XEOMIN is indicated in adults for the following:
Aesthetic indications
Temporary improvement in the appearance of upper facial lines in adults below 65 years when the
severity of these lines has an important psychological impact for the patient:
• moderate to severe vertical lines between the eyebrows seen at maximum frown (glabellar
frown lines) and/or
• moderate to severe lateral periorbital lines seen at maximum smile (crow’s feet lines) and/or
• moderate to severe horizontal forehead lines seen at maximum contraction;
Neurologic indications
Symptomatic treatment of
• blepharospasm and hemifacial spasm,
• cervical dystonia of a predominantly rotational form (spasmodic torticollis),
• spasticity of the upper limb,
• chronic sialorrhea due to neurological disorders.

Due to unit differences in the potency assay, unit doses for XEOMIN are not interchangeable
with those for other preparations of Botulinum toxin type A.

For detailed information regarding clinical studies with XEOMIN in comparison to conventional
Botulinum toxin type A complex (900 kD), see section 5.1.
XEOMIN may only be administered by physicians with suitable qualifications and the requisite
experience in the application of Botulinum toxin type A.
For neurologic indications the optimum dose, frequency and number of injection sites in the treated
muscle should be determined by the physician individually for each patient. A titration of the dose
should be performed.
The recommended single doses of XEOMIN should not be exceeded.
Posology
Aesthetic indications
Vertical lines between the eyebrows seen at maximum frown (glabellar frown lines)
After reconstitution of XEOMIN a dose of 4 units is injected into each of the 5 injection sites: two
injections in each corrugator muscle and one injection in the procerus muscle, which corresponds to a
standard dose of 20 units. The dose may be increased by the physician to up to 30 units if required by
the individual needs of the patients, with at least ‘3-months’ interval between treatments.

An improvement in the vertical lines between the eyebrows seen at maximum frown (glabellar frown
lines) generally takes place within 2 to 3 days with the maximum effect observed on day 30. The
effect lasts up to 4 months after the injection.
Lateral periorbital lines seen at maximum smile (crow’s feet lines)
After reconstitution of XEOMIN 4 units are injected bilaterally into each of the 3 injection sites. One
injection is placed approximately 1 cm lateral from the bony orbital rim. The other two injections each
should be placed approximately 1 cm above and below the area of the first injection.

 

The total recommended standard dose per treatment is 12 units per side (overall total dose: 24 units).
An improvement in lateral periorbital lines seen at maximum smile (crow’s feet lines) mostly takes
place within the first 6 days with the maximum effect observed on day 30. The effect lasts up to
4 months after the injection.
Horizontal forehead lines seen at maximum contraction
The recommended total dose range is 10 to 20 units according to the individual needs of the patients,
with at least ‘3-months’ interval between treatments. After reconstitution of XEOMIN a total dose of
10 to 20 units is injected into the frontalis muscle in five horizontally aligned injection sites at least
2 cm above the orbital rim. Per injection point, 2 units, 3 units or 4 units are applied, respectively.

 

An improvement in the horizontal forehead lines seen at maximum contraction usually occurs within
7 days with the maximum effect observed on day 30. The effect lasts up to 4 months after the
injection.
Neurologic indications
Blepharospasm and hemifacial spasm
The initial recommended dose is 1.25 to 2.5 units per injection site. The initial dose should not exceed
25 units per eye. Total dosing should not exceed 50 units per eye per treatment session. Repeated
treatment should generally be no more frequent than every 12 weeks. Treatment intervals should be
determined based on the actual clinical need of the individual patient.
The median time to first onset of effect is observed within four days after injection. The effect of a
XEOMIN treatment generally lasts approximately 3-4 months, however, it may last significantly longer
or shorter. The treatment can be repeated if required.

At repeat treatment sessions, the dose may be increased up to two-fold if the response to the initial
treatment is considered insufficient. However, there appears to be no additional benefit obtainable from
injecting more than 5.0 units per site.
Patients with hemifacial spasm should be treated as for unilateral blepharospasm.
Spasmodic torticollis
In the management of spasmodic torticollis, XEOMIN dosing must be tailored to the individual patient,
based on the patient’s head and neck position, location of possible pain, muscle hypertrophy, patient’s
body weight, and response to the injection.
No more than 200 units should be injected for the first course of therapy, with adjustments made in the
subsequent courses depending on the response. A total dose of 300 units at any one session should not
be exceeded. No more than 50 units should be administered at any one injection site.
The median first onset of effect is observed within seven days after injection. The effect of a XEOMIN
treatment generally lasts approximately 3-4 months, however, it may last significantly longer or shorter.
Treatment intervals of less than 10 weeks are not recommended. Treatment intervals should be
determined based on the actual clinical need of the individual patient.
Spasticity of the upper limb
The exact dose and number of injection sites should be tailored to the individual patient based on the
size, number and location of muscles involved, the severity of spasticity, and the presence of local
muscle weakness.
Recommended treatment doses per muscle:

The maximum total dose for the treatment of upper limb spasticity should not exceed 500 units per
treatment session, and no more than 250 units should be administered to the shoulder muscles.
Patients reported the onset of action 4 days after treatment. The maximum effect as an improvement of
muscle tone was perceived within 4 weeks. In general, the treatment effect lasted 12 weeks, however, it
may last significantly longer or shorter. Repeated treatment should generally be no more frequent than
every 12 weeks. Treatment intervals should be determined based on the actual clinical need of the
individual patient.
Chronic sialorrhea
A reconstituted solution at a concentration of 5 units/0.1 ml should be used.
XEOMIN is injected into the parotid and submandibular glands on both sides (per treatment four
injections in total). The dose is divided with a ratio of 3:2 between the parotid and submandibular
glands as follows:

Glands	Units	Volume
Parotid glands	30 per side	0.6 ml per injection
Submandibular glands	20 per side	0.4 ml per injection

The injection site should be close to the centre of the gland.

