Xeomin 100 LD₅₀ units powder for solution for injection

1 vial contains 100 LD₅₀ units* of Clostridium Botulinum neurotoxin type A (150 kD), free of complexing proteins.

* One unit corresponds to the median lethal dose (LD₅₀) when the reconstituted product is injected intraperitoneally into mice under defined conditions.

Due to differences in the LD₅₀ assay, these units are specific to Xeomin and are not interchangeable with other Botulinum toxin preparations.

Excipient(s):

For a full list of excipients, see section 6.1.

Powder for solution for injection

White powder

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.

Unit doses recommended for Xeomin are not interchangeable with those for other preparations of Botulinum toxin.

Xeomin may only be used by physicians with suitable qualifications and proven experience in the application of Botulinum toxin and in the use of the necessary equipment, e.g. electromyography (EMG).

Reconstituted Xeomin is intended for intramuscular injection.

The optimum dosage 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.

For instructions on reconstitution / dilution of the vials, see section 6.6. After reconstitution, Xeomin should be used for only one injection session and for only one patient.

A decrease or increase in the Xeomin dose is possible by administering a smaller or larger injection volume. The smaller the injection volume the less pressure sensation and the less spread of Botulinum neurotoxin type A in the injected muscle occurs. This is of benefit in reducing effects on nearby muscles when small muscle groups are being injected.

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 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 initial recommended dose is 1.25 to 2.5 U (0.05-0.1 ml volume) per injection site. The initial dose should not exceed 25 U per eye. In the management of blepharospasm, total dosing should not exceed 100 U every 12 weeks.

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.

The median time to first onset of effect is observed within four days after injection. The effect of each 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 – usually defined as an effect that does not last longer than two months. However, there appears to be no additional benefit obtainable from injecting more than 5.0 U per site. Normally, no additional benefit is conferred by treating more frequently than every three months.

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. 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 usually 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.

Normally, in practice, the total dose administered does not exceed 200 U. Doses of up to 300 U may be given. No more than 50 U should be given at any one injection site.

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 is dependent upon 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.

The median first onset of effect is observed within seven days after injection. The effect of each treatment generally lasts approximately 3-4 months, however, it may last significantly longer or shorter. The period between each treatment session should be at least 10 weeks.

Post-stroke 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 electromyographic guidance or nerve stimulation techniques may be useful. 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.

The exact dosage 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.

In the management of post-stroke spasticity of the upper limb the following initial doses (units) were administered in the pivotal clinical trial:

In the pivotal clinical trial, the minimal and maximum total dose were 170 U and 400 U, respectively.

For repeated treatments dosing should be tailored to the individual patient's need. The recommended dose ranges per muscle are provided in the following table:

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. Reinjections should not be performed within intervals of less than 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

A treatment-naïve patient should be regarded as a primary non-responder in cases of first injection failure. It has not been investigated whether secondary non-response due to the development of antibodies is less frequent under Xeomin therapy than under treatment with conventional preparations containing the Botulinum toxin type A complex. In cases of non-response, alternative therapies should be considered.

Xeomin has not been studied in the paediatric population and is therefore not recommended in the paediatric age group until further data become available.

Hypersensitivity to the active substance Botulinum neurotoxin type A or to any of the excipients.

Generalised disorders of muscle activity (e.g. myasthenia gravis, Lambert-Eaton syndrome).

Presence of infection at the proposed injection site.

Side effects related to spread of Botulinum 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.

Patients treated with therapeutic doses may experience exaggerated muscle weakness. Patients with underlying neurological disorders including swallowing difficulties are at increased risk of these side effects. 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.

Dysphagia has also been reported following injection to sites other than the cervical musculature (see section 4.4 “spasmodic torticollis”).

An anaphylactic reaction may occur rarely after injection of Botulinum neurotoxin type A (see section 4.8). Adrenaline and other medical aids for treating anaphylaxis should be available.

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. Extra caution is required when injecting at sites close to sensitive structures such as the carotid artery and lung apices.

Xeomin should be used with caution:

• If bleeding disorders of any type occur

• In patients receiving anticoagulant therapy

• In patients suffering from amyotrophic lateral sclerosis or other diseases which result in peripheral neuromuscular dysfunction

• In targeted muscles which display pronounced weakness or atrophy.

The recommended single doses of Xeomin should not be exceeded and the intervals between injections should not be shortened.

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.

Too frequent dosing of Botulinum toxin may result in antibody formation which may lead to treatment resistance (see section 4.2).

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

Xeomin contains albumin, a derivative of human blood. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include careful selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. There are no reports of viral transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes.

