, 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.
Tabulated list of adverse reactions
Based on clinical experience information on the frequency of adverse reactions for the individual indications is given below. The frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
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
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
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:
Nervous system disorders
Uncommon: dysaesthesia, headache, hypoaesthesia
Vascular disorders
Uncommon: haematoma
Respiratory, thoracic and mediastinal disorders
Uncommon: cough
Gastrointestinal disorders
Uncommon: dysphagia, nausea, dry mouth
Skin and subcutaneous tissue disorders
Uncommon: erythema
Musculoskeletal and connective tissue disorders
Common: muscular weakness
Uncommon: pain in extremity, joint swelling, myalgia
General disorders and administration site conditions
Common: injection site pain, injection site haematoma
Uncommon: feeling hot, asthenia, oedema peripheral
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 generalized) and breathlessness have been reported.
General
The following additional information is also based on publications on conventional preparations containing the Botulinum toxin type A complex.
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).
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: 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 is prevented (chemical denervation). Recovery of impulse transmission is re-established by the formation of new nerve terminals and 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 injection normally occurs within 3-4 months as nerve terminals sprout and reconnect with the 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).
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 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 r