significant
medical history and concomitant medications should be treated with caution.
There is limited data in patients older than 65 years managed with BOTOX for urinary
incontinence with neurogenic detrusor overactivity and for facial lines (see section 5.1).
Paediatric population
The safety and efficacy of BOTOX in the treatment of individual indications have not been
established in children and adolescents under the ages listed in the table below. No data are
available.
• Focal spasticity associated with paediatric 2 years

cerebral palsy
• Upper and lower limb spasticity associated with 18 years
stroke
• Blepharospasm/Hemifacial spasm/ Idiopathic 12 years
Cervical dystonia
• Chronic migraine (CM) 18 years
• Overactive Bladder (OAB) and Neurogenic 18 years

Detrusor Overactivity (NDO)
• Primary hyperhidrosis of the axillae 12 years
(limited experience in adolescents between
12 and 17 years, see sections 4.8 and 5.1)
• Glabellar lines seen at maximum frown and/or 18 years
crow’s feet lines seen at maximum smile

Method of Administration
BOTOX should only be administered by physicians with appropriate qualifications and

expertise in the treatment and the use of the required equipment.
This product is for single use only and any unused solution should be discarded. The
most appropriate vial size should be selected for the indication.
An injection volume of approximately 0.1 ml is recommended. A decrease or increase in the

BOTOX dose is possible by administering a smaller or larger injection volume. The smaller
the injection volume the less discomfort and less spread of toxin in the injected muscle
occurs. This is of benefit in reducing effects on nearby muscles when small muscle groups
are being injected.
For instructions on reconstitution of the powder for solution for injection, handling and
disposal of vials please refer to section 6.6.
Refer to specific guidance for each indication described below.
Generally valid optimum dose levels and number of injection sites per muscle have not been
established for all indications. In these cases, individual treatment regimens should therefore
be drawn up by the physician. Optimum dose levels should be determined by titration but the
recommended maximum dose should not be exceeded.
NEUROLOGIC DISORDERS:
Focal spasticity associated with paediatric cerebral palsy
Recommended needle: Sterile 23-26 gauge/0.60-0.45 mm needle.
Administration guidance: To be administered as a divided dose through single

injections into the medial and lateral heads of the affected
gastrocnemius muscle.
Recommended dose: Hemiplegia: the initial recommended total dose is 4 Units/kg

body weight in the affected limb.
Diplegia: the initial recommended total dose is 6 Units/kg
body weight divided between the affected limbs.
Maximum dose: 200 Units in total
Additional information: Clinical improvement generally occurs within the first two
weeks after injection. Repeat doses should be administered
when the clinical effect of a previous injection diminishes
but not more frequently than every three months. It may be
possible to adapt the dosage regimen to obtain an interval of
at least six months between treatment sessions.
Focal upper limb spasticity associated with stroke
Recommended needle: Sterile 25, 27 or 30 gauge needle. Needle length should be

determined based on muscle location and depth.
Administration guidance: Localisation of the involved muscles with techniques such as
electromyographic guidance, nerve stimulation, or ultrasound
is recommended. Multiple injection sites may allow BOTOX
to have more uniform contact with the innervation areas of
the muscle and are especially useful in larger muscles.
Recommended dose: The exact dosage and number of injection sites may be
tailored to the individual based on the size, number and
location of muscles involved, the severity of spasticity, the
presence of local muscle weakness, and the patient response
to previous treatment.
The following doses are recommended:

Muscle Total Dosage;
Number of Sites
Flexor digitorum profundus 15 - 50 Units; 1-2 sites
Flexor digitorum sublimis 15 - 50 Units; 1-2 sites
Flexor carpi radialis 15 - 60 Units; 1-2 sites
Flexor carpi ulnaris 10 - 50 Units; 1-2 sites
Adductor Pollicis 20 Units; 1-2 sites
Flexor Pollicis Longus 20 Units; 1-2 sites
Maximum dose: Between 200 and 240 Units divided among selected muscles.
Additional information: If it is deemed appropriate by the treating physician, the

patient should be considered for re-injection when the
clinical effect of the previous injection has diminished. Re-
injections should occur no sooner than 12 weeks after the
previous injection. The degree and pattern of muscle
spasticity at the time of re-injection may necessitate
alterations in the dose of BOTOX and muscles to be injected.
The lowest effective dose should be used.
Focal lower limb spasticity associated with stroke
Recommended needle: Sterile 25, 27 or 30 gauge needle. Needle length should be

determined based on muscle location and depth.
Administration guidance: Localisation of the involved muscles with techniques such as

electromyographic guidance, nerve stimulation, or ultrasound
is recommended. Multiple injection sites may allow BOTOX
to have more uniform contact with the innervation areas of
the muscle and are especially useful in larger muscles.
The following diagrams indicate the injection sites for adult

lower limb spasticity:
Recommended dose: The recommended dose for treating adult lower limb
spasticity involving the ankle is 300 Units divided among 3
muscles.
Muscle Recommended Dose

Total Dosage; Number of Sites
Gastrocnemius
Medial head 75 Units; 3 sites
Lateral head 75 Units; 3 sites
Soleus 75 Units; 3 sites
Tibialis Posterior 75 Units; 3 sites
Additional information: If it is deemed appropriate by the treating physician, the

patient should be considered for re-injection when the
clinical effect of the previous injection has diminished, but
generally no sooner than 12 weeks after the previous
injection.
Blepharospasm/hemifacial spasm
Recommended needle: Sterile, 27-30 gauge/0.40-0.30 mm needle.
Administrative guidance: Electromyographic guidance is not necessary.
Recommended dose: The initial recommended dose is 1.25-2.5 Units (0.05-0.1 ml

volume at each site) injected into the medial and lateral
orbicularis oculi of the upper lid and the lateral orbicularis
oculi of the lower lid. Additional sites in the brow area, the
lateral orbicularis and in the upper facial area may also be
injected if spasms here interfere with vision.
The following diagrams indicate the possible injection sites:
Maximum dose: The initial dose should not exceed 25 Units per eye. In the
management of blepharospasm total dosing should not
exceed 100 Units in total every 12 weeks.
Additional information: Avoiding injection near levator palpebrae superioris may

reduce the complication of ptosis. Avoiding medial lower lid
injections, and thereby reducing diffusion into the inferior
oblique, may reduce the complication of diplopia.
In general, the initial effect of the injections is seen within

three days and reaches a peak at one to two weeks post-
treatment. Each treatment lasts approximately three months,
following which the procedure can be repeated indefinitely.
Normally no additional benefit is conferred by treating more
frequently than every three months.
At repeat treatment sessions, the dose may be increased up to

two-fold if the response from the initial treatment is
considered insufficient - usually defined as an effect that
does not last longer than two months. However, there
appears to be little benefit obtainable from injecting more
than 5 Units per site.
Patients with hemifacial spasm or VIIth nerve disorders

should be treated as for unilateral blepharospasm, with other
affected facial muscles being injected as needed.
Electromyographic control may be necessary to identify
affected small circumoral muscles.
Cervical dystonia
Recommended needle: A 25, 27 or 30 gauge/0.50-0.30 mm needle may be used for

superficial muscles, and a 22 gauge needle may be used for
deeper musculature.
Administrative guidance: The treatment of cervical dystonia typically may include

injection of BOTOX into the sternocleidomastoid, levator
scapulae, scalene, splenius capitis, semispinalis, longissimus
and/or the trapezius muscle(s). This list is not exhaustive as
any of the muscles responsible for controlling head position
may be involved and therefore require treatment. The
muscle mass and the degree of hypertrophy are factors to be
taken into consideration when selecting the appropriate dose.
Muscle activation patterns can change spontaneously in
cervical dystonia without a change in the clinical
presentation of dystonia.
In case of any difficulty in isolating the individual muscles,

injections should be made under electromyographic
assistance.
Multiple injection sites allow BOTOX to have more uniform

contact with the innervation areas of the dystonic muscle and
are especially useful in larger muscles. The optimal number
of injection sites is dependent upon the size of the muscle to
be chemically denervated.
Recommended dose: Dosing must be tailored to the individual patient based on the
patient's head and neck position, location of pain, muscle
hypertrophy, patient's body weight, and patient response.
Initial dosing in a naïve patient should begin at the lowest
effective dose.
To minimise the incidence of dysphagia, the sternomastoid

should not be injected bilaterally.
The following doses are recommended:
Type I Sternomastoid 50 - 100 Units; at least 2 sites

Head rotated Levator scapulae 50 Units; 1 - 2 sites
toward side of Scalene 25 - 50 Units; 1 - 2 sites
shoulder elevation Splenius capitis 25 - 75 Units; 1 - 3 sites
Trapezius 25 - 100 Units; 1 - 8 sites
Type II Sternomastoid 25 - 100 Units; at least 2 sites if >25 Units
Head rotation only given
Type III Sternomastoid 25 - 100 Units at posterior border; at least 2
Head tilted toward sites if >25 Units given
side of shoulder Levator scapulae 25 - 100 Units; at least 2 sites
elevation Scalene 25 - 75 Units; at least 2 sites
Trapezius 25 - 100 Units; 1 - 8 sites
Type IV Splenius capitis and 50 - 200 Units; 2 - 8 sites, treat bilaterally
Bilateral posterior cervicis (This is the total dose and not the dose for
cervical muscle each side of the neck)
spasm with
elevation of the face
Maximum dose: No more than 50 Units should be given at any one injection
site.
No more than 100 Units should be given to the
sternomastoid.
No more than 200 Units in total should be injected for the
first course of therapy, with adjustments made in subsequent
courses dependent on the initial response, up to a maximum
total dose of 300 Units.
Additional information: Treatment intervals of less than 10 weeks are not

recommended.
Chronic migraine
Recommended needle: Sterile 30 gauge, 0.5 inch needle.
A 1 inch needle may be needed in the neck region for

patients with extremely thick neck muscles.
Administration guidance: Injections should be divided across 7 specific head/neck

muscle areas as specified in the diagrams below. With the
exception of the procerus muscle, which should be injected at
1 site (midline), all muscles should be injected bilaterally
with half the number of injection sites administered to the
left, and half to the right side of the head and neck.
The following diagrams indicate the injection sites:
If there is a predominant pain location(s), additional