The recommended dose per treatment session is 100 units. This maximum dose should not be
exceeded.
Treatment intervals should be determined based on the actual clinical need of the individual patient.
Repeat treatment more frequent than every 16 weeks is not recommended.
All indications
If no treatment effect occurs within one month after the initial injection, the following measures
should be taken:
• Clinical verification of the neurotoxin effect on the injected muscle for neurologic indications:
e.g. an electromyographic investigation in a specialised facility
• Analysis of the reasons for non-response, e.g. poor isolation of the muscles intended to be
injected, too low dose, poor injection technique, fixed contracture, too weak antagonist,
possible development of antibodies
• Review of Botulinum neurotoxin type A treatment as an adequate therapy
• If no adverse reactions have occurred during the initial treatment:
For neurologic indications an additional course of treatment can be performed under the
following conditions: 1) dose adjustment with regard to analysis of the most recent therapy
failure, 2) localisation of the involved muscles with techniques such as electromyographic
guidance, 3) the recommended minimum interval between the initial and repeat treatment is
followed;
For aesthetic indications an additional course of treatment can be performed in compliance
with a minimum interval of three months between the initial and the repeat treatment.
Special populations
For aesthetic indications there are limited clinical data from phase 3 studies of XEOMIN in patients
over 65 years of age. Until further data are available in this age group, XEOMIN is not recommended
for use in patients over 65 years of age.
Paediatric population
The safety and efficacy of XEOMIN in children and adolescents aged 0-17 years has not yet been
established. No recommendations on posology can be made for indications other than those described
in section 4.1.
Currently available paediatric clinical data with XEOMIN are described in section 5.1.
Method of administration
All indications
XEOMIN is intended for intramuscular and intraglandular (intra-salivary gland) use.
After reconstitution, XEOMIN should be used immediately and may only be used for one treatment
per patient.
For instructions on reconstitution of the medicinal product before administration and for instructions
on disposal of the vials, see section 6.6.
Aesthetic indications
The intervals between treatments should not be shorter than 3 months. If the treatment fails, or the
effect lessens with repeated injections, alternative treatment methods should be used.
Vertical lines between the eyebrows seen at maximum frown (glabellar frown lines)
Before and during the injection, the thumb or index finger should be used to apply firm pressure below
the edge of the eye socket in order to prevent diffusion of the solution in this region. Superior and
medial alignment of the needle should be maintained during the injection. To reduce the risk of
blepharoptosis, injections near the levator palpebrae superioris and into the cranial portion of the

orbicularis oculi should be avoided. Injections into the corrugator muscle should be done in the
medial portion of the muscle, and in the central portion of the muscle belly at least 1 cm above the
bony edge of the eye socket.
Reconstituted XEOMIN is injected using a thin sterile needle (e.g. 30-33 gauge/0.20-0.30 mm
diameter/13 mm length needle). An injection volume of approximately 0.04 to 0.1 ml per injection
site is recommended.
Lateral periorbital lines seen at maximum smile (crow’s feet lines)
The injection should be done intramuscularly into the orbicularis oculi muscle, directly under the
dermis to avoid diffusion of XEOMIN. Injections too close to the zygomaticus major muscle should
be avoided to prevent lip ptosis.
Reconstituted XEOMIN is injected using a thin sterile needle (e.g. 30-33 gauge/0.20-0.30 mm
diameter/13 mm length needle). An injection volume of approximately 0.04 to 0.1 ml per injection
site is recommended.
Horizontal forehead lines seen at maximum contraction
Paralyzing of lower muscle fibers by injecting XEOMIN near the orbital rim should be avoided to
reduce the risk of brow ptosis.
Reconstituted XEOMIN is injected using a thin sterile needle (e.g. 30-33 gauge/0.20-0.30 mm
diameter/13 mm length needle). An injection volume of approximately 0.04 to 0.1 ml per injection
site is recommended.
Neurologic indications
Blepharospasm and hemifacial spasm
After reconstitution, the XEOMIN solution is injected using a suitable sterile needle
(e.g. 27-30 gauge/0.30-0.40 mm diameter/12.5 mm length). Electromyographic guidance is not
necessary. An injection volume of approximately 0.05 to 0.1 ml is recommended.
XEOMIN is injected into the medial and lateral orbicularis oculi muscle of the upper lid and the lateral
orbicularis oculi muscle of the lower lid. Additional sites in the brow area, the lateral orbicularis oculi
muscle and in the upper facial area may also be injected if spasms here interfere with vision.
In cases of unilateral blepharospasm the injections should be confined to the affected eye.
Patients with hemifacial spasm should be treated as for unilateral blepharospasm.
There is no experience with injections in the lower facial area from clinical studies with XEOMIN.
Muscles in the lower facial area should not be injected due to pronounced risk of local weakness as
reported in literature after injections of botulinum toxin into this area in patients with hemifacial spasm.
Spasmodic torticollis
A suitable sterile needle (e.g. 25-30 gauge/0.30-0.50 mm diameter/37 mm length) is used for injections
into superficial muscles, and an e.g. 22 gauge/0.70 mm diameter/75 mm length needle may be used for
injections into deeper musculature. An injection volume of approximately 0.1 to 0.5 ml per injection site
is recommended.
In the management of spasmodic torticollis, XEOMIN is injected into the sternocleidomastoid, levator
scapulae, scalenus, splenius capitis, 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. If
difficulties arise isolating single muscles, injections should be performed using techniques such as