Blepharospasm

Because of the anticholinergic effect of Botulinum neurotoxin type A, Xeomin should be used with caution in patients at risk of developing an angle closure 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). Dysphagia can last for up to two to three weeks after injection, but a duration of up to five months has been reported in one case. Limiting the dose injected into the sternocleidomastoid muscle to less than 100 U 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.

Post-stroke spasticity of the upper limb

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.

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-Aminochinolines may reduce the effect of Xeomin.

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.

It is not known whether Botulinum neurotoxin type A is excreted into the breast milk. Therefore, the use of Xeomin during lactation cannot be recommended.

No studies on the effects on the ability to drive and use machines have been performed. However, Xeomin may cause tiredness, muscle weakness, dizziness and visual disturbance, which could affect driving.

Due to the nature of the diseases being treated, the ability to drive and to operate machines may be reduced. Due to the latency of onset, some of the therapeutic and/or adverse effects of Xeomin, which may also interfere with the ability to drive and operate machinery. Consequently affected persons should avoid these tasks until their faculties are fully recovered.

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. Usually, undesirable effects are observed within the first week after treatment and are temporary in nature. They may be restricted to the area around the injection site (e.g. local pain, tenderness at the injection site, and injection site haemorrhage).

As is expected for any injection procedure, localized pain, inflammation, paraesthesia, hypoesthesia, tenderness, swelling/oedema, erythema, localized infection 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.

Frequency by different indications

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, <1/10); uncommon (1/1,000, <1/100), rare (1/10,000, <1/1,000); very rare (<1/10,000).

Blepharospasm

The following adverse reactions were reported with Xeomin:

Spasmodic torticollis

The following adverse reactions were reported with Xeomin:

Post-stroke spasticity of the upper limb

The following adverse reactions were reported with Xeomin:

Some of these undesirable effects may be disease related.

General

Localised allergic reactions like swelling, oedema, erythema, pruritus or rash have been rarely reported from post-marketing experience with Xeomin.

The following additional information is also based on publications on conventional preparations containing the Botulinum toxin type A complex.

Side 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).

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

The following other adverse events have been reported following administration of conventional Botulinum toxin type A complex: dysarthria, abdominal pain, hyperhidrosis, anorexia, hypoacusis, tinnitus, radiculopathy.

There have been rare reports of undesirable effects related to the cardiovascular system, such as arrhythmia and myocardial infarction, some with fatal outcomes following treatment with botulinum toxins. It remains unclear whether these deaths were induced by botulinum toxin or whether these were caused by pre-existing cardiovascular disease. 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 conventional Botulinum toxin type A complex either alone or in combination with other agents known to cause similar reactions.

A case of peripheral neuropathy has been reported in a male after receiving four sets of injections of a conventional preparation containing the Botulinum toxin type A complex (for neck and back spasm, and severe pain) over an 11 week period.

Angle closure glaucoma has been reported very rarely following administration of conventional Botulinum toxin type A complex for blepharospasm.

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.

A female patient developed brachial plexopathy two days after injection of a conventional preparation containing the Botulinum toxin type A complex for the treatment of cervical dystonia, with recovery after five months.

Erythema multiforme, urticaria, and psoriasis-like rash have been described with the use of conventional preparations containing the Botulinum toxin type A complex, but their causal relationship remains unclear.

Following injection of conventional Botulinum toxin type A complex, EMG showed increased jitter in some distant muscles which was not associated with muscle weakness or other types of electrophysiological abnormalities.

Symptoms of overdose:

Increased doses of Botulinum neurotoxin type A may result in pronounced neuromuscular paralysis distant from the injection site. Symptoms of overdose are not immediately apparent post-injection and may include general weakness, ptosis, diplopia, breathing, swallowing and speech difficulties, or paralysis of the respiratory muscles resulting in an aspiration pneumonia.

Measures in cases of overdose:

In case of an overdose the patient must be monitored medically for several days. If signs of intoxication appear, hospitalisation with general supportive measures is necessary. Intubation and assisted ventilation will become necessary until improvement if paralysis of the respiratory muscles occurs.

Pharmacotherapeutic group: Muscle relaxant, peripherally acting agent, 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 is prevented (chemical denervation). Recovery of impulse transmission is re-established by the formation of new nerve terminals and motor endplates.

The mechanism of action by which Botulinum neurotoxin type A exerts its effects on cholinergic nerve terminals can be described by a three-step sequential process which includes the following steps:

a) binding to the cholinergic nerve terminals,

b) entry or internalisation into the nerve terminal,

c) inhibition of acetylcholine release by intracellular poisoning within the nerve terminal.