injections to one or both sides may be administered in up to 3
specific muscle groups (occipitalis, temporalis and
trapezius), up to the maximum dose per muscle as indicated
in the table below.
The following diagrams indicate recommended muscle

groups for optional additional injections:
Recommended dose: 155 Units to 195 Units administered intramuscularly as 0.1
ml (5 Units) injections to 31 and up to 39 sites.
Recommended Dose
Head/Neck Area Total Dosage (number of sitesa)
Corrugatorb 10 Units (2 sites)
Procerus 5 Units (1 site)
Frontalisb 20 Units (4 sites)
Temporalisb 40 Units (8 sites) up to 50 Units (up to 10
sites)
Occipitalisb 30 Units (6 sites) up to 40 Units (up to 8 sites)
Cervical Paraspinal Muscle
20 Units (4 sites)
Groupb
Trapeziusb 30 Units (6 sites) up to 50 Units (up to 10
sites)
Total Dose Range: 155 Units to 195 Units
31 to 39 sites
a
1 IM injection site = 0.1 ml = 5 Units BOTOX
b
Dose distributed bilaterally
Additional information: The recommended re-treatment schedule is every 12 weeks.
BLADDER DISORDERS:
Overactive bladder
Recommended needle: The injection needle should be filled (primed) with

approximately 1 ml of the reconstituted BOTOX solution
prior to the start of the injections (depending on the needle
length) to remove any air.
Administration guidance: The reconstituted solution of BOTOX (100 Units/10 ml) is

injected via a flexible or rigid cystoscope, avoiding the
trigone and base. The bladder should be instilled with enough
saline to achieve adequate visualisation for the injections and
avoid backflow of the product, but over-distension should be
avoided.
The needle should be inserted approximately 2 mm into the

detrusor, and 20 injections of 0.5 ml each (total volume 10
ml) should be spaced approximately 1 cm apart (see figure
below). For the final injection, approximately 1 ml of sterile
unpreserved normal saline (0.9% sodium chloride for
injection) should be injected so the full dose is delivered.
Recommended dose: The recommended dose is 100 Units of BOTOX, as 0.5 ml (5
Units) injections across 20 sites in the detrusor muscle.
Additional information: For the patient preparation and monitoring, see section 4.4.
After the injections are given, the saline used for bladder
wall visualisation should not be drained so that the patients
can demonstrate their ability to void prior to leaving the
clinic. The patient should be observed for at least 30 minutes
post-injection and until a spontaneous void has occurred.
Patients should be considered for reinjection when the

clinical effect of the previous injection has diminished but no
sooner than 3 months from the prior bladder injection.
Urinary incontinence due to neurogenic detrusor overactivity
Recommended needle: The injection needle should be filled (primed) with

approximately 1 ml of the reconstituted BOTOX solution
prior to the start of the injections (depending on the needle
length) to remove any air.
Administration guidance: The reconstituted solution of BOTOX (200 Units/30 ml) is

injected via a flexible or rigid cystoscope, avoiding the
trigone and base. The bladder should be instilled with enough
saline to achieve adequate visualisation for the injections and
avoid backflow of the product, but over-distension should be
avoided.
The needle should be inserted approximately 2 mm into the

detrusor, and 30 injections of 1 ml each (total volume 30 ml)
should be spaced approximately 1 cm apart (see figure
above). For the final injection, approximately 1 ml of sterile
unpreserved normal saline (0.9% sodium chloride for
injection) should be injected so the full dose is delivered.
After the injections are given, the saline used for bladder
wall visualisation should be drained.
Recommended dose: The recommended dose is 200 Units of BOTOX, as 1 ml

(~6.7 Units) injections across 30 sites in the detrusor muscle.
Additional information: For the patient preparation and monitoring, see section 4.4.
Patients should be considered for reinjection when the

clinical effect of the previous injection has diminished, but
no sooner than 3 months from the prior bladder injection.
Limited data are available beyond 2 treatments. No

urodynamic data beyond 2 treatments and no
histopathological data after repeated treatment are currently
available.
Patients should not receive multiple treatments in the event

of limited symptomatic improvement.
SKIN AND SKIN APPENDAGE DISORDERS:
Primary hyperhidrosis of the axillae
Recommended needle: Sterile 30 gauge needle.
Administration guidance: The hyperhidrotic area to be injected may be defined by

using standard staining techniques, e.g. Minor´s iodine-starch
test.
Recommended dose: 50 Units of BOTOX is injected intradermally to each axilla,

evenly distributed in multiple sites approximately 1-2 cm
apart.
The recommended injection volume for intradermal injection
is 0.1-0.2 ml.
Maximum dose: Doses other than 50 Units per axilla cannot be recommended.
Additional information: Clinical improvement generally occurs within the first week
after injection and persists for 4-7 months.
Repeat injection of BOTOX can be administered when the

clinical effect of a previous injection diminishes and the
treating physician deems it necessary. Injections should not
be repeated more frequently than every 16 weeks.
Glabellar lines seen at maximum frown
Administration guidance: Before injection, the thumb or index finger is to be placed

firmly below the orbital rim in order to prevent extravasation
below the orbital rim. The needle should be oriented
superiorly and medially during the injection. In addition,
injections near the levator palpebrae superioris muscle must
be avoided, particularly in patients with larger brow-
depressor complexes (depressor supercilii). Injections in the
corrugator muscle must be done in the central part of that
muscle, a distance of at least 1 cm above the arch of the
eyebrows (see figure).
Care should be taken to ensure that BOTOX is not injected

into a blood vessel when it is injected in the glabellar lines
seen at maximum frown, see section 4.4.
Recommended dose: A volume of 0.1 ml (4 Units) is administered in each of the 5

injection sites (see Figure): 2 injections in each corrugator
muscle and 1 injection in the procerus muscle for a total dose
of 20 Units.
Maximum dose: In order to reduce the risk of eyelid ptosis, the maximum
dose of 4 Units for each injection site as well as the number
of injection sites should not be exceeded.
Additional Information Treatment intervals 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 insufficient dose a second treatment session should

be initiated by adjusting the total dose up to 40 or 50 Units,
taking into account the analysis of the previous treatment
failure (see information in All indications).
The efficacy and safety of repeat injections of BOTOX for

the treatment of glabellar lines beyond 12 months has not
been evaluated.
Crow’s feet lines seen at maximum smile
Administration guidance: Injections should be given with the needle tip bevel up and
oriented away from the eye. The first injection (A) should be
made approximately 1.5 to 2.0 cm temporal to the lateral
canthus and just temporal to the orbital rim. If the lines in the
crow’s feet region are above and below the lateral canthus,
inject as shown in Figure 1. Alternatively, if the lines in the
crow’s feet region are primarily below the lateral canthus,
inject as shown in Figure 2.
In order to reduce the risk of eyelid ptosis, injections should

be made temporal to the orbital rim, thereby maintaining a
safe distance from the muscle controlling eyelid elevation.
Figure 1: Figure 2:
Care should be taken to ensure that BOTOX is not injected

into a blood vessel when it is injected in the crow’s feet lines
seen at maximum smile (see section 4.4).
Recommended dose: A volume of 0.1 ml (4 Units) is administered in each of the 3

injection sites per side (total of 6 injection sites) in the lateral
orbicularis oculi muscle, for a total dose of 24 Units in a total
volume of 0.6 ml (12 Units per side).
For simultaneous treatment with glabellar lines seen at

maximum frown, the dose is 24 Units for crow’s feet lines
seen at maximum smile and 20 Units for glabellar lines (see
Administration guidance for glabellar lines) for a total dose
of 44 Units in a total volume of 1.1 ml.
Maximum dose: In order to reduce the risk of eyelid ptosis, the maximum
dose of 4 Units for each injection site as well as the number
of injection sites should not be exceeded.
Additional information: Treatment intervals should not be more frequent than every 3
months.
The efficacy and safety of repeat injections of BOTOX for

the treatment of crow’s feet lines beyond 12 months has not
been evaluated.
ALL INDICATIONS:
In case of treatment failure after the first treatment session, i.e. absence, at one month after
injection, of significant clinical improvement from baseline, the following actions should be
taken:
− Clinical verification, which may include electromyographic examination in a specialist

setting, of the action of the toxin on the injected muscle(s);
− Analysis of the causes of failure, e.g. bad selection of muscles to be injected, insufficient
dose, poor injection technique, appearance of fixed contracture, antagonist muscles too
weak, formation of toxin-neutralising antibodies;
− Re-evaluation of the appropriateness of treatment with botulinum toxin type A;
− In the absence of any undesirable effects secondary to the first treatment session, instigate
a second treatment session as following: i) adjust the dose, taking into account the
analysis of the earlier treatment failure; ii) use EMG; and iii) maintain a three-month
interval between the two treatment sessions.
In the event of treatment failure or diminished effect following repeat injections alternative
treatment methods should be employed.
4.3 Contraindications
- known hypersensitivity to botulinum toxin type A or to any of the excipients listed in

section 6.1;
- presence of infection at the proposed injection site(s).
For the management of bladder disorders:

- urinary tract infection at the time of treatment;
- acute urinary retention at the time of treatment, in patients who are not routinely
catheterising;
- patients who are not willing and/or able to initiate catheterisation post-treatment if required;
- presence of bladder calculi.
4.4 Special warnings and precautions for use
The recommended dosages and frequencies of administration of BOTOX should not be

exceeded due to the potential for overdose, exaggerated muscle weakness, distant spread of
toxin and the formation of neutralising antibodies. Initial dosing in treatment naïve patients
should begin with the lowest recommended dose for the specific indication.
Prescribers and patients should be aware that side effects can occur despite previous
injections being well tolerated. Caution should therefore be exercised on the occasion of each
administration.
Side effects related to spread of toxin distant from the site of administration have been
reported (see section 4.8), sometimes resulting in death, which in some cases was associated
with dysphagia, pneumonia and/or significant debility.
The symptoms are consistent with the mechanism of action of botulinum toxin and have been
reported hours to weeks after injection. The risk of symptoms is probably greatest in patients
who have underlying conditions and comorbidities that would predispose them to these
symptoms, including children and adults treated for spasticity, and are treated with high
doses.
Patients treated with therapeutic doses may also experience exaggerated muscle weakness.
Elderly and debilitated patients should be treated with caution. Generally, clinical studies of
BOTOX did not identify differences in responses between the elderly and younger patients
except for facial lines (see section 5.1). Dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range.
Consideration should be given to the risk-benefit implications for the individual patient before
embarking on treatment with BOTOX.
Dysphagia has also been reported following injection to sites other than the cervical
musculature (see section 4.4 ‘Cervical Dystonia’).
BOTOX should only be used with extreme caution and under close supervision in patients
with subclinical or clinical evidence of defective neuromuscular transmission e.g. myasthenia
gravis or Lambert-Eaton Syndrome in patients with peripheral motor neuropathic diseases
(e.g. amyotrophic lateral sclerosis or motor neuropathy) and in patients with underlying
neurological disorders. Such patients may have an increased sensitivity to agents such as
BOTOX, even at therapeutic doses, which may result in excessive muscle weakness and an
increased risk of clinically significant systemic effects including severe dysphagia and
respiratory compromise. 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 or caregivers should be advised to seek immediate medical care if swallowing,

speech or respiratory disorders arise.
As with any treatment with the potential to allow previously-sedentary patients to resume
activities, the sedentary patient should be cautioned to resume activity gradually.
The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures,
must be understood prior to administering BOTOX and injection into vulnerable anatomic
structures must be avoided.
Pneumothorax associated with injection procedure has been reported following the
administration of BOTOX near the thorax.
Caution is warranted when injecting in proximity to the lung (particularly the apices) or other
vulnerable anatomic structures.
Serious adverse events including fatal outcomes have been reported in patients who had
received off-label injections of BOTOX directly into salivary glands, the oro-lingual-
pharyngeal region, oesophagus and stomach. Some patients had pre-existing dysphagia or
significant debility.
Serious and/or immediate hypersensitivity reactions have been rarely reported including
anaphylaxis, serum sickness, urticaria, soft tissue oedema, and dyspnoea. Some of these
reactions have been reported following the use of BOTOX either alone or in conjunction with
other products associated with similar reactions. If such a reaction occurs further injection of
BOTOX should be discontinued and appropriate medical therapy, such as epinephrine,
immediately instituted. One case of anaphylaxis has been reported in which the patient died
after being injected with BOTOX inappropriately diluted with 5 ml of 1% lidocaine.
As with any injection, procedure-related injury could occur. An injection could result in
localised infection, pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling,
erythema, and/or bleeding/bruising. Needle-related pain and/or anxiety may result in
vasovagal responses, e.g. syncope, hypotension, etc.
Caution should be used when BOTOX is used in the presence of inflammation at the
proposed injection site(s) or when excessive weakness or atrophy is present in the target
muscle. Caution should also be exercised when BOTOX is used for treatment of patients
with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis or motor
neuropathy).
There have been reports of adverse events following administration of BOTOX involving the
cardiovascular system, including arrhythmia and myocardial infarction, some with fatal
outcomes. Some of these patients had risk factors including pre-existing cardiovascular
disease.
New onset or recurrent seizures have been reported, typically in patients who are predisposed
to experiencing these events. The exact relationship of these events to botulinum toxin
injection has not been established. The reports in children were predominantly from cerebral
palsy patients treated for spasticity.
Formation of neutralising antibodies to botulinum toxin type A may reduce the effectiveness
of BOTOX treatment by inactivating the biological activity of the toxin. Results from some
studies suggest that BOTOX injections at more frequent intervals or at higher doses may lead
to greater incidence of antibody formation. When appropriate, the potential for antibody
formation may be minimised by injecting with the lowest effective dose given at the longest
clinically indicated intervals between injections.
Clinical fluctuations during the repeated use of BOTOX (as with all botulinum toxins) may be
a result of different vial reconstitution procedures, injection intervals, muscles injected and
slightly differing potency values given by the biological test method used.
Paediatric use
The safety and efficacy of BOTOX in indications other than those described for the paediatric
population in section 4.1 has not been established. Post-marketing reports of possible distant
spread of toxin have been very rarely reported in paediatric patients with comorbidities,
predominantly with cerebral palsy. In general the dose used in these cases was in excess of
that recommended (see section 4.8).
There have been rare spontaneous reports of death sometimes associated with aspiration
pneumonia in children with severe cerebral palsy after treatment with botulinum toxin,
including following off-label use (e.g. neck area). Extreme caution should be exercised when
treating paediatric patients who have significant neurologic debility, dysphagia, or have a
recent history of aspiration pneumonia or lung disease.
Treatment in patients with poor underlying health status should be administered only if the
potential benefit to the individual patient is considered to outweigh the risks.
NEUROLOGIC DISORDERS
Focal spasticity associated with paediatric cerebral palsy and spasticity of the ankle, hand
and wrist in adult post-stroke patients
BOTOX is a treatment of focal spasticity that has only been studied in association with usual
standard of care regimens, and is not intended as a replacement for these treatment modalities.
BOTOX is not likely to be effective in improving range of motion at a joint affected by a
fixed contracture.
BOTOX should only be used for the treatment of focal spasticity in adult post-stroke patients
if muscle tone reduction is expected to result in improved function (e.g. improvements in
gait), or improved symptoms (e.g. reduction in muscle spasms or pain), and/or to facilitate
care.
Caution should be exercised when treating adult patients with post-stroke spasticity who may
be at increased risk of fall. In clinical studies where patients were treated for lower limb
spasticity (some of whom also received concurrent treatment for upper limb spasticity), the
incidence of fall was 7.2% and 4.9% of patients in the BOTOX and placebo groups,
respectively.
There have been post-marketing reports of death (sometimes associated with aspiration
pneumonia) and of possible distant spread of toxin in children with co-morbidities,
predominantly cerebral palsy following treatment with botulinum toxin. See warnings under
section 4.4, ‘Paediatric use’.
Blepharospasm
Reduced blinking following botulinum toxin injection into the orbicularis muscle can lead to
corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients
with VII nerve disorders. Careful testing of corneal sensation in eyes previously operated
upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment
of any epithelial defect should be employed. This may require protective drops, ointment,
therapeutic soft contact lenses, or closure of the eye by patching or other means.
Ecchymosis occurs easily in the soft eyelid tissues. This can be minimised by applying gentle
pressure at the injection site immediately after injection.
Because of the anticholinergic activity of botulinum toxin, caution should be exercised when
treating patients at risk for angle closure glaucoma, including patients with anatomically
narrow angles.
Cervical dystonia
Patients with cervical dystonia should be informed of the possibility of experiencing
dysphagia which may be very mild, but could be severe. Dysphagia may persist for two to
three weeks after injection, but has been reported to last up to five months post-injection.
Consequent to the dysphagia there is the potential for aspiration, dyspnoea and occasionally
the need for tube feeding. In rare cases dysphagia followed by aspiration pneumonia and
death has been reported.
Limiting the dose injected into the sternocleidomastoid muscle to less than 100 Units may
decrease the occurrence of dysphagia. Patients with smaller neck muscle mass, or patients
who receive bilateral injections into the sternocleidomastoid muscle, have been reported to be
at greater risk of dysphagia. Dysphagia is attributable to the spread of the toxin to the
oesophageal musculature. Injections into the levator scapulae may be associated with an
increased risk of upper respiratory infection and dysphagia.
Dysphagia may contribute to decreased food and water intake resulting in weight loss and
dehydration. Patients with subclinical dysphagia may be at increased risk of experiencing
more severe dysphagia following a BOTOX injection.
Chronic migraine
No efficacy has been shown for BOTOX in the prophylaxis of headaches in patients with
episodic migraine (headaches on < 15 days per month).
BLADDER DISORDERS
Patient preparation and monitoring

Prophylactic antibiotics should be administered to patients with sterile urine or asymptomatic
bacteriuria in accordance with local standard practice.
The decision to discontinue anti-platelet therapy should be subject to local guidance and
benefit/risk consideration for the individual patient. Patients on anti-coagulant therapy need to
be managed appropriately to decrease the risk of bleeding.
Appropriate medical caution should be exercised when performing the cystoscopy. The
patient should be observed for at least 30 minutes post-injection.
In patients who are not regularly practicing catheterisation, post-void residual urine volume
should be assessed within 2 weeks post-treatment and periodically as medically appropriate.
Patients should be instructed to contact their physician if they experience difficulties in
voiding as catheterisation may be required.
Overactive bladder
Prior to injection an intravesical instillation of diluted local anaesthetic, with or without
sedation, may be used, per local site practice. If a local anaesthetic instillation is performed,
the bladder should be drained and rinsed with sterile saline before the next steps of the
injection procedure.

