SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

XEOMIN 200 units powder for solution for injection

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

One vial contains 200 units of Clostridium Botulinum neurotoxin type A (150 kD), free from complexing proteins*

*    Botulinum neurotoxin type A, purified from cultures of Clostridium

Botulinum (Hall strain)

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Powder for solution for injection White powder

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

XEOMIN is indicated for the symptomatic treatment of blepharospasm, cervical dystonia of a predominantly rotational form (spasmodic torticollis) and of post-stroke spasticity of the upper limb presenting with flexed wrist and clenched fist in adults.

Posology and method of administration

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

For detailed information regarding clinical studies with XEOMIN in comparison to conventional Botulinum toxin type A complex (900 kD), see section 5.1.

General

XEOMIN may only be administered by healthcare professionals with suitable qualifications and the requisite experience in the application of Botulinum toxin.

The optimum dose 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.

Posology

Blepharospasm

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 100 units 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.

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 sitting 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.

Post-stroke 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 initial doses:

Clinical Pattern Muscle	Units
Flexed Wrist
Flexor carpi radialis	50
Flexor carpi ulnaris	40
Clenched Fist
Flexor digitorum superficialis	40
Flexor digitorum profundus	40
Flexed Elbow
Brachioradialis	60
Biceps	80
Brachialis	50
Pronated Forearm
Pronator quadratus	25
Pronator teres	40
Thumb-in-Palm
Flexor pollicis longus	20
Adductor pollicis	10
Flexor pollicis brevis/ Opponens pollicis	10

In the pivotal clinical trial, the minimum and maximum total doses were 170 units and 400 units per treatment session, respectively.

Recommended doses for repeated treatment:

Clinical Pattern	Units (Range) Number of
Muscle	injection sites
	per muscle

Flexed Wrist
Flexor carpi radialis	25-100	1-2
Flexor carpi ulnaris	20-100	1-2
Clenched Fist
Flexor digitorum superficialis	40-100	2
Flexor digitorum profundus	40-100	2
Flexed Elbow
Brachioradialis	25-100	1-3
Biceps	75-200	1-4
Brachialis	25-100	1-2
Pronated Forearm
Pronator quadratus	10-50	1
Pronator teres	25-75	1-2
Thumb-in-Palm
Flexor pollicis longus	10-50	1
Adductor pollicis	5-30	1
Flexor pollicis brevis/ Opponens pollicis	5-30	1

The maximum total recommended dose is up to 400 units per treatment session.

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. Repeated treatment should generally be no more frequent than every 12 weeks.

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: e.g. an electromyographic investigation in a specialised facility

-    Analysis of the reason 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, 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) EMG-guidance, 3) the recommended minimum interval between the initial and repeat treatment is followed

Paediatric population

The safety and efficacy of XEOMIN in children and adolescents aged 0-17 years has not yet been established. XEOMIN is thus not recommended in the paediatric population until further data become available.

Method of administration

Reconstituted XEOMIN is intended for intramuscular injection.

Blepharospasm

After reconstitution, the XEOMIN solution is injected using a suitable sterile needle (e.g. 27-30 gauge/0.30-0.40 mm). 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.

Spasmodic torticollis

A suitable sterile needle (e.g. 25-30 gauge/0.30-0.50 mm) is used for injections into superficial muscles, and an e.g. 22 gauge/0.70 mm 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 electromyographic guidance. 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.

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).

In case of any difficulty in isolating the individual muscles, injections should be made under electromyographic assistance. 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.

All indications

For instructions on reconstitution of the medicinal product before administration and for instructions on disposal of the vials, see section 6.6. After reconstitution, XEOMIN should be used for only one injection session and for only one patient.

4.3 Contraindications

•    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.

4.4 Special warnings and precautions for use

General

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. For the treatment of cervical dystonia and post-stroke spasticity, XEOMIN should be injected carefully when injecting at sites close to sensitive structures such as the carotid artery lung apices and oesophagus.

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.

Previously akinetic or sedentary patients should be reminded to gradually resume activities following the injection of XEOMIN.

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 injected muscles 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 form the injection site.

There have been reports of undesirable effects that might be related to the spread of Botulinum toxin to sites far from the injection site (see section 4.8). 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.

Dysphagia has also been reported following injection to sites other than the cervical musculature.

Pre-existing neuromuscular disorders

Patients treated with therapeutic doses may experience exaggerated muscle weakness. Patients with neuromuscular disorders may be at increased risk of exaggerated muscle weakness. 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 occur.

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 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.

Indications

Blepharospasm

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

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.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

4-Aminoquinolines may reduce the effect of XEOMIN.

4.6 Fertility, pregnancy and lactation

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).

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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 and syncope.

Undesirable effects of the substance class Botulinum toxin type A

Localised muscle weakness is one expected pharmacological effect of Botulinum toxin.