The heavy chain of the Botulinum neurotoxin type A binds with an exceptionally high selectivity and affinity to receptors only found on cholinergic terminals. After internalisation of the neurotoxin the light chain cleaves a specific target protein (SNAP 25) that is essential for the release of acetylcholine.

Recovery after injection normally takes place within 3-4 months as nerve terminals sprout and reconnect with the endplate.

In the pivotal study (double-blind, placebo-controlled, multicentre, EudraCT Number 2005-003951-11) 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 SPC. 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 4 point Ashworth Scale score), patients treated with NT 201 (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 NT 201 treated patients were consistently higher in all muscle groups treated compared to placebo.

Responder rates were similar in men compared to women in the open label extension period of the pivotal study (flexible dosing was possible in this trial period) in which 145 patients were enrolled and up to 5 injection cycles were performed, as well as in the observer-blind study (EudraCT Number 2006-003036-30) in which efficacy and safety of Xeomin in two different dilutions in 192 patients were assessed in patients with upper limb spasticity of diverse etiology.

a) General characteristics of the active substance:

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

Native Botulinum toxin is a high molecular weight complex, which, in addition to the neurotoxin (150 kD), contains other non-toxic proteins, like haemagglutinins and non-haemagglutinins. In contrast to conventional preparations containing the Botulinum toxin type A complex, Xeomin contains pure (150 kD) neurotoxin since it is free of complexing proteins.

Like many other proteins of its size, Botulinum neurotoxin type A has been shown to undergo retrograde axonal transport after intramuscular injection. Retrograde transsynaptic passage of active Botulinum neurotoxin type A into the central nervous system however has not been found.

Receptor-bound Botulinum neurotoxin type A is endocytosed into the nerve terminal prior to reaching its target (SNAP 25) and is eventually degraded intracellularly. Free circulating Botulinum neurotoxin type A molecules that have not bound to presynaptic cholinergic nerve terminal receptors will be phagocytosed or pinocytosed and degraded like any other free circulating protein.

b) Distribution of the active substance in patients:

Human pharmacokinetic studies with Xeomin have not been performed for the reasons detailed above.

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

The findings made in repeat-dose toxicity studies conducted with Xeomin were mainly related to its pharmacodynamic action.

No evidence of local intolerability was noted. Reproductive toxicity studies with Xeomin, performed in rabbits, did not show adverse effects on male or female fertility nor direct effects on embryo-foetal development. However, the administration of Xeomin at dose levels exhibiting clear maternal toxicity at weekly to biweekly intervals increased the number of abortions in a prenatal toxicity study in rabbits. A continuous systemic exposure of the dams during the (unknown) sensitive phase of the organogenesis as a pre-requisite for the induction of teratogenic effects cannot necessarily be assumed.

No genotoxicity, carcinogenicity or pre- and postnatal development studies have been conducted with Xeomin.

Human albumin

Sucrose

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

Unopened vial: 4 years

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 2 to 8°C. From a microbiological point of view, the product should be used immediately.

Unopened vial: Do not store above 25°C

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

Vial (type 1 glass) with rubber stopper (bromobutyl rubber) and tamper-proof seal (aluminium) in pack sizes of 1 (single unit pack), 2, 3, 4 or 6 vials (multi-packs). A clinical pack is also available with 6 vials.

Not all pack sizes may be marketed.

Xeomin is reconstituted prior to use with sterile unpreserved sodium chloride 9 mg/ml (0.9%) solution for injection. Reconstitution and dilution should be performed in accordance with good clinical practice guidelines, particularly with respect to asepsis.

It is good practice to perform vial reconstitution and syringe preparation over plastic-lined paper towels to catch any spillage. An appropriate amount of solvent (see dilution table) is drawn up into a syringe. The exposed portion of the rubber stopper of the vial is cleaned with alcohol (70%) prior to insertion of the needle. The solvent must be injected gently into the vial. The vial must be discarded, if the vacuum does not pull the solvent into the vial. Reconstituted Xeomin is a clear colourless solution free of particulate matter.

Xeomin should not be used if the reconstituted solution (prepared as above) has a cloudy appearance or contains floccular or particulate matter.

Possible dilutions are indicated in the following table:

Any solution for injection that has been stored for more than 24 hours as well as any unused solution for injection should be discarded.

For safe disposal, unused vials should be reconstituted with a small amount of water and then autoclaved. Any used vials, syringes, and spillage etc. should be autoclaved and any residual Xeomin should be inactivated using diluted sodium hydroxide solution (0.1 N NaOH).

Merz Pharmaceuticals GmbH

Eckenheimer Landstraße 100

60318 Frankfurt/Main

Germany

P.O. Box 11 13 53

60048 Frankfurt/Main

Germany

PL 29978/0001

20 December 2007

January 2011