BOTOX injection can be performed under general or local anaesthesia with or without
sedation. If a local anaesthetic intravesical instillation is performed, the bladder should be
drained and rinsed with sterile saline before the next steps of the injection procedure.
Autonomic dysreflexia associated with the procedure can occur and greater vigilance is
required in patients known to be at risk.
SKIN AND SKIN APPENDAGE DISORDER

Medical history and physical examination, along with specific additional investigations as
required, should be performed to exclude potential causes of secondary hyperhidrosis (e.g.
hyperthyroidism, phaeochromocytoma). This will avoid symptomatic treatment of
hyperhidrosis without the diagnosis and/or treatment of underlying disease.
Glabellar lines seen at maximum frown and/or crow’s feet lines seen at maximum smile
It is mandatory that BOTOX is used for one single patient treatment only during a single
session. The excess of unused product must be disposed of as detailed in section 6.6.
Particular precautions should be taken for product preparation and administration as well as
for the inactivation and disposal of the remaining unused solution (see section 6.6).
The use of BOTOX is not recommended in individuals under 18 years. There is limited phase
3 clinical data with BOTOX in patients older than 65 years.
Care should be taken to ensure that BOTOX is not injected into a blood vessel when it is
injected in the glabellar seen at maximum frown or in the crow’s feet lines seen at maximum
smile , see section 4.2. There is a risk of eyelid ptosis following treatment, refer to Section 4.2
for administration instructions on how to minimise this risk.
4.5 Interaction with other medicinal products and other forms of interaction
Theoretically, the effect of botulinum toxin may be potentiated by aminoglycoside antibiotics

or spectinomycin, or other medicinal products that interfere with neuromuscular transmission
(e.g. neuromuscular blocking agents).
The effect of administering different botulinum neurotoxin serotypes at the same time or
within several months of each other is unknown. Excessive neuromuscular weakness may be
exacerbated by administration of another botulinum toxin prior to the resolution of the effects
of a previously administered botulinum toxin.
No interaction studies have been performed. No interactions of clinical significance have

been reported.
There are no data available on the concomitant use of anticholinergics with BOTOX
injections in the management of overactive bladder.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of botulinum toxin type A in pregnant women.
Studies in animals have shown reproductive toxicity (see Section 5.3). The potential risk for
humans is unknown. BOTOX is not recommended during pregnancy and in women of
childbearing potential not using contraception.
Breast-feeding
There is no information on whether BOTOX is excreted in human milk. The use of BOTOX
during breast-feeding cannot be recommended.
Fertility
There are no adequate data on the effects on fertility from the use of botulinum toxin type A
in women of childbearing potential. Studies in male and female rats have shown fertility
reductions (see section 5.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
However, BOTOX may cause asthenia, muscle weakness, somnolence, dizziness and visual
disturbance, which could affect driving and the operation of machinery.
4.8 Undesirable effects
a) General
In controlled clinical trials adverse events considered by the investigators to be related to

BOTOX were reported in 35% of the patients with blepharospasm, 28% with cervical
dystonia, 17% with paediatric cerebral palsy, 11% with primary hyperhidrosis of the axillae,
16% with focal spasticity of the upper limb associated with stroke, 15% with focal spasticity
of the lower limb associated with stroke, 26% with overactive bladder, and 32% with
neurogenic detrusor overactivity. In clinical trials for chronic migraine, the incidence was
26% with the first treatment and declined to 11% with a second treatment.
In controlled clinical trials for glabellar lines seen at maximum frown, adverse events
considered by the investigators to be related to BOTOX were reported in 23% (placebo 19%)
of patients. In treatment cycle 1 of the pivotal controlled clinical trials for crow’s feet lines
seen at maximum smile, such events were reported in 8% (24 Units for crow’s feet lines
alone) and 6% (44 Units: 24 Units for crow’s feet lines administered simultaneously with 20
Units for glabellar lines) of patients compared to 5% for placebo.
Adverse reactions may be related to treatment, injection technique or both. In general, adverse
reactions occur within the first few days following injection and, while generally transient,
may have a duration of several months or, in rare cases, longer.
Local muscle weakness represents the expected pharmacological action of botulinum toxin in
muscle tissue. However, weakness of adjacent muscles and/or muscles remote from the site of
injection has been reported.
As is expected for any injection procedure, localised pain, inflammation, paraesthesia,

hypoaesthesia, tenderness, swelling/oedema, erythema, localised infection, bleeding and/or
bruising have been associated with the injection. Needle-related pain and/or anxiety have
resulted in vasovagal responses, including transient symptomatic hypotension and syncope.
Fever and flu syndrome have also been reported after injections of botulinum toxin.
b) Adverse reactions - frequency by indication
The frequency of adverse reactions reported in the clinical trials is defined as follows:
Very Common (≥ 1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare
(≥1/10,000 to <1/1,000); Very Rare (<1/10,000).
NEUROLOGIC DISORDERS:
Focal spasticity associated with paediatric cerebral palsy
System Organ Class Preferred Term Frequency

Infections and infestations Viral infection, ear infection Very Common
Nervous system disorders Somnolence, gait disturbance, paraesthesia Common
Skin and subcutaneous Rash Common
tissue disorders
Musculoskeletal and Myalgia, muscular weakness, pain in Common
connective tissue extremity
disorders
Renal and urinary Urinary incontinence Common
disorders
General disorders and Malaise, injection site pain, asthenia Common
administration site
conditions
Injury, poisoning and Fall Common
procedural complications

Psychiatric disorders Depression, insomnia Uncommon
Nervous system disorders Hypertonia Common
Hypoasthesia, headache, paraesthesia, Uncommon
incoordination, amnesia
Ear and labyrinth Vertigo Uncommon
disorders
Vascular disorders Orthostatic hypotension Uncommon
Gastrointestinal disorders Nausea, oral paraesthesia Uncommon
Skin and subcutaneous Ecchymosis, purpura Common
tissue disorders Dermatitis, pruritus, rash Uncommon
Musculoskeletal and Pain in extremity, muscle weakness Common
connective tissue Arthralgia, bursitis Uncommon
disorders
General disorders and Injection site pain, pyrexia, influenza-like Common
administration site illness, injection site haemorrhage, injection
conditions site irritation
Asthenia, pain, injection site Uncommon
hypersensitivity, malaise, peripheral oedema
Some of the uncommon events may be disease related.

Skin and subcutaneous Rash Common
tissue disorders
Musculoskeletal and Arthralgia, musculoskeletal stiffness Common
connective tissue
disorders
General disorders and Peripheral oedema Common
administration site
conditions
Blepharospasm/hemifacial spasm

Nervous system disorders Dizziness, facial paresis, facial palsy Uncommon
Eye disorders Eyelid ptosis Very Common
Punctate keratitis, lagophthalmos, dry eye, Common
photophobia, eye irritation, lacrimation
increase
Keratitis, ectropion, diplopia, entropion, Uncommon
visual disturbance, blurred vision
Eyelid oedema Rare
Corneal ulceration, corneal epithelium Very Rare
defect, corneal perforation
Skin and subcutaneous Ecchymosis Common
tissue disorders Rash/dermatitis Uncommon
General disorders and Irritation, face oedema Common
administration site Fatigue Uncommon
conditions
Cervical dystonia

Infections and infestations Rhinitis, upper respiratory infection Common
Nervous system disorders Dizziness, hypertonia, hypoaesthesia, Common
somnolence, headache
Eye disorders Diplopia, eyelid ptosis Uncommon
Respiratory, thoracic and Dyspnoea, dysphonia Uncommon
mediastinal disorders
Gastrointestinal disorders Dysphagia Very common
Dry mouth, nausea Common
Musculoskeletal and Muscular weakness Very common
connective tissue Musculoskeletal stiffness and Common
disorders musculoskeletal soreness
General disorders and Pain Very common
administration site Asthenia, influenza-like illness, malaise Common
conditions Pyrexia Uncommon
Chronic migraine

Nervous system disorders Headache*, migraine*, facial paresis Common
Eye disorders Eyelid ptosis Common
Eyelid oedema Uncommon
Gastrointestinal disorders Dysphagia Uncommon
Skin and subcutaneous Pruritis, rash Common
tissue disorders Pain of skin Uncommon
Musculoskeletal and Neck pain, myalgia, musculoskeletal pain, Common
connective tissue musculoskeletal stiffness, muscle spasms,
disorders muscle tightness, muscular weakness
Pain in jaw Uncommon
General disorders and Injection site pain Common
administration site
conditions
* In placebo-controlled trials, headache and migraine, including serious cases of intractable or

worsening of headache/migraine, were reported more frequently with BOTOX (9%) than with
placebo (6%). They typically occurred within the first month after the injections and their
incidence declined with repeated treatments.

BLADDER DISORDERS:
Overactive bladder

Infections and infestations Urinary tract infection Very common
Bacteriuria Common
Renal and urinary Dysuria† Very common
disorders Urinary retention, pollakiuria, leukocyturia Common
Investigations Residual urine volume* Common
*elevated post-void residual urine volume (PVR) not requiring catheterisation
†procedure-related adverse reactions
In the phase 3 clinical trials urinary tract infection was reported in 25.5% of patients treated
with BOTOX 100 Units and 9.6% of patients treated with placebo. Urinary retention was
reported in 5.8% of patients treated with BOTOX 100 Units and in 0.4% of patients treated
with placebo. Clean intermittent catheterisation was initiated in 6.5% of patients following
treatment with BOTOX 100 Units versus 0.4% in the placebo group.
Overall, 42.5% of patients (n = 470) were ≥ 65 years of age and 15.1% (n = 167) were ≥ 75
years of age. No overall difference in the safety profile following BOTOX treatment was
observed between patients ≥ 65 years compared to patients < 65 years in these studies, with
the exception of urinary tract infection where the incidence was higher in elderly patients in
both the placebo and BOTOX groups compared to the younger patients.
No change was observed in the overall safety profile with repeat dosing.

Infections and infestations Urinary tract infectiona, b, bacteriuriab Very Common
Investigations Residual urine volume**b Very Common
Psychiatric disorders Insomnia†a Common
Gastrointestinal disorders Constipation†a Common
Musculoskeletal and Muscular weakness†a, muscle spasma Common
connective tissue
disorders
Renal and urinary Urinary retentiona, b Very Common
disorders Haematuria*a, b, bladder diverticuluma, Common
dysuria*b
General disorders and Fatigue†a, gait disturbance†a Common
administration site
conditions
Injury, poisoning and Autonomic dysreflexia*a, fall†a Common
procedural complications
* procedure-related adverse reactions
** elevated PVR not requiring catheterisation
† only in multiple sclerosis
a Adverse reactions occurring in the pivotal Phase 3 clinical trials
b Adverse reactions occurring in the post-approval study of BOTOX 100U in MS patients not
catheterising at baseline
In the phase 3 clinical trials, urinary tract infection was reported in 49% of patients treated
with BOTOX 200 Units and in 36% of patients treated with placebo (in multiple sclerosis
patients: 53% vs. 29%, respectively; in spinal cord injury patients: 45% vs. 42%,
respectively). Urinary retention was reported in 17% of patients treated with BOTOX 200
Units and in 3% of patients treated with placebo (in multiple sclerosis patients: 29% vs. 4%,
respectively; in spinal cord injury patients: 5% vs. 1%, respectively). Among patients who
were not catheterising at baseline prior to treatment, catheterisation was initiated in 39%
following treatment with BOTOX 200 Units versus 17% on placebo. The risk of urinary
retention increased in patients older than 65 years.
No change in the type and frequency of adverse reactions was observed following 2
treatments.
In the post-approval study of BOTOX 100 Units in MS patients not catheterising at baseline,
no difference on the MS exacerbation annualised rate (i.e. number of MS exacerbation events
per patient-year) was observed (BOTOX=0, placebo=0.07).
Catheterisation was initiated in 15.2% of patients following treatment with BOTOX 100 Units
versus 2.6% on placebo (refer to section 5.1).
SKIN AND SKIN APPENDAGE DISORDER:

Nervous system disorders Headache, paraesthesia Common
Vascular disorders Hot flushes Common
Gastrointestinal disorders Nausea Uncommon
Skin and subcutaneous Hyperhidrosis (non axillary sweating), Common
tissue disorders abnormal skin odour, pruritus, subcutaneous
nodule, alopecia
Musculoskeletal and Pain in extremity Common
connective tissue Muscular weakness, myalgia, arthropathy Uncommon
disorders
General disorders and Injection site pain Very common
administration site Pain, injection site oedema, injection site Common
conditions haemorrhage, injection site hypersensitivity,
injection site irritation, asthenia, injection
site reactions
Increase in non axillary sweating was reported in 4.5% of patients within 1 month after
injection and showed no pattern with respect to anatomical sites affected. Resolution was
seen in approximately 30% of the patients within four months.
Weakness of the arm has been also reported uncommonly (0.7%) and was mild, transient, did
not require treatment and recovered without sequelae. This adverse event may be related to
treatment, injection technique, or both. In the uncommon event of muscle weakness being
reported a neurological examination may be considered. In addition, a re-evaluation of
injection technique prior to subsequent injection is advisable to ensure intradermal placement
of injections.
In an uncontrolled safety study of BOTOX (50 Units per axilla) in paediatric patients 12 to 17
years of age (n= 144), adverse reactions occurring in more than a single patient (2 patients
each) comprised injection site pain and hyperhidrosis (non-axillary sweating).
Glabellar lines

Infections and infestations Infection Uncommon
Psychiatric disorders Anxiety Uncommon
Nervous system disorders Headache Common
Paraesthesia, dizziness Uncommon
Eye disorders Eyelid ptosis Common
Blepharitis, eye pain, visual disturbance Uncommon
Gastrointestinal disorders Nausea, oral dryness Uncommon
Skin and subcutaneous tissue Erythema Common
disorders Skin tightness, oedema (face, eyelid, Uncommon
periorbital), photosensitivity reaction, pruritus,
dry skin
Musculoskeletal and Localised muscle weakness Common
connective tissue disorders Muscle twitching Uncommon
General disorders and Face pain Common
administration site conditions Flu syndrome, asthenia, fever Uncommon
Crow’s feet lines
The following adverse drug reactions were reported in the double-blind, placebo-controlled
clinical studies following injection of BOTOX 24 Units for crow’s feet lines alone:

Eye disorders Eyelid oedema Common
General disorders and Injection site haemorrhage*, injection site Common
administration site haematoma*
conditions Injection site pain*, injection site Uncommon
paraesthesia
*procedure-related adverse reactions
Crow’s feet lines and glabellar lines
The following adverse drug reactions were reported in double-blind, placebo-controlled

clinical studies following injection of BOTOX 44 Units (simultaneous treatment of crow’s
feet lines and glabellar lines):

General disorders and Injection site haematoma* Common
administration site Injection site haemorrhage*, injection site Uncommon
conditions pain*
*procedure-related adverse reactions
No change was observed in the overall safety profile following repeat dosing.
c) Additional information
The following list includes adverse drug reactions or other medically relevant adverse events
that have been reported since the drug has been marketed, regardless of indication, and may
be in addition to those cited in section 4.4 (Special warnings and precautions for use), and
section 4.8 (Undesirable effects).
System Organ Class Preferred Term

Immune system disorders Anaphylaxis, angioedema, serum sickness, urticaria
Metabolism and nutrition Anorexia
disorders
Nervous system disorders Brachial plexopathy, dysphonia, dysarthria, facial paresis,
hypoaesthesia, muscle weakness, myasthenia gravis, peripheral
neuropathy, paraesthesia, radiculopathy, seizures, syncope,
facial palsy
Eye disorders Angle-closure glaucoma (for treatment of blepharospasm),
lagophthalmos, strabismus, blurred vision, visual disturbance
Ear and labyrinth Hypoacusis, tinnitus, vertigo
disorders
Cardiac disorders Arrhythmia, myocardial infarction
Respiratory, thoracic and Aspiration pneumonia (some with fatal outcome), dyspnoea,
mediastinal disorders respiratory depression, respiratory failure
Gastrointestinal disorders Abdominal pain, diarrhoea, constipation, dry mouth,
dysphagia, nausea, vomiting
Skin and subcutaneous Alopecia, dermatitis psoriasiform, erythema multiforme,
tissue disorders hyperhidrosis, madarosis, pruritus, rash
Musculoskeletal and Muscle atrophy, myalgia
connective tissue disorders
General disorders and Denervation atrophy, malaise, pyrexia
administration site
conditions
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions via the
Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Overdose of BOTOX is a relative term and depends upon dose, site of injection, and
underlying tissue properties. No cases of systemic toxicity resulting from accidental injection
of BOTOX have been observed. Excessive doses may produce local, or distant, generalised
and profound neuromuscular paralysis.
No cases of ingestion of BOTOX have been reported.
Signs and symptoms of overdose are not apparent immediately post-injection. Should
accidental injection or ingestion occur or overdose be suspected, the patient should be
medically monitored for up to several weeks for progressive signs and symptoms of muscular
weakness, which could be local or distant from the site of injection and may include ptosis,
diplopia, dysphagia, dysarthria, generalised weakness or respiratory failure. These patients
should be considered for further medical evaluation and appropriate medical therapy
immediately instituted, which may include hospitalisation.
If the musculature of the oropharynx and oesophagus are affected, aspiration may occur
which may lead to development of aspiration pneumonia. If the respiratory muscles become
paralysed or sufficiently weakened, intubation and assisted respiration will be required until
recovery takes place and may involve the need for a tracheostomy and prolonged mechanical
ventilation, in addition to other general supportive care.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC class M03A X01 and ATC class D11AX.
The active constituent in BOTOX is a protein complex derived from Clostridium botulinum.
The protein consists of type A neurotoxin and several other proteins. Under physiological
conditions it is presumed that the complex dissociates and releases the pure neurotoxin.
Clostridium botulinum toxin type A neurotoxin complex blocks peripheral acetyl choline
release at presynaptic cholinergic nerve terminals.
Intramuscular injection of the neurotoxin complex blocks cholinergic transport at the

neuromuscular junction by preventing the release of acetylcholine. The nerve endings of the
neuromuscular junction no longer respond to nerve impulses and secretion of the
chemotransmitter is prevented (chemical denervation). Re-establishment of impulse
transmission is by newly formed nerve endings and motor end plates. Clinical evidence
suggests that BOTOX reduces pain and neurogenic inflammation and elevates cutaneous heat
pain thresholds in a capsaicin induced trigeminal sensitization model. Recovery after
intramuscular injection takes place normally within 12 weeks of injection as nerve terminals
sprout and reconnect with the endplates.
After intradermal injection, where the target is the eccrine sweat glands, the effect lasted for
about 4-7 months in patients treated with 50 Units per axilla.
There is limited clinical trial experience of the use of BOTOX in primary axillary
hyperhidrosis in adolescents between the ages of 12 and 18. A single, year long, uncontrolled,
repeat dose, safety study was conducted in US paediatric patients 12 to 17 years of age
(N=144) with severe primary hyperhidrosis of the axillae. Participants were primarily female
(86.1%) and Caucasian (82.6%). Participants were treated with a dose of 50 Units per axilla
for a total dose of 100 Units per patient per treatment. However, no dose finding studies have
been conducted in adolescents so no recommendation on posology can be made. Efficacy and
safety of BOTOX in this group have not been established.
BOTOX blocks the release of neurotransmitters associated with the genesis of pain. The
presumed mechanism for headache prophylaxis is by blocking peripheral signals to the
central nervous system, which inhibits central sensitisation, as suggested by pre-clinical and
clinical pharmacodynamic studies.
Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity
via inhibition of acetylcholine release. In addition BOTOX inhibits afferent neurotransmitters
and sensory pathways.
Clinical efficacy and safety
NEUROLOGIC DISORDERS
In controlled and open, non-controlled studies, doses between 200 and 240 Units in wrist and
flexor muscles were divided among the selected muscles at a given treatment session. In
controlled studies, improvement in muscle tone occurred within two weeks with the peak
effect generally seen within four to six weeks. In an open, non-controlled continuation study,
most patients were re-injected after an interval of 12 to 16 weeks, when the effect on muscle
tone had diminished. These patients received up to four injections with a maximal cumulative
dose of 960 Units over 54 weeks.
A double-blind, placebo-controlled, randomised, multi-centre, phase 3 clinical study was

conducted in adult post-stroke patients with lower limb spasticity affecting the ankle. A total
of 120 patients were randomised to receive either BOTOX (n=58; total dose of 300 Units) or
placebo (n=62).
Significant improvement compared to placebo was observed in the primary endpoint for the
overall change from baseline up to week 12 in Modified Ashworth Scale (MAS) ankle score,
which was calculated using the area under the curve (AUC) approach. Significant
improvements compared to placebo were also observed for the mean change from baseline in
MAS ankle score at individual post-treatment visits at weeks 4, 6 and 8. The proportion of
responders (patients with at least a 1-grade improvement) was also significantly higher (67%-
68%) than in placebo-treated patients (31%-36%) at these visits.
BOTOX treatment was also associated with significant improvement in the investigator’s
clinical global impression (CGI) of functional disability compared to placebo although the
difference was not significant for the patient’s CGI.
Cervical dystonia
In initial controlled clinical trials to establish safety and efficacy for cervical dystonia, doses
of reconstituted BOTOX ranged from 140 to 280 Units. In more recent studies, doses ranged
from 95 to 360 Units (with an approximate mean of 240 Units). Clinical improvement
generally occurs within the first two weeks after injection. The maximum clinical benefit
generally occurs by six weeks post-injection. The duration of beneficial effect reported in
clinical studies showed substantial variation (from 2 to 33 weeks) with a typical duration of
approximately 12 weeks.
Chronic migraine
Chronic migraine patients without any concurrent headache prophylaxis who, during a 28-day
baseline, had at least 4 episodes and ≥ 15 headache days (with at least 4 hours of continuous
headache) with at least 50% being migraine/probable migraine, were studied in two Phase 3
clinical trials. Patients were allowed to use acute headache treatments and 66% overused
acute treatments during the baseline period.
During the double-blind phase of the trials, the main results achieved after two BOTOX
treatments administered at a 12-week interval are shown in the table below.
Mean change from baseline at Week 24 BOTOX Placebo