Toxin spread

Undesirable effects related to spread of toxin distant from the site of administration have been reported very rarely (exaggerated muscle weakness, dysphagia, and aspiration pneumonitis with 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 dependent on indication

Headache, presyncope, dizziness Speech disorder

Respiratory, thoracic and mediastinal disorders Uncommon:    Dysphonia, dyspnoea

Gastrointestinal disorders

Very common:    Dysphagia

Common:    Dry mouth, nausea

Skin and subcutaneous tissue disorders Common:    Hyperhidrosis

Uncommon:    Rash

Musculoskeletal and connective tissue disorders

Common:    Neck pain, muscular weakness, myalgia, muscle spasm,

musculoskeletal stiffness

General disorders and administration site conditions Common:    Injection site pain, asthenia

Infections and infestations

Common:    Upper respiratory tract infection

Post-stroke spasticity of the upper limb

The following adverse reactions were reported with XEOMIN:

Nervous system disorders

Common:    Headache, dysaesthesia, hypoaesthesia

Gastrointestinal disorders Common:    Dysphagia

Musculoskeletal and connective tissue disorders Common:    Muscular weakness, pain in extremity

Uncommon:    Myalgia

General disorders and administration site conditions

Asthenia

Feeling hot, injection site pain

Some of these undesirable effects may be disease related.

Post-Marketing Experience

Flu-like symptoms and hypersensitivity reactions like swelling, oedema (also apart from injection site), erythema, pruritus, rash (local and generalised) and breathlessness have been reported.

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 at www.mhra.gov.uk/yellowcard.

4.9 Overdose

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 a 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

Non-inferiority of XEOMIN efficacy as compared to a comparator product containing the conventional Botulinum toxin type A complex onabotulinumtoxinA (900 kD) was shown in two comparative single-dosing 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 in 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, multi-center 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 onabotulinumtoxinA (Botox).

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 onabotulinumtoxinA 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 (1^st interval) and 12.00 weeks (2^nd to 5^th interval).

Spasmodic torticollis

XEOMIN has been investigated in a Phase III, randomised, double-blind, placebo-controlled, multi-center 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 U vs. placebo, and -7.5 points for 120 U 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 U or 240 U 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 (1^st interval) and 13.14 weeks (3^rd and 6^th interval).

Post-stroke spasticity of the upper limb

In the pivotal study (double-blind, placebo-controlled, multicentre) conducted in patients with post-stroke 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.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with XEOMIN in all subsets of the paediatric population in the treatment of dystonia and in infants and toddlers from 0-24 months in the treatment of muscle spasticity (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

General characteristics of the active substance

Classic kinetic and distribution studies cannot be conducted with Botulinum neurotoxin type A because the active substance is applied in such small quantities (picograms per injection) and binds rapidly and irreversibly to the cholinergic nerve terminals.

Native Botulinum toxin 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.

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.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of cardiovascular safety pharmacology.

The findings from repeated-dose toxicity studies on the systemic toxicity of XEOMIN in animals were mainly related to its pharmacodynamic action, i.e. atony, paresis and atrophy of the injected muscle.

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 pre- and postnatal development in rats and/or rabbits. However, the administration of XEOMIN at daily, weekly or biweekly intervals 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Human albumin

Sucrose

6.2 Incompatibilities

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

6.3 Shelf life

XEOMIN 200 units powder for solution for injection: 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.

6.4 Special precautions for storage

Do not store above 25 °C.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Vial (type 1 glass) with a stopper (bromobutyl rubber) and tamper-proof seal (aluminium).

XEOMIN 200 units powder for solution for injection: Pack sizes of 1, 2, 3, 4 or 6 vials

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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 solvent (see dilution table) is drawn up into a syringe. After vertical insertion of the needle through the rubber stopper, the solvent is injected gently into the vial in order to avoid foam formation. A 20-27 gauge short bevel needle is recommended for reconstitution. The vial must be discarded if the vacuum does not pull the solvent into the vial. Remove the syringe from the vial and mix XEOMIN with the solvent by carefully swirling and inverting the vial - do not shake 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 diluent 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 diluent when reconstituting a particular number of units per 0.1 ml. The amount of diluent

varies between XEOMIN 50 units, XEOMIN 100 units and XEOMIN 200 units. Each syringe should be labelled accordingly.

Possible dilutions for XEOMIN 50, 100, and 200 units are indicated in the following table:

Resulting dose (in units per 0.1 ml)	Solvent added (sodium chloride 9 mg/ml (0.9 %) solution for injection)
	Vial with 50 units	Vial with 100 units	Vial with 200 units
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
2.5 units	2 ml	4 ml	8 ml
1.25 units	4 ml	8 ml	Not applicable

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, residual reconstituted 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

•    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, it should be proceeded 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, rinse the affected area abundantly with water.

•    If product gets into the eyes, the eyes 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 area should be rinsed thoroughly with plenty of water and the appropriate medical steps according to the dose injected should be taken.

These instructions for use, handling and disposal should be strictly followed.

7    MARKETING AUTHORISATION HOLDER

Merz Pharmaceuticals GmbH Eckenheimer LandstraBe 100 60318 Frankfurt/Main Germany

P.O. Box 11 13 53 60048 Frankfurt/Main German

8    MARKETING AUTHORISATION NUMBER(S)

PL 29978/0004

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/04/2016

10    DATE OF REVISION OF THE TEXT

19/04/2016