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Xeomin

1. Name Of The Medicinal Product

Xeomin 100 LD50 units powder for solution for injection

2. Qualitative And Quantitative Composition

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.

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.

4.2 Posology And Method Of Administration

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:

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 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:

Clinical Pattern

Muscle

Units (Range)

Number of 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. 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-na?ve 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.

4.3 Contraindications

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.

4.4 Special Warnings And Precautions For Use

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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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.

4.6 Pregnancy And Lactation

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.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, 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.

4.8 Undesirable Effects

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 (

Blepharospasm

The following adverse reactions were reported with Xeomin:

Nervous system disorders

Uncommon:

paraesthesia, headache

Eye disorders

Common:

ptosis, dry eyes

Uncommon:

conjunctivitis

Gastrointestinal disorders

Uncommon:

dry mouth

Skin and subcutaneous tissue disorders

Uncommon:

skin rash

Musculoskeletal and connective tissue disorders

Uncommon:

muscle weakness

Injury, poisoning and procedural complications

Uncommon:

inflicted injury

Additionally, the following undesirable effects and accordingly their frequencies are known for the comparative compound containing conventional Botulinum toxin type A complex used in clinical trials with Xeomin. It is possible that these undesirable effects may also occur with Xeomin.

Nervous system disorders

Uncommon:

dizziness, facial paralysis

Eye disorders

Common:

superficial punctate keratitis, lagophthalmos, eye irritation, photophobia, lacrimation

Uncommon:

keratitis, ectropion, diplopia, entropion, visual disturbance, blurred vision

Rare:

swelling of eyelid

Very rare:

angle closure glaucoma, corneal ulceration

Skin and subcutaneous tissue disorders

Uncommon:

dermatitis

Musculoskeletal and connective tissue disorders

Uncommon:

facial muscle weakness

General disorders and administration site conditions

Uncommon:

tiredness

Spasmodic torticollis

The following adverse reactions were reported with Xeomin:

Nervous system disorders

Uncommon:

headache, tremor

Eye disorders

Uncommon:

eye pain

Respiratory, thoracic and mediastinal disorders

Uncommon:

dysphonia

Gastrointestinal disorders

Common:

dysphagia

Uncommon:

diarrhoea, dry mouth, vomiting, colitis

Skin and subcutaneous tissue disorders

Uncommon:

skin rash, erythema, pruritus, sweating increased

Musculoskeletal and connective tissue disorders

Common:

muscle weakness, back pain

Uncommon:

skeletal pain, myalgia

General disorders and administration site conditions

Uncommon:

asthenia, injection site inflammation, injection site tenderness

Additionally, the following undesirable effects and accordingly their frequencies are known for the comparative compound containing conventional Botulinum toxin type A complex used in clinical trials with Xeomin. It is possible that these undesirable effects may also occur with Xeomin.

Nervous system disorders

Common:

dizziness, numbness, drowsiness

Eye disorders

Uncommon:

diplopia, ptosis

Respiratory, thoracic and mediastinal disorders

Common:

rhinitis, upper respiratory tract infection

Uncommon:

dyspnoea, voice alteration

Gastrointestinal disorders

Common:

nausea, oral dryness

Skin and subcutaneous tissue disorders

Common:

skin sores

Musculoskeletal and connective tissue disorders

Common:

stiffness, hypertonia

General disorders and administration site conditions

Very common:

pain, local weakness

Common:

generalised weakness, flu like symptoms, malaise

Uncommon:

fever

The management of spasmodic torticollis may cause dysphagia with varying degrees of severity with the potential for aspiration which may require medical intervention. Dysphagia may persist for two to three weeks after injection, but has been reported in one case to last five months. Dysphagia appears to be dose-dependent. In clinical trials with Botulinum toxin type A complex it was reported that dysphagia occurs less frequently with total doses below 200 U per treatment session.

Post-stroke spasticity of the upper limb

The following adverse reactions were reported with Xeomin:

General disorders and administration site conditions

Common:

injection site pain, injection site haematoma

Uncommon:

feeling hot, asthenia, oedema peripheral

Musculoskeletal and connective tissue disorders

Common:

muscular weakness

Uncommon:

pain in extremity, joint swelling, myalgia

Gastrointestinal disorders

Uncommon:

dysphagia, nausea, dry mouth

Nervous system disorders

Uncommon:

dysaesthesia, headache, hypoaesthesia

Vascular disorders

Uncommon:

haematoma

Respiratory, thoracic and mediastinal disorders

Uncommon:

cough

Skin and subcutaneous tissue disorders

Uncommon:

erythema

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.

4.9 Overdose

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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

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 neuroto





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