N=688 N=696 P-value
Frequency of headache days -8.4 -6.6 < 0.001
Frequency of moderate/severe headache days -7.7 -5.8 < 0.001
Frequency of migraine/probable migraine days -8.2 -6.2 < 0.001
% patients with 50% reduction in headache days 47% 35% < 0.001
Total cumulative hours of headache on headache days 120 80 < 0.001
Frequency of headache episodes -5.2 -4.9 0.009
Total HIT-6* scores -4.8 -2.4 < 0.001
* Headache Impact Test
The treatment effect appeared smaller in the subgroup of male patients (n=188) than in the
whole study population.
BLADDER DISORDERS
Overactive bladder
Two double-blind, placebo-controlled, randomised, 24-week phase 3 clinical studies were

conducted in patients with overactive bladder with symptoms of urge urinary incontinence,
urgency, and frequency. A total of 1105 patients (mean age of 60 years), whose symptoms
had not been adequately managed with at least one anticholinergic therapy (inadequate
response or intolerable side effects), were randomised to receive either 100 Units of BOTOX
(n=557), or placebo (n=548), after having discontinued anticholinergics for more than one
week.
Primary and Secondary Endpoints at Baseline and Change from Baseline in Pooled Pivotal
Studies:
Botox Placebo P-value

100 Units
(N=557) (N=548)
Daily Frequency of Urinary Incontinence
Episodes
Mean Baseline 5.49 5.39
Mean Change† at Week 2 -2.66 -1.05 < 0.001
Mean Change† at Week 6 -2.97 -1.13 < 0.001
Mean Change† at Week 12a -2.74 -0.95 < 0.001
Proportion with Positive Treatment Response
using Treatment Benefit Scale (%)
Week 2 64.4 34.7 < 0.001
Week 6 68.1 32.8 < 0.001
Week 12a 61.8 28.0 < 0.001
Daily Frequency of Micturition Episodes
Mean Change† at Week 12b -2.19 -0.82 < 0.001
Daily Frequency of Urgency Episodes
Mean Change† at Week 12b -3.08 -1.12 < 0.001
Incontinence Quality of Life Total Score
Mean Change† at Week 12bc +21.3 +5.4 < 0.001
King’s Health Questionnaire: Role Limitation
Mean Change† at Week 12bc -24.3 -3.9 < 0.001
King’s Health Questionnaire: Social
Limitation
Mean Change† at Week 12bc -16.1 -2.5 < 0.001
Percentage of patients achieving
full continence at Week 12 (dry patients over a 27.1% 8.4% < 0.001
3-day diary)
Percentage of patients achieving reduction
from baseline in urinary incontinence episodes
at Week 12
at least 75% 46.0% 17.7%
at least 50% 60.5% 31.0%
†
Least Squares (LS) mean changes are presented
a
Co-primary endpoints
b
Secondary endpoints
c
Pre-defined minimally important change from baseline was +10 points for I-QOL and -
5 points for KHQ
The median duration of response following BOTOX treatment, based on patient request for
re-treatment, was 166 days (~24 weeks). The median duration of response, based on patient
request for re-treatment, in patients who continued into the open label extension study and
received treatments with only BOTOX 100 Units (N=438), was 212 days (~30 weeks).
A total of 839 patients were evaluated in a long-term open-label extension study. For all
efficacy endpoints, patients experienced consistent response with re-treatments. The mean
reductions from baseline in daily frequency of urinary incontinence were -3.07 (n=341), -3.49
(n=292), and -3.49 (n=204) episodes at week 12 after the first, second, and third BOTOX 100
Unit treatments, respectively. The corresponding proportions of patients with a positive
treatment response on the Treatment Benefit Scale were 63.6% (n=346), 76.9% (n=295), and
77.3% (n=207), respectively.
In the pivotal studies, none of the 615 patients with analysed serum specimens developed
neutralising antibodies after 1 – 3 treatments. In patients with analysed specimens from the
pivotal phase 3 and the open-label extension studies, neutralising antibodies developed in 0 of
954 patients (0.0%) while receiving BOTOX 100 Unit doses and 3 of 260 patients (1.2%)
after subsequently receiving at least one 150 Unit dose. One of these three patients continued
to experience clinical benefit. Compared to the overall BOTOX treated population, patients
who developed neutralising antibodies generally had shorter duration of response and
consequently received treatments more frequently (see section 4.4).
Pivotal Phase 3 Clinical Trials

Two double-blind, placebo-controlled, randomised phase 3 clinical studies were conducted in
a total of 691 patients with spinal cord injury or multiple sclerosis, who were not adequately
managed with at least one anticholinergic agent and were either spontaneously voiding or
using catheterisation. These patients were randomised to receive either 200 Units of BOTOX
(n=227), 300 Units of BOTOX (n=223), or placebo (n=241).
Primary and Secondary Endpoints at Baseline and Change from Baseline in Pooled Pivotal
Studies:
BOTOX Placebo P-value
200 Units
(N=227) (N=241)
Weekly Frequency of Urinary Incontinence
Mean Change† at Week 2 -16.8 -9.1 <0.001
Mean Change† at Week 6a -20.0 -10.5 <0.001
†
Mean Change at Week 12 -19.8 -9.3 <0.001
Maximum Cystometric Capacity (ml)
Mean Change† at Week 6b +140.4 +6.9 <0.001
Maximum Detrusor Pressure during 1st Involuntary
Detrusor Contraction (cmH20)
Mean Change† at Week 6b -27.1 -0.4 <0.001
c,d
Mean Change† at Week 6b +23.6 +8.9 <0.001
Mean Change† at Week 12 +26.9 +7.1 <0.001
Percentage of patients achieving full continence at
Week 6 (dry patients over a 7 day diary) 37% 9%
Percentage of patients achieving reduction from
baseline in urinary incontinence episodes at Week 6
at least 75% 63% 24%
at least 50% 76% 39%
†
LS mean changes are presented
a
Primary endpoint
b
Secondary endpoints
c
I-QOL total score scale ranges from 0 (maximum problem) to 100 (no problem at all).
d
In the pivotal studies, the pre-specified minimally important difference (MID) for I-QOL
total score was 8 points based on MID estimates of 4-11 points reported in neurogenic
detrusor overactivity patients.
The median duration of response, based on time to qualification for re-treatment (time to <
50% reduction in incontinence episodes), was 42 weeks in the 200 Unit dose group. The
median interval between the first and second administrations was 42 weeks in patients with
spinal cord injury and 45 weeks in patients with multiple sclerosis. The median duration of
response, based on time to qualification for re-treatment (at least 1 urinary incontinence
episode in a 3 day diary), in patients who continued into the open label extension study and
received treatments with only BOTOX 200 Units (N=174), was 264 days (~38 weeks).
For all efficacy endpoints in the pivotal phase 3 studies, patients experienced consistent
response with re-treatment (n=116).
None of the 475 patients with analysed serum specimens developed neutralising antibodies
after 1-2 treatments. In patients with analysed specimens in the drug development program
(including the open-label extension study), neutralising antibodies developed in 3 of 300
patients (1.0%) after receiving only BOTOX 200 Unit doses and 5 of 258 patients (1.9%)
after receiving at least one 300 Unit dose. Four of these eight patients continued to experience
clinical benefit. Compared to the overall BOTOX treated population, patients who developed
neutralising antibodies generally had shorter duration of response and consequently received
treatments more frequently (see section 4.4).
In the multiple sclerosis (MS) patients enrolled in the pivotal studies, the MS exacerbation
annualised rate (i.e. number of MS exacerbation events per patient year) was 0.23 in the 200
Unit dose group and 0.20 in the placebo group. With repeated BOTOX treatments, including
data from a long term study, the MS exacerbation annualised rate was 0.19 during each of the
first two BOTOX treatment cycles.
Post-approval Study
A placebo controlled, double-blind post-approval study was conducted in multiple sclerosis
(MS) patients with urinary incontinence due to neurogenic detrusor overactivity who were not
adequately managed with at least one anticholinergic agent and not catheterising at baseline.
These patients were randomised to receive either 100 Units of BOTOX (n=66) or placebo
(n=78).
Significant improvements compared to placebo in the primary efficacy variable of change

from baseline in daily frequency of incontinence episodes were observed for BOTOX (100
Units) at the primary efficacy time point at week 6, including the percentage of dry patients.
Significant improvements in urodynamic parameters, and Incontinence Quality of Life
questionnaire (I-QOL), including avoidance limiting behaviour, psychosocial impact and
social embarrassment were also observed.
Results from the post-approval study are presented below:
Primary and Secondary Endpoints at Baseline and Change from Baseline in Post-
Approval Study of BOTOX 100 Units in MS patients not catheterising at baseline:
BOTOX Placebo p-values

100 Units (N=78)
(N=66)
Daily Frequency of Urinary Incontinence*
Mean Change at Week 2 -2.9 -1.2 p<0.001
Mean Change at Week 6a -3.3 -1.1 p<0.001
Mean Change at Week 12 -2.8 -1.1 p<0.001
Maximum Cystometric Capacity (mL)
Mean Change at Week 6b +127.2 -1.8 p<0.001
st
Maximum Detrusor Pressure during 1
Involuntary Detrusor Contraction
(cmH2O)
Mean Change at Week 6b -19.6 +3.7 p=0.007
c,d
Mean Change at Week 6b +40.4 +9.9 p<0.001
Mean Change at Week 12 +38.8 +7.6 p<0.001
* Percentage of dry patients (without incontinence) throughout week 6 was 53.0% (100 Unit
BOTOX group) and 10.3% (placebo)
a
Primary endpoint
b
Secondary endpoints
c
I-QOL total score scale ranges from 0 (maximum problem) to 100 (no problem at all).
d
The pre-specified minimally important difference (MID) for I-QOL total score was 11 points
based on MID estimates of 4-11 points reported in neurogenic detrusor overactivity patients.
The median duration of response in this study, based on patient request for re-treatment, was
362 days (~52 weeks) for BOTOX 100 Unit dose group compared to 88 days (~13 weeks)
with placebo.
SKIN AND SKIN APPENDAGE DISORDER
Glabellar lines
537 patients with moderate to severe glabellar lines between the eyebrows seen at maximum
frown have been included in clinical studies.
BOTOX injections significantly reduced the severity of glabellar lines seen at maximum
frown for up to 4 months, as measured by the investigator assessment of glabellar line
severity at maximum frown and by subject’s global assessment of change in appearance of
his/her glabellar lines seen at maximum frown. Improvement generally occurred within one
week of treatment. None of the clinical endpoints included an objective evaluation of the
psychological impact. Thirty days after injection, 80% (325/405) of BOTOX-treated patients
were considered by investigators as treatment responders (none or mild severity at maximum
frown), compared to 3% (4/132) of placebo-treated patients. At this same timepoint, 89%
(362/405) of BOTOX-treated patients felt they had a moderate or better improvement,
compared to 7% (9/132) of placebo-treated patients.
BOTOX injections also significantly reduced the severity of glabellar lines at rest. Of the 537
patients enrolled, 39% (210/537) had moderate to severe glabellar lines at rest (15% had no
lines at rest). Of these, 74% (119/161) of BOTOX-treated patients were considered treatment
responders (none or mild severity) thirty days after injection, compared with 20% (10/49) of
placebo-treated patients.
There is limited phase 3 clinical data with BOTOX in patients older than 65 years. Only 6.0%
(32/537) of subjects were >65 years old and efficacy results obtained were lower in this
population.
Crow’s feet lines
1362 patients with moderate to severe crow’s feet lines seen at maximum smile, either alone
(n=445, Study 191622-098) or also with moderate to severe glabellar lines seen at maximum
frown (n=917, Study 191622-099), were enrolled.
BOTOX injections significantly reduced the severity of crow’s feet lines seen at maximum
smile compared to placebo at all timepoints (p <0.001) for up to 5 months (median 4 months).
Improvement assessed by the investigator occurred within one week of treatment. This was
measured by the proportion of patients achieving a crow’s feet lines severity rating of none or
mild at maximum smile in both pivotal studies; until day 150 (end of study) in Study 191622-
098 and day 120 (end of first treatment cycle) in Study 191622-099. For both investigator and
subject assessments, the proportion of subjects achieving none or mild crow’s feet lines
severity seen at maximum smile was greater in patients with moderate crow’s feet lines seen
at maximum smile at baseline, compared to patients with severe crow’s feet lines seen at
maximum smile at baseline. Table 1 summarises results at day 30, the timepoint of the
primary efficacy endpoint.
In Study 191622-104 (extension to Study 191622-099), 101 patients previously randomised to
placebo were enrolled to receive their first treatment at the 44 Units dose. Patients treated
with BOTOX had a statistically significant benefit in the primary efficacy endpoint compared
to placebo at day 30 following their first active treatment. The response rate was similar to the
44 Units group at day 30 following first treatment in Study 191622-099. A total of 123
patients received 4 cycles of 44 Units BOTOX for combined crow’s feet and glabellar lines
treatment.
Day 30: Investigator and Patient Assessment of Crow’s Feet Lines Seen at Maximum Smile -
Responder Rates (% of Patients Achieving Crow’s Feet Lines Severity Rating of None or
Mild)
Clinical Dose BOTOX Placebo BOTOX Placebo
Study
Investigator Assessment Patient Assessment
191622- 24 Units 66.7%* 6.7% 58.1%* 5.4%
098 (crow’s feet lines) (148/222) (15/223) (129/222) (12/223)
191622- 24 Units 54.9%* 3.3% 45.8%* 3.3%
099 (crow’s feet lines) (168/306) (10/306) (140/306) (10/306)
44 Units 59.0%* 3.3% 48.5%* 3.3%

(24 Units crow’s feet (180/305) (10/306) (148/305) (10/306)
lines;
20 Units glabellar lines)
*p < 0.001 (BOTOX vs placebo)
Improvements from baseline in subject-assessment of the appearance of crow’s feet lines seen
at maximum smile were seen for BOTOX (24 Units and 44 Units) compared to placebo, at
day 30 and at all timepoints following each treatment cycle in both pivotal studies (p<0.001).
Treatment with BOTOX 24 Units also significantly reduced the severity of crow’s feet lines
at rest. Of the 528 patients treated, 63% (330/528) had moderate to severe crow’s feet lines at
rest at baseline. Of these, 58% (192/330) of BOTOX-treated patients were considered
treatment responders (none or mild severity) thirty days after injection, compared with 11%
(39/352) of placebo-treated patients.
Improvements in subject’s self-assessment of age and attractiveness were also seen for
BOTOX (24 Units and 44 Units) compared to placebo using the Facial Line Outcomes (FLO-
11) questionnaire, at the primary timepoint of day 30 (p<0.001) and at all subsequent
timepoints in both pivotal studies.
In the pivotal studies, 3.9% (53/1362) of patients were older than 65 years of age. Patients in
this age group had a treatment response as assessed by the investigator, of 36% (at day 30) for
BOTOX (24 Units and 44 Units).When analysed by age groups of ≤50 years and >50 years,
both populations demonstrated statistically significant improvements compared to placebo.
Treatment response for BOTOX 24 Units, as assessed by the investigator, was lower in the
group of subjects >50 years of age than those ≤50 years of age (42.0% and 71.2%,
respectively).
Overall BOTOX treatment response for crow’s feet lines seen at maximum smile is lower
(60%) than that observed with treatment for glabellar lines seen at maximum frown (80%).
916 patients (517 patients at 24 Units and 399 patients at 44 Units) treated with BOTOX had
specimens analysed for antibody formation. No patients developed the presence of
neutralising antibodies.
5.2 Pharmacokinetic properties
a) General characteristics of the active substance:

Classical absorption, distribution, biotransformation and elimination studies on the active
substance have not been performed due to the extreme toxicity of botulinum toxin type A.
b) Characteristics in patients:
Human ADME studies have not been performed due to the nature of the product. It is
believed that little systemic distribution of therapeutic doses of BOTOX occurs. BOTOX is
probably metabolised by proteases and the molecular components recycled through normal
metabolic pathways.
5.3 Preclinical safety data
Non-clinical data based on conventional studies of safety pharmacology, repeated dose

toxicity and genotoxicity reveal no special hazard for humans other than exaggerated
pharmacological effects predictable at high doses, given the neurotoxic nature of BOTOX.
Carcinogenicity studies have not been conducted.
Acute toxicity
In monkeys receiving a single intramuscular (i.m.) injection of BOTOX, the No Observed
Effect Level (NOEL) ranged from 4 to 24 Units/kg. The i.m. LD50 was reported to be 39
Units/kg.
Toxicity on repeated injection

In three different studies (six months in rats; 20 weeks in juvenile monkeys; 1 year in
monkeys) where the animals received i.m. injections, the NOEL was at the following
respective BOTOX dosage levels: < 4 Units/kg, 8 Units/kg and 4 Units/kg. The main
systemic effect was a transient decrease in body weight gain.
There was no indication of a cumulative effect in the animal studies when BOTOX was given
at dosage intervals of 1 month or greater.
Decrease in bodyweight was observed following a single intradetrusor injection of <10

Units/kg BOTOX in rats. To simulate inadvertent injection, a single dose of BOTOX (~7
Units/kg) was administered into the prostatic urethra and proximal rectum, the seminal vesicle
and urinary bladder wall, or the uterus of monkeys (~3 Units/kg) without adverse clinical
effects. However, bladder stones have been observed in monkeys given a single dose of
BOTOX to the prostatic urethra and proximal rectum, and in a repeated dose intraprostatic
study. Due to anatomical differences the clinical relevance of these findings is unknown. In a
9 month repeat dose intradetrusor study (4 injections), eyelid ptosis was observed at 24
Units/kg, and mortality was observed at doses ≥24 Units/kg. No adverse effects were
observed in monkeys at 12 Units/kg, which corresponds to a 3-fold greater exposure than the
recommended clinical dose of 200 Units for urinary incontinence due to neurogenic detrusor
overactivity (based on a 50 kg person).
Local toxicity
BOTOX was shown not to cause ocular or dermal irritation, or give rise to toxicity when
injected into the vitreous body in rabbits.
Allergic or inflammatory reactions in the area of the injection sites are rarely observed after
BOTOX administration. However, formation of haematoma may occur.
Reproduction toxicology
Teratogenic effects
When pregnant mice and rats were injected intramuscularly during the period of
organogenesis, the developmental NOEL of BOTOX was at 4 Units/kg. Reductions in
ossification were observed at 8 and 16 Units/kg (mice) and reduced ossification of the hyoid
bone at 16 Units/kg (rats). Reduced foetal body weights were observed at 8 and 16 Units/kg
(rats).
In a range-finding study in rabbits, daily injections at dosages of 0.5 Units/kg/day (days 6 to

18 of gestation), and 4 and 6 Units/kg (administered on days 6 and 13 of gestation), caused
death and abortions among surviving dams. External malformations were observed in one
foetus each in the 0.125 Units/kg/day and the 2 Units/kg dosage groups. The rabbit appears
to be a very sensitive species to BOTOX treatment.
Impairment of fertility and reproduction

The reproductive NOEL following i.m. injection of BOTOX was 4 Units/kg in male rats and
8 Units/kg in female rats. Higher dosages were associated with dose-dependent reductions in
fertility. Provided impregnation occurred, there were no adverse effects on the numbers or
viability of the embryos sired or conceived by treated male or female rats.
Pre- and post-natal developmental effects

In female rats, the reproductive NOEL was 16 Units/kg. The developmental NOEL was
4 Units/kg.
Antigenicity
BOTOX showed antigenicity in mice only in the presence of adjuvant. BOTOX was found to
be slightly antigenic in the guinea pig.
Blood compatibility
No haemolysis was detected up to 100 Units/ml of BOTOX in normal human blood.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Human albumin
Sodium chloride
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product should not be mixed with other
medicinal products.
6.3 Shelf life
3 years.
After reconstitution, stability has been demonstrated for 24 hours at 2°C – 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 (see also section 6.6).
6.4 Special precautions for storage
Store in a refrigerator (2°C-8°C), or store in a freezer (at or below -5°C).
For storage conditions of the reconstituted medicinal product see section 6.3.
6.5 Nature and contents of container
Clear glass vial, with rubber stopper and tamper-proof aluminium seal, containing white
powder for solution for injection.
Pack size:
• Carton comprising one 50 Allergan Unit vial and package leaflet.
• Packs containing one, two, three or six cartons.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Reconstitution
BOTOX is reconstituted prior to use with sterile unpreserved normal saline (0.9% sodium
chloride for injection). It is good practice to perform vial reconstitution and syringe
preparation over plastic-lined paper towels to catch any spillage. An appropriate amount of
diluent (see dilution table below) is drawn up into a syringe. The exposed portion of the
rubber septum of the vial is cleaned with alcohol (70%) prior to insertion of the needle. Since
BOTOX is denatured by bubbling or similar violent agitation, the diluent should be injected
gently into the vial. Discard the vial if a vacuum does not pull the diluent into the vial.
Reconstituted BOTOX is a clear colourless to slightly yellow solution free of particulate
matter. When reconstituted, BOTOX may be stored in a refrigerator (2-8°C) for up to 24
hours prior to use. After this period used or unused vials should be discarded.
Each vial is for single use only.
Care should be taken to use the correct diluent volume for the presentation chosen to prevent
accidental overdose. If different vial sizes of BOTOX are being used as part of one injection
procedure, care should be taken to use the correct amount of diluent when reconstituting a
particular number of units per 0.1 ml. The amount of diluent varies between BOTOX 50
Allergan Units, BOTOX 100 Allergan Units and BOTOX 200 Allergan Units. Each syringe
should be labelled accordingly.
Dilution table for BOTOX 50, 100 and 200 Allergan Units vial size for all indications
except bladder disorders:
50 Unit vial 100 Unit vial 200 Unit vial
Resulting Amount of diluent Amount of diluent Amount of diluent
dose (sterile unpreserved (sterile unpreserved (sterile unpreserved
(Units per normal saline (0.9% normal saline (0.9% normal saline (0.9%
0.1 ml) sodium chloride for sodium chloride for sodium chloride for
injection)) added in a injection)) added in a injection)) added in a
50 Unit vial 100 Unit vial 200 Unit vial
20 Units 0.25 ml 0.5 ml 1 ml
10 Units 0.5 ml 1 ml 2 ml
5 Units 1 ml 2 ml 4 ml
4 Units 1.25 ml 2.5 ml 5 ml
2.5 Units 2 ml 4 ml 8 ml
1.25 Units 4 ml 8 ml N/A
Overactive bladder:
It is recommended that a 100 Unit or two 50 Unit vials are used for convenience of
reconstitution.
Dilution instructions using two 50 Unit vials:

• Reconstitute two 50 Unit vials of BOTOX each with 5 ml of sterile unpreserved
normal saline (0.9% sodium chloride for injection) and mix the vials gently.
• Draw the 5 ml from each of the vials into a single 10 ml syringe.
This will result in a 10 ml syringe containing a total of 100 Units of reconstituted
BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused
saline.
Dilution instructions using a 100 Unit vial:

• Reconstitute a 100 Unit vial of BOTOX with 10 ml of sterile unpreserved normal saline
(0.9% sodium chloride for injection) and mix gently.
• Draw the 10 ml from the vial into a 10 ml syringe.
This will result in a 10 ml syringe containing a total of 100 Units of reconstituted BOTOX.
Use immediately after reconstitution in the syringe. Dispose of any unused saline.

(0.9% sodium chloride for injection) and mix gently.
• Draw 4 ml from the vial into a 10 ml syringe.
• Complete the reconstitution by adding 6 ml of sterile unpreserved normal saline (0.9%
sodium chloride for injection) into the 10 ml syringe and mix gently.
This will result in a 10 ml syringe containing a total of 100 Units of reconstituted BOTOX.
Use immediately after reconstitution in the syringe. Dispose of any unused saline.
This product is for single use only and any unused reconstituted product should be disposed
of.
Urinary incontinence due to neurogenic detrusor overactivity:

It is recommended that a 200 Unit vial or two 100 Unit vials are used for convenience of
reconstitution.
Dilution instructions using four 50 Unit vials:
• Reconstitute four 50 Unit vials of BOTOX, each with 3 ml of sterile unpreserved
normal saline (0.9% sodium chloride for injection) and mix the vials gently.
• Draw 3 ml from the first vial and 1 ml from the second vial into one 10 ml syringe.
• Draw 3 ml from the third vial and 1 ml from the fourth vial into a second 10 ml
syringe.
• Draw the remaining 2 ml from the second and fourth vials into a third 10 ml
syringe.
• Complete the reconstitution by adding 6 ml of sterile unpreserved normal
saline (0.9% sodium chloride for injection) into each of the three 10 ml syringes, and
mix gently
This will result in three 10 ml syringes containing a total of 200 Units of reconstituted
BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused
saline.
Dilution instructions using two 100 Unit vials:

• Reconstitute two 100 Unit vials of BOTOX, each with 6 ml of sterile unpreserved normal
saline (0.9% sodium chloride for injection) and mix the vials gently.
• Draw 4 ml from each vial into each of two 10 ml syringes.
• Draw the remaining 2 ml from each vial into a third 10 ml syringe.
sodium chloride for injection) into each of the 10 ml syringes, and mix gently.
BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline.

(0.9% sodium chloride for injection) and mix the vials gently.
• Draw 2 ml from the vial into each of three 10 ml syringes.
sodium chloride for injection) into each of the 10 ml syringes, and mix gently.
BOTOX. Use immediately after reconstitution in the syringe. Dispose of any unused saline.
The 'unit' by which the potency of preparations of BOTOX is measured should be used
to calculate dosages of BOTOX only and is not transferable to other preparations of
botulinum toxin.
Disposal
For safe disposal, unused vials should be reconstituted with a small amount of water then
autoclaved. Any used vials, syringes, and spillages etc. should be autoclaved, or the residual
BOTOX inactivated using dilute hypochlorite solution (0.5%).
Any unused product or waste material should be disposed of in accordance with local
requirements.
7 MARKETING AUTHORISATION HOLDER
Allergan Limited
Marlow International
The Parkway, Marlow,
Bucks SL7 1YL, UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 00426/0118
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION
21/09/2007
10 DATE OF REVISION OF THE TEXT
03/02/2017

Summary of Product Characteristics: 4.1 Therapeutic Indications

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Summary of Product Characteristics: 4.1 Therapeutic Indications

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Botulinum toxin* type A, 50 Allergan Units/vial.

For a full list of excipients, see section 6.1.

Powder for solution for injection.

4.1 Therapeutic indications

BOTOX is indicated for:

• treatment of focal spasticity, including:

4.2 Posology and method of administration

• Focal spasticity associated with paediatric 2 years

• Overactive Bladder (OAB) and Neurogenic 18 years

BOTOX should only be administered by physicians with appropriate qualifications and

An injection volume of approximately 0.1 ml is recommended. A decrease or increase in the

Refer to specific guidance for each indication described below.

Focal spasticity associated with paediatric cerebral palsy

Recommended needle: Sterile 23-26 gauge/0.60-0.45 mm needle.

Administration guidance: To be administered as a divided dose through single

Recommended dose: Hemiplegia: the initial recommended total dose is 4 Units/kg

Maximum dose: 200 Units in total

Focal upper limb spasticity associated with stroke

Recommended needle: Sterile 25, 27 or 30 gauge needle. Needle length should be

The following doses are recommended:

Additional information: If it is deemed appropriate by the treating physician, the

Focal lower limb spasticity associated with stroke

Recommended needle: Sterile 25, 27 or 30 gauge needle. Needle length should be

Administration guidance: Localisation of the involved muscles with techniques such as

The following diagrams indicate the injection sites for adult

Muscle Recommended Dose

Additional information: If it is deemed appropriate by the treating physician, the

Recommended needle: Sterile, 27-30 gauge/0.40-0.30 mm needle.

Administrative guidance: Electromyographic guidance is not necessary.

Recommended dose: The initial recommended dose is 1.25-2.5 Units (0.05-0.1 ml

Additional information: Avoiding injection near levator palpebrae superioris may

In general, the initial effect of the injections is seen within

At repeat treatment sessions, the dose may be increased up to

Patients with hemifacial spasm or VIIth nerve disorders

Recommended needle: A 25, 27 or 30 gauge/0.50-0.30 mm needle may be used for

Administrative guidance: The treatment of cervical dystonia typically may include

In case of any difficulty in isolating the individual muscles,

Multiple injection sites allow BOTOX to have more uniform

To minimise the incidence of dysphagia, the sternomastoid

The following doses are recommended:

Type I Sternomastoid 50 - 100 Units; at least 2 sites

Additional information: Treatment intervals of less than 10 weeks are not

Recommended needle: Sterile 30 gauge, 0.5 inch needle.

A 1 inch needle may be needed in the neck region for

Administration guidance: Injections should be divided across 7 specific head/neck

The following diagrams indicate the injection sites:

If there is a predominant pain location(s), additional

The following diagrams indicate recommended muscle

Additional information: The recommended re-treatment schedule is every 12 weeks.

Recommended needle: The injection needle should be filled (primed) with

Administration guidance: The reconstituted solution of BOTOX (100 Units/10 ml) is

The needle should be inserted approximately 2 mm into the

Patients should be considered for reinjection when the

Urinary incontinence due to neurogenic detrusor overactivity

Recommended needle: The injection needle should be filled (primed) with

Administration guidance: The reconstituted solution of BOTOX (200 Units/30 ml) is

The needle should be inserted approximately 2 mm into the

Recommended dose: The recommended dose is 200 Units of BOTOX, as 1 ml

Patients should be considered for reinjection when the