. 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 aged 0-17 years has not yet been established. XEOMIN is thus not recommended in the paediatric population until further data become available.
4.3 Contraindications
Hypersensitivity to the active substance Botulinum neurotoxin type A or to any of the excipients listed in section 6.1.
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
Undesirable 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 undesirable 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).
It should be considered that pre-treated patients might have been immunised by previously administered botulinum toxin injections. 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.
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
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-Aminochinolines 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 not known whether Botulinum neurotoxin type A is excreted into the breast milk. Therefore, the use of XEOMIN during lactation cannot be recommended.
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.
XEOMIN may cause tiredness, muscle weakness, dizziness and visual disturbance, which may temporarily impair the ability to drive or operate machinery.
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