One vial contains 50 LD50 units* of Botulinum toxin type A (150 kD), free from complexing proteins.
0.1 ml solution contains 4 LD50 units* of Botulinum toxin type A (150 kD), free from complexing proteins when reconstituted in 1.25 ml.
* One unit corresponds to the mean lethal dose (LD50) when the reconstituted product is injected intraperitoneally into mice under defined conditions.
For the full list of excipients, see section 6.1.
Powder for solution for injection
BOCOUTURE is indicated for the temporary improvement in the appearance of moderate to severe
• vertical lines between the eyebrows seen at frown (glabellar frown lines)
• lateral periorbital lines seen at maximum smile (crow’s feet lines) in adults below 65 years when the severity of these lines has an important psychological impact for the patient.
Unit doses recommended for BOCOUTURE are not interchangeable with those for other preparations of Botulinum toxin.
For detailed information regarding clinical studies with BOCOUTURE in comparison to conventional Botulinum toxin type A complex (900 kD) see section 5.1.
BOCOUTURE may only be administered by physicians with suitable qualifications and the requisite experience with this therapy, and who have the necessary equipment.
Reconstituted BOCOUTURE is intended for intramuscular injection.
After reconstitution, BOCOUTURE should be used immediately and may only be used for one treatment per patient.
For instructions on disposal of the vials, see section 6.6.
Reconstituted BOCOUTURE is injected using a thin sterile needle (e.g. 30 gauge needle).
Vertical Lines between the Eyebrows (Glabellar Frown Lines)
After reconstitution of BOCOUTURE (50 units/1.25 ml) the recommended injection volume of 0.1 ml (4 units) is injected into each of the 5 injection sites: two injections in each corrugator muscle and one injection in the procerus muscle, which corresponds to a standard dose of 20 units. The dose may be increased by the physician to up to 30 units if required by the individual needs of the patients, with at least ‘3-months’ interval between treatments.
An improvement in the vertical lines between the eyebrows (glabellar frown lines) generally takes place within 2 to 3 days with the maximum effect observed on day 30. The effect lasts up to 4 months after the injection.
Method of administration
Before and during the injection, the thumb and index finger should be used to apply firm pressure below the edge of the eye socket in order to prevent diffusion of the solution in this region. Superior and medial alignment of the needle should be maintained during the injection. To reduce the risk of blepharoptosis, injections near the levator palpebrae superioris and into the cranial portion of the orbicularis oculi should be avoided. Injections into the corrugator muscle should be done in the medial portion of the muscle, and in the central portion of the muscle belly at least 1 cm above the bony edge of the eye socket.
Lateral Periorbital Lines seen at maximum smile (Crow’s feet lines)
After reconstitution of BOCOUTURE (50 units/1.25 ml) the recommended injection volume of 0.1 ml (4 units) is injected bilaterally into each of the 3 injection sites. One injection of 0.1 ml is placed approximately 1 cm lateral from the bony orbital rim. The other two injections of 0.1 ml each should be placed approximately 1 cm above and below the area of the first injection.
The total recommended standard dose per treatment is 12 units per side (overall total dose: 24 units).
An improvement in lateral periorbital lines seen at maximum smile (crow’s feet lines) mostly takes place within the first 6 days with the maximum effect observed on day 14. The effect lasts up to 3 months after the injection.
No efficacy and safety data are currently available for more than two injections in lateral periorbital lines seen at maximum smile separated by a 4-month interval.
Method of administration
The injection should be done intramuscularly into the orbicularis oculi muscle, directly under the dermis to avoid diffusion of BOCOUTURE. Injections too close to the zygomaticus major muscle should be avoided to prevent lip ptosis.
The intervals between treatments should not be shorter than 3 months. If the treatment fails, or the effect lessens with repeated injections, alternative treatment methods should be used.