electromyographic guidance or ultrasound. The muscle mass and the degree of hypertrophy or atrophy
are factors to be taken into consideration when selecting the appropriate dose.
Multiple injection sites permit XEOMIN more uniform coverage of the innervated areas of the dystonic
muscle and are especially useful in larger muscles. The optimum number of injection sites depends on
the size of the muscle to be chemically denervated.
The sternocleidomastoid should not be injected bilaterally as there is an increased risk of adverse
reactions (in particular dysphagia) when bilateral injections or doses in excess of 100 U are administered
into this muscle.
Spasticity of the upper limb
Reconstituted XEOMIN is injected using a suitable sterile needle (e.g. 26 gauge/0.45 mm
diameter/37 mm length, for superficial muscles and a longer needle, e.g. 22 gauge/0.7 mm
diameter/75 mm length, for deeper musculature).
Localisation of the involved muscles with techniques such as electromyographic guidance or ultrasound
is recommended in case of any difficulty in isolating the individual muscles. Multiple injection sites may
allow XEOMIN to have more uniform contact with the innervation areas of the muscle and are
especially useful when larger muscles are injected.
Chronic sialorrhea
After reconstitution the XEOMIN solution is injected intraglandularly using a suitable sterile needle
(e.g. 27-30 gauge / 0.30-0.40 mm diameter / 12.5 mm length). Anatomic landmarks or ultrasound
guidance are both possible for the localization of the involved salivary glands, however the ultrasound
guided method should be preferred, because it could result in a better therapeutic outcome (see
section 5.1).

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Generalised disorders of muscle activity (e.g. myasthenia gravis, Lambert-Eaton syndrome). • Infection or inflammation at the proposed injection site.

Prior to administering XEOMIN, the physician must familiarise himself/herself with the patient’s
anatomy and any alterations to the anatomy due to prior surgical procedures.
Care should be taken to ensure that XEOMIN is not injected into a blood vessel.
XEOMIN should be used with caution:
• if bleeding disorders of any type occur
• in patients receiving anticoagulant therapy or taking other substances that could have an
anticoagulant effect.
The clinical effects of Botulinum neurotoxin type A may increase or decrease by repeated injections.
The possible reasons for changes in clinical effects are different techniques of reconstitution, the chosen
injection intervals, the injection sites and marginally varying toxin activity resulting from the biological
testing procedure employed or secondary non-response.
Local and distant spread of toxin effect

Undesirable effects may occur from misplaced injections of Botulinum neurotoxin type A that
temporarily paralyse nearby muscle groups. Large doses may cause paralysis in muscles distant from
the injection site.
There have been reports of undesirable effects that might be related to the spread of Botulinum toxin
type A to sites distant from the injection site (see section 4.8). When treating neurologic indications
some of these can be life threatening and there have been reports of death, which in some cases was
associated with dysphagia, pneumonia and/or significant debility.
Patients treated with therapeutic doses may experience excessive muscle weakness.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or
respiratory disorders occur.
Dysphagia has also been reported following injection to sites other than the cervical musculature.
Pre-existing neuromuscular disorders
Patients with neuromuscular disorders may be at increased risk of excessive muscle weakness particular
when treated intramuscularly. The Botulinum toxin type A 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.
Generally, patients with a history of aspiration or dysphagia should be treated with caution. Extreme
caution should be exercised when treating these patients for cervical dystonia.
The injection of XEOMIN for aesthetic indications is not recommended for patients with a history of
aspiration and dysphagia.
XEOMIN should be used with caution:
• in patients suffering from amyotrophic lateral sclerosis
• in patients with other diseases which result in peripheral neuromuscular dysfunction
• in targeted muscles which display pronounced weakness or atrophy.
Hypersensitivity reactions
Hypersensitivity reactions have been reported with Botulinum neurotoxin type A products. If serious
(e.g. anaphylactic reactions) and/or immediate hypersensitivity reactions occur, appropriate medical
therapy should be instituted.
Antibody formation
Too frequent doses may increase the risk of antibody formation, which can result in treatment failure
(see section 4.2). The potential for antibody formation may be minimised by injecting with the lowest
effective dose at the longest intervals between injections as clinically indicated.
Paediatric population
Spontaneous reports of possible distant spread of toxin have been very rarely reported for other
preparations of Botulinum toxin type A in paediatric patients with comorbidities, predominantly with
cerebral palsy. In general the dose used in these cases was in excess of that recommended for these
products.
There have been rare spontaneous reports of death sometimes associated with aspiration pneumonia in
children with severe cerebral palsy after treatment with botulinum toxin products, including following
off label use (e.g. neck area). The risk is considered particularly high in paediatric patients with a poor
underlying health status or in patients who have significant neurologic debility, dysphagia, or in patients
who have a recent history of aspiration pneumonia or lung disease.

Indication-specific warnings
Aesthetic indications
If proposed injection sites are marked with a pen, the product must not be injected through the pen
marks; otherwise a permanent tattooing effect may occur.
Horizontal forehead lines
It should be taken into consideration that horizontal forehead lines may not only be dynamic, but may
also result from the loss of dermal elasticity (e.g. associated with aging or photodamage). In this case,
patients may not respond to Botulinum toxin products.
Neurologic indications
Blepharospasm and hemifacial spasm
Injections near the levator palpebrae superioris should be avoided to reduce the occurrence of ptosis.
Diplopia may develop as a result of Botulinum neurotoxin type A diffusion into the inferior oblique.
Avoiding medial injections into the lower lid may reduce this adverse reaction.
Because of the anticholinergic effect of Botulinum neurotoxin type A, XEOMIN should be used with
caution in patients at risk of developing a narrow angle glaucoma.
In order to prevent ectropion, injections into the lower lid area should be avoided, and vigorous
treatment of any epithelial defect is necessary. This may require protective drops, ointments, soft
bandage contact lenses, or closure of the eye by patching or similar means.
Reduced blinking following XEOMIN injection into the orbicularis muscle can lead to corneal
exposure, persistent epithelial defects and corneal ulceration, especially in patients with cranial nerve
disorders (facial nerve). Careful testing of corneal sensation should be performed in patients with
previous eye operations.
Ecchymosis easily occurs in the soft tissues of the eyelid. Immediate gentle pressure at the injection site
can limit that risk.
Spasmodic torticollis
XEOMIN should be injected carefully when injecting at sites close to sensitive structures such as the
carotid artery lung apices and oesophagus.
Previously akinetic or sedentary patients should be reminded to gradually resume activities following
the injection of XEOMIN.
Patients should be informed that injections of XEOMIN for the management of spasmodic torticollis
may cause mild to severe dysphagia with the risk of aspiration and dyspnoea. Medical intervention
may be necessary (e.g. in the form of a gastric feeding tube) (see also section 4.8). 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 require bilateral injections into
the sternocleidomastoid muscles are at greater risk. The occurrence of dysphagia is attributable to the
spread of the pharmacological effect of XEOMIN as the result of the neurotoxin spread into the
oesophageal musculature.
Spasticity of the upper limb
XEOMIN should be injected carefully when injecting at sites close to sensitive structures such as the
carotid artery lung apices and oesophagus.

Previously akinetic or sedentary patients should be reminded to gradually resume activities following
the injection of XEOMIN.
XEOMIN as a treatment for focal spasticity has been studied in association with usual standard care
regimens, and is not intended as a replacement for these treatment modalities. XEOMIN is not likely
to be effective in improving range of motion at a joint affected by a fixed contracture.
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.
Chronic sialorrhea
In cases of medication-induced sialorrhea (e.g. by aripiprazole, clozapine, pyridostigmine) first of all the
possibility of replacement, reduction or even termination of the inducing medication should be
considered before using XEOMIN for the treatment of sialorrhea.
Efficacy and safety of XEOMIN in patients with medication-induced sialorrhea were not investigated.
If cases of “dry mouth” develop in association with the administration of XEOMIN reduction of the
dose should be considered.
A dental visit at the beginning of treatment is recommended. The dentist should be informed about
sialorrhea treatment with XEOMIN to be able to decide about appropriate measures for caries
prophylaxis.

 

No interaction studies have been performed.
Theoretically, the effect of Botulinum neurotoxin may be potentiated by aminoglycoside antibiotics or
other medicinal products that interfere with neuromuscular transmission e.g. tubocurarine-type muscle
relaxants.
Therefore, the concomitant use of XEOMIN with aminoglycosides or spectinomycin requires special
care. Peripheral muscle relaxants should be used with caution, if necessary reducing the starting dose
of relaxant, or using an intermediate-acting substance such as vecuronium or atracurium rather than
substances with longer lasting effects.
In addition, when used for the treatment of chronic sialorrhea, irradiation to the head and neck
including salivary glands and/or co-administration of anticholinergics (e.g. atropine, glycopyrronium,
scopolamine) may increase the effect of the toxin. The treatment of sialorrhea with XEOMIN during
radiotherapy is not recommended.
4-Aminoquinolines may reduce the effect of XEOMIN.

Pregnancy
There are no adequate data from the use of Botulinum neurotoxin type A in pregnant women. Studies
in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown. Therefore, XEOMIN should not be used during pregnancy unless clearly necessary and
unless the potential benefit justifies the risk.
Breast-feeding

It is unknown whether Botulinum neurotoxin type A is excreted into breast milk. Therefore,
XEOMIN should not be used during breast-feeding.
Fertility
There are no clinical data from the use of Botulinum neurotoxin type A. No adverse effects on male or
female fertility were detected in rabbits (see section 5.3).

XEOMIN has a minor or moderate influence on the ability to drive and use machines. Patients should
be counselled that if asthenia, muscle weakness, dizziness, vision disorders or drooping eyelids occur,
they should avoid driving or engaging in other potentially hazardous activities.

Usually, undesirable effects are observed within the first week after treatment and are temporary in
nature. Undesirable effects may be related to the active substance, the injection procedure, or both.
Undesirable effects independent from indication
Application related undesirable effects
Localised pain, inflammation, paraesthesia, hypoaesthesia, tenderness, swelling, oedema, erythema,
itching, localised infection, haematoma, bleeding and/or bruising may be associated with the
injection.
Needle related pain and/or anxiety may result in vasovagal responses, including transient symptomatic
hypotension, nausea, tinnitus and syncope.
Undesirable effects of the substance class Botulinum toxin type A
Localised muscle weakness is one expected pharmacological effect of Botulinum toxin type A.
Blepharoptosis, which can be caused by injection technique, is associated with the pharmacological
effect in aesthetic indications of XEOMIN.
Toxin spread
When treating neurologic indications with Botulinum toxins, undesirable effects related to spread of
toxin distant from the site of administration have been reported very rarely to produce symptoms
consistent with Botulinum toxin type A effects (excessive muscle weakness, dysphagia, and aspiration
pneumonia with a fatal outcome in some cases) (see section 4.4).
Hypersensitivity reactions
Serious and/or immediate hypersensitivity reactions including anaphylaxis, serum sickness, urticaria,
soft tissue oedema, and dyspnoea have been rarely reported. Some of these reactions have been
reported following the use of conventional Botulinum toxin type A complex either alone or in
combination with other agents known to cause similar reactions.
Undesirable effects from clinical experience
Based on clinical experience, information on the frequency of adverse reactions for the individual
indications is given below. The frequency categories are 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), not known (cannot be estimated from the available data).
Aesthetic indications
Vertical lines between the eyebrows seen at maximum frown (glabellar frown lines)

Hemifacial spasm

In Saudi Arabia: Side effects are to be reported to: The National Pharmacovigilance and Drug Safety
Centre (NPC), Fax: +996-11-203-7662, Call NPC at +996-11-2038222, Exts: 2317-2356-2353-2354-
2334-2340, Toll free phone: 8002490000, E-mail: npc.drug@sfda.gov.sa, Website:
www.sfda.gov.sa/npc
In other GCC countries: Please contact the relevant competent authorities

Please see information on risks associated with local and distant spread of toxin effect in section 4.4.
Symptoms of overdose
Increased doses of Botulinum neurotoxin type A may result in pronounced neuromuscular paralysis
distant from the injection site with a variety of symptoms. Symptoms may include general weakness,
ptosis, diplopia, breathing difficulties, speech difficulties, paralysis of the respiratory muscles or
swallowing difficulties which may result in aspiration pneumonia.
Measures in cases of overdose
In the event of overdose, the patient should be medically monitored for symptoms of excessive muscle
weakness or muscle paralysis. Symptomatic treatment may be necessary. Respiratory support may be
required if paralysis of the respiratory muscles occurs.

Pharmacotherapeutic group: other muscle relaxants, peripherally acting agents,
ATC code: M03AX01
Botulinum neurotoxin type A blocks cholinergic transmission at the neuromuscular junction by
inhibiting the release of acetylcholine. The nerve terminals of the neuromuscular junction no longer
respond to nerve impulses, and secretion of the neurotransmitter at the motor endplates is prevented
(chemical denervation). Recovery of impulse transmission is re-established by the formation of new
nerve terminals and reconnection with the motor endplates.
Mechanism of action
The mechanism of action by which Botulinum neurotoxin type A exerts its effects on cholinergic nerve
terminals can be described by a four-step sequential process which includes the following steps:
• Binding: The heavy chain of Botulinum neurotoxin type A binds with exceptionally high
selectivity and affinity to receptors only found on cholinergic terminals.
• Internalisation: Constriction of the nerve terminal’s membrane and absorption of the toxin into
the nerve terminal (endocytosis).
• Translocation: The amino-terminal segment of the neurotoxin’s heavy chain forms a pore in the
vesicle membrane, the disulphide bond is cleaved and the neurotoxin’s light chain passes through
the pore into the cytosol.
• Effect: After the light chain is released, it very specifically cleaves the target protein (SNAP 25)
that is essential for the release of acetylcholine.
Complete recovery of endplate function/impulse transmission after intramuscular injection normally
occurs within 3-4 months as nerve terminals sprout and reconnect with the motor endplate.

Results of the clinical studies (aesthetic indications)
Vertical lines between the eyebrows seen at maximum frown (glabellar frown lines)
A total of 994 subjects with moderate to severe glabellar frown lines at maximum frown participated in
studies with XEOMIN in the indication glabellar frown lines. Of these, 169 subjects ( 18 years) were
treated with XEOMIN in the Main Period of the pivotal Phase III double-blind placebo controlled trial
and 236 subjects were treated in the Open-label Extension (OLEX) of that study. Treatment success was
defined as a ‘none’ or ‘mild’ assessment on a 4-point Facial Wrinkle Scale assessed by the investigator
at week 4 at maximum frown. The study demonstrated a statistically significant and clinically relevant
efficacy of 20 units XEOMIN when compared to placebo. The overall success rate was 51.5% in the
XEOMIN group vs. 0% in the placebo group. No worsening was observed in any patient treated with
XEOMIN in the pivotal study. This was validated by the higher number of responders at Day 30
according to the Facial Wrinkle Scale at maximum frown by both the investigator and the patient’s
assessment showing a significantly higher proportion of responders among the patients receiving
20 units XEOMIN compared to placebo.
Subgroup analysis showed that efficacy in patients older than 50 years is lower compared to younger
patients. Of those, 113 subjects were in the age of 50 years or younger and 56 subjects were older than
50 years of age. Efficacy in men is lower compared to women. Of those, 33 subjects were male and
136 subjects were female.
Therapeutic equivalence of XEOMIN as compared to a comparator product Vistabel/Botox containing
Botulinum toxin type A complex (onabotulinumtoxinA, 900 kD) was shown in two comparative,
prospective, multicentre, randomised, double-blind studies (n=631) using single-doses (20 and 24 units,
respectively). Study results demonstrated that XEOMIN and the comparator product have a similar
efficacy and safety profile in patients with moderate to severe glabellar frown lines when used with a
dosing conversion ratio of 1:1 (see section 4.2).
Long-term safety in repeat-dose (20 units) treatment of glabellar frown lines has been demonstrated in a
Phase III study over a treatment period of up to two years with up to 8 consecutive injection cycles
(MRZ 60201-0609, n=796) [Rzany et al., 2013].
Lateral periorbital lines seen at maximum smile (crow’s feet lines)
In a Phase III study, 111 subjects with moderate to severe lateral periorbital lines (crow’s feet lines) at
maximum smile were treated during 1 cycle with 12 units XEOMIN or placebo per side (right/left eye
area) with a comparison of a 3-point and a 4-point injection schemes. Treatment success was defined as
an improvement of at least 1 point on a 4-point scale assessed by an independent rater at week 4 using
standardised digital photographs taken at maximum smile for either eye area compared to baseline. Both
the 3-point injection and 4-point injection schemes showed superiority over placebo. For the 3-point
injection scheme, the success rate was 69.9% in the XEOMIN group vs. 21.4% in the placebo group,
and for the 4-point injection scheme, 68.7% vs. 14.3%, respectively. No worsening was observed in any
patient treated with XEOMIN. This was validated by the higher number of responders at Day 30
according to a 4-point scale at maximum smile by both the investigator and the patient’s assessment
showing a significantly higher proportion of responders among the patients receiving 12 units of
XEOMIN per eye area compared to placebo.
Upper facial lines
Efficacy and safety of 54 to 64 units XEOMIN in the combined treatment of upper facial lines (glabellar
frown lines, lateral periorbital lines and horizontal forehead lines) were investigated in a placebocontrolled
Phase III study including 156 subjects. Responders were defined as patients having a score of
‘none’ or ‘mild’ at maximum contraction as assessed by the investigator according to the 5-point Merz
Aesthetics Scales. The analysis demonstrated statistically significant treatment differences and high
responder rates under XEOMIN in the treatment of glabellar frown lines, lateral periorbital lines and
horizontal forehead lines alone as well as for all areas combined:

A total of 82.9% of XEOMIN treated subjects showed response for glabellar frown lines, while none of
the placebo subjects was a responder. For lateral periorbital lines, response was seen for a total of 63.8%
of XEOMIN treated subjects compared to 2.0% of placebo subjects. A total of 71.4% of XEOMIN
treated subjects showed response for horizontal forehead lines, while only one placebo subject (2.0%)
was a responder. For all three areas combined, response was reported for the majority of subjects in the
XEOMIN group (54.3%) and for none of the subjects in the placebo group (0.0%).
Results of the clinical studies (neurologic indications)
Therapeutic equivalence of XEOMIN as compared to the comparator product Botox containing the
Botulinum toxin type A complex (onabotulinumtoxinA, 900 kD) was shown in two comparative singledosing
Phase III studies, one in patients with blepharospasm (study MRZ 60201-0003, n=300) and one
in patients with cervical dystonia (study MRZ 60201-0013, n=463). Study results also suggest that
XEOMIN and this comparator product have a similar efficacy and safety profile in patients with
blepharospasm or cervical dystonia when used with a dosing conversion ratio of 1:1 (see section 4.2).
Blepharospasm
XEOMIN has been investigated in a Phase III, randomised, double-blind, placebo-controlled, multicenter
trial in a total of 109 patients with blepharospasm. Patients had a clinical diagnosis of benign
essential blepharospasm, with baseline Jankovic Rating Scale (JRS) Severity subscore ≥ 2, and a stable
satisfactory therapeutic response to previous administrations of the comparator product
(onabotulinumtoxinA).
Patients were randomised (2:1) to receive a single administration of XEOMIN (n=75) or placebo (n=34)
at a dose that was similar (+/- 10 %) to the 2 most recent Botox injection sessions prior to study entry.
The highest dose permitted in this study was 50 units per eye; the mean XEOMIN dose was 32 units per
eye.
The primary efficacy endpoint was the change in the JRS Severity subscore from baseline to Week 6
post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient’s most
recent value (last observation carried forward). In the ITT population, the difference between the
XEOMIN group and the placebo group in the change of the JRS Severity subscore from baseline to
Week 6 was -1.0 (95 % CI -1.4; -0.5) points and statistically significant (p<0.001).
Patients could continue with the Extension Period if a new injection was required. The patients received
up to five injections of XEOMIN with a minimum interval between two injections of at least six weeks
(48-69 weeks total study duration and a maximum dose of 50 units per eye. Over the entire study, the
median injection interval in subjects treated with NT 201 ranged between 10.14 (1st interval) and
12.00 weeks (2nd to 5th interval).
Spasmodic torticollis
XEOMIN has been investigated in a Phase III, randomised, double-blind, placebo-controlled, multicenter
trial in a total of 233 patients with cervical dystonia. Patients had a clinical diagnosis of
predominantly rotational cervical dystonia, with baseline Toronto Western Spasmodic Torticollis Rating
Scale (TWSTRS) total score ≥ 20. Patients were randomised (1:1:1) to receive a single administration of
XEOMIN 240 units (n=81), XEOMIN 120 units (n=78), or placebo (n=74). The number and sites of the
injections were to be determined by the Investigator.
The primary efficacy variable was the LS mean change from Baseline to Week 4 following injection in
the TWSTRS-Total score, in the Intent-to-Treat (ITT) Population with missing values replaced by the
patient’s baseline value (full statistical model). The change in TWSTRS-Total score from Baseline to
Week 4 was significantly greater in the NT 201 groups, compared with the change in the placebo group
(p<0.001 across all statistical models). These differences were also clinically meaningful:
e.g. -9.0 points for 240 units vs. placebo, and -7.5 points for 120 units vs. placebo in the full statistical
model.
Patients could continue with the Extension Period if a new injection was required. The patients received
up to five injections of 120 units or 240 units of XEOMIN with a minimum interval between two
injections of at least six weeks (48-69 weeks total study duration). Over the entire study, the median

injection interval in subjects treated with NT 201 ranged between 10.00 (1st interval) and 13.14 weeks
(3rd and 6th interval).
Spasticity of the upper limb (adults)
In the pivotal study (double-blind, placebo-controlled, multicentre) conducted in patients with poststroke
spasticity of the upper limb, 148 patients were randomised to receive XEOMIN (n=73) or
Placebo (n=75) in accordance with the dose recommendations for initial treatment presented in
section 4.2 of the SmPC. The cumulative dose after up to 6 repeated treatments in a clinical trial was in
average 1333 units (maximum 2395 units) over a period of up to 89 weeks.
As determined for the primary efficacy parameter (response rates for the wrist flexors Ashworth Scale
score at Week 4, response defined as improvement of at least 1-point in the 5-point Ashworth Scale
score), patients treated with XEOMIN (response rate: 68.5 %) had a 3.97 fold higher chance of being
responders relative to patients treated with placebo (response rate: 37.3 %; 95 % CI: 1.90 to 8.30;
p<0.001, ITT population).
This fixed dose study was not designed to differentiate between female and male patients, nevertheless
in a post-hoc analysis the response rates were higher in female (89.3 %) compared to male (55.6 %)
patients, the difference being statistically significant for women only. However, in male patients
response rates in Ashworth Scale after 4 weeks in XEOMIN treated patients were consistently higher in
all muscle groups treated compared to placebo.
Responder rates were similar in men compared to women in the open label extension period of the
pivotal study (flexible dosing was possible in this trial period) in which 145 patients were enrolled and
up to 5 injection cycles were performed, as well as in the observer-blind study (EudraCT Number 2006-
003036-30) in which efficacy and safety of XEOMIN in two different dilutions in 192 patients were
assessed in patients with upper limb spasticity of diverse aetiology.
Another double-blind, placebo-controlled Phase III clinical trial enrolled a total of 317 treatment-naïve
patients with spasticity of the upper limb who were at least three months post-stroke. During the Main
Period (MP) a fixed total dose of XEOMIN (400 units) was administered intramuscularly to the defined
primary target clinical pattern chosen from among the flexed elbow, flexed wrist, or clenched fist
patterns and to other affected muscle groups (n=210). The confirmatory analysis of the primary and coprimary
efficacy variables at week 4 post-injection demonstrated statistically significant improvements
in the responder rate of the Ashworth score, or changes from baseline in the Ashworth score and the
Investigator's Global Impression of Change.
296 treated patients completed the MP and participated in the first Open-label Extension (OLEX) cycle.
During the Extension Period patients received up to three injections. Each OLEX cycle consisted of a
single treatment session (400 units of XEOMIN total dose, distributed flexibly among all affected
muscles) followed by a 12 week observation period. The overall study duration was 48 weeks.
Treatment of shoulder muscles was investigated in an open-label Phase III study which included
155 patients with a clinical need for treatment of combined upper and lower limb spasticity. The study
protocol allowed for administration of doses up to 600 units of XEOMIN to the upper limb.
This study showed a positive relationship between increasing doses of XEOMIN and improvement of
the patients’ condition as assessed by Ashworth Scale and other efficacy variables without
compromising the patients’ safety or the tolerability of XEOMIN.
Spasticity of the lower and upper limb due to cerebral palsy (children/adolescents)
Lower limb evaluation
In a double-blind, parallel-group, dose-response Phase III clinical study 311 children and adolescents
(aged 2-17 years) with uni- or bilateral lower limb spasticity due to cerebral palsy were enrolled. For
treatment of lower limb spasticity XEOMIN was administered in three treatment groups (4 units/kg)

body weight with a maximum of 100 units, 12 units/kg body weight with a maximum of 300 units or
16 units/kg body weight with a maximum of 400 units, respectively) for treatment of two selected
lower limb clinical patterns (pes equinus, flexed knee, adducted thigh).
In this study the low dose group was intended to act as control group. No statistically significant
differences were demonstrated in the comparison of the high dose vs low dose neither regarding the
primary nor the co-primary efficacy endpoint. LS-Mean change (SE, 95% CI) from baseline in
Ashworth Scale of plantar flexors 4 weeks after injection was -0.70 (0.061, 95% CI: -0.82; -0.58) for
the high dose and -0.66 (0.084, 95% CI: -0.82; -0.50) for the low dose with a p-value of 0.650.
Improvement in muscle tone was not reflected in an effect on function or Investigator’s Global
Impression of Change. Adequate posology of XEOMIN for the treatment of lower limb spasticity in
children and adolescents cannot be determined. No unexpected adverse events were observed in the
double-blind treatment and open-label long-term treatment with XEOMIN over four injection cycles.
Upper limb evaluation
In a second double-blind, parallel-group, dose-response Phase III study a total of 350 children and
adolescents (aged 2-17 years) with upper limb spasticity alone or with combined upper and lower
limb spasticity due to cerebral palsy were treated with XEOMIN. For treatment of upper limb (flexed
elbow, flexed wrist, clenched fist, pronated forearm, thumb-in-palm) or combined upper and lower
limb spasticity (pes equinus, flexed knee, adducted thigh) XEOMIN was administered in three
treatment groups in the Main Period with one injection cycle: 2 to 5 units/kg body weight with a
maximum of 50 to 125 units, 6 to 15 units/kg body weight with a maximum of 150 to 375 units and 8
to 20 units/kg body weight with a maximum of 200 to 500 units. Patients continued with the highest
dose in the Open-label Extension Period of the study with three injection cycles.
A statistical significant difference between the low and high dose was seen in change from baseline in
Ashworth Scale for elbow flexor or wrist flexor at week 4 post injection (-0.22 [95% CI -0.4;-0.04]
p=0.017). Improvements in muscle tone was not reflected in an effect on function and Investigator’s
Global Impression of Change. Adequate posology of XEOMIN for the treatment of upper limb
spasticity in paediatric patients can therefore not be determined from this study.
No unexpected safety concerns were reported in the upper limb and lower limb spasticity treatment
with XEOMIN up to four injection cycles (14± 2 weeks each).
Chronic sialorrhea
The pivotal double-blind, placebo-controlled Phase III clinical trial enrolled a total of 184 patients
suffering at least three months from sialorrhea resulting from Parkinson’s disease, atypical
parkinsonism, stroke or traumatic brain injury. During the Main Period (MP) a fixed total dose of
XEOMIN (100 or 75 units) or placebo was administered intraglandularly at a defined dose ratio of 3:2
into parotid and submandibular salivary glands, respectively.

injection) demonstrated statistically significant improvements of the 100 units treatment group
compared to placebo. Improvements in efficacy parameters at weeks 8 and 12 post-injection could be
shown and were maintained up to the last observation point of the MP at week 16. Co-primary
efficacy variables at week 4 demonstrated superior results for ultrasound guided application in
comparison with anatomic landmark method (uSFR p-value 0.019 vs 0.099 and GICS 0.003 vs
0.171).
173 treated patients completed the MP and entered the Extension Period (EP). The EP consisted of
three dose-blinded cycles each with a single treatment session (100 or 75 units of XEOMIN total
dose, with the same dose ratio as in the MP) followed by a 16 week observation period. 151 patients
completed the EP. Results from the EP confirmed the findings of the MP showing continued
treatment benefits of 100 units XEOMIN.

 

General characteristics of the active substance
Classic kinetic and distribution studies cannot be conducted with Botulinum neurotoxin type A because
the active substance is applied in such small quantities (picograms per injection) and binds rapidly and
irreversibly to the cholinergic nerve terminals.
Native Botulinum toxin type A is a high molecular weight complex which, in addition to the neurotoxin
(150 kD), contains other non-toxic proteins, like haemagglutinins and non-haemagglutinins. In contrast
to conventional preparations containing the Botulinum toxin type A complex, XEOMIN contains pure
(150 kD) neurotoxin because it is free from complexing proteins and thus has a low foreign protein
content. The foreign protein content administered is considered as one of the factors for secondary
therapy failure.
Botulinum neurotoxin type A has been shown to undergo retrograde axonal transport after intramuscular
injection. However, retrograde transsynaptic passage of active Botulinum neurotoxin type A into the
central nervous system has not been found at therapeutically relevant doses.
Receptor-bound Botulinum neurotoxin type A is endocytosed into the nerve terminal prior to reaching
its target (SNAP 25) and is then degraded intracellularly. Free circulating Botulinum neurotoxin type A
molecules, which have not bound to presynaptic cholinergic nerve terminal receptors, are phagocytosed
or pinocytosed and degraded like any other free circulating protein.
Distribution of the active substance in patients
Human pharmacokinetic studies with XEOMIN have not been performed for the reasons detailed above.

Non-clinical data reveal no special hazard for humans based on conventional studies of cardiovascular
and intestinal safety pharmacology.
The findings from repeated-dose toxicity studies on the systemic toxicity of XEOMIN after
intramuscular injection in animals were mainly related to its pharmacodynamic action, i.e. atony, paresis
and atrophy of the injected muscle.
Similarly, the weight of the injected submandibular salivary gland was reduced at all dose levels, and
salivary gland acinar atrophy was seen at the highest dose of 40 units/kg after four repeated injections of
XEOMIN at 8 weeks intervals in rats.

No evidence of local intolerability was noted. Reproductive toxicity studies with XEOMIN did neither
show adverse effects on male or female fertility in rabbits nor direct effects on embryo-foetal or on preand
postnatal development in rats and/or rabbits. However, the administration of XEOMIN at different
intervals (daily or less frequently) in embryotoxicity studies at dose levels exhibiting maternal body
weight reductions increased the number of abortions in rabbits and slightly decreased foetal body weight
in rats. Continuous systemic exposure of the dams during the (unknown) sensitive phase of
organogenesis as a pre-requisite for the induction of teratogenic effects cannot necessarily be assumed in
these studies. Accordingly, safety margins with regard to clinical therapy were generally low in terms of
high clinical doses.
No genotoxicity or carcinogenicity studies have been conducted with XEOMIN.

 

 

Human albumin
Sucrose

This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.

3 years Reconstituted solution Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Do not store above 25 °C.
For storage conditions after reconstitution of the medicinal product, see section 6.3.

Vial (type 1 glass) with a stopper (bromobutyl rubber) and tamper-proof seal (aluminium).
XEOMIN 50 units powder for solution for injection: Pack sizes of 1, 2, 3 or 6 vials, each containing
50 units
XEOMIN 100 units powder for solution for injection: Pack sizes of 1, 2, 3, 4 or 6 vials, each containing
100 units
Not all pack sizes may be marketed.

Reconstitution
XEOMIN is reconstituted prior to use with sodium chloride 9 mg/mL (0.9%) solution for injection.
Reconstitution and dilution should be performed in accordance with good clinical practice guidelines,
particularly with respect to asepsis.
It is good practice to reconstitute the vial contents and prepare the syringe over plastic-lined paper
towels to catch any spillage. An appropriate amount of sodium chloride solution is drawn up into a
syringe. A 20-27 gauge short bevel needle is recommended for reconstitution. After vertical insertion of
the needle through the rubber stopper, the solvent is injected gently into the vial in order to avoid foam
formation. If the vacuum does not pull the solvent into the vial the vial should be discarded. The syringe
should be removed from the vial and XEOMIN should be mixed with the solvent by carefully swirling
and inverting/flipping the vial – the solution should not be shaken vigorously. If needed, the needle
used for reconstitution should remain in the vial and the required amount of solution should be drawn up
with a new sterile syringe suitable for injection.

Reconstituted XEOMIN is a clear, colourless solution.
XEOMIN must not be used if the reconstituted solution has a cloudy appearance or contains floccular or
particulate matter.
Care should be taken to use the correct solvent volume for the presentation chosen to prevent accidental
overdose. If different vial sizes of XEOMIN are being used as part of one injection procedure, care
should be taken to use the correct amount of solvent when reconstituting a particular number of units per
0.1 ml. The amount of solvent varies between XEOMIN 50 units, XEOMIN 100 units and XEOMIN
200 units. Each syringe should be labelled accordingly.
Possible concentrations for XEOMIN 50 and 100 units are indicated in the following table:

Any solution for injection that has been stored for more than 24 hours as well as any unused solution for
injection should be discarded.
Procedure to follow for a safe disposal of vials, syringes and materials used
Any unused vials or remaining solution in the vial and/or syringes should be autoclaved. Alternatively,
the remaining XEOMIN can be inactivated by adding one of the following solutions: 70 % ethanol, 50
% isopropanol, 0.1 % SDS (anionic detergent), diluted sodium hydroxide solution (0.1 N NaOH), or
diluted sodium hypochlorite solution (at least 0.1 % NaOCl).
After inactivation used vials, syringes and materials should not be emptied and must be discarded into
appropriate containers and disposed of in accordance with local requirements.
Recommendations should any incident occur during the handling of Botulinum toxin type A
• Any spills of the product must be wiped up: either using absorbent material impregnated with any
of the above listed solutions in case of the powder, or with dry, absorbent material in case of
reconstituted product.
• The contaminated surfaces should be cleaned using absorbent material impregnated with any of
the above solutions, then dried.
• If a vial is broken, one should proceed as mentioned above by carefully collecting the pieces of
broken glass and wiping up the product, avoiding any cuts to the skin.
• If the product comes into contact with skin, the affected area should be rinsed abundantly with
water.
• If product gets into the eyes, they should be rinsed thoroughly with plenty of water or with an
ophthalmic eyewash solution.
• If product comes into contact with a wound, cut or broken skin, the skin should be rinsed
thoroughly with plenty of water. Appropriate medical steps according to the dose injected should
be taken.
These instructions for use, handling and disposal should be strictly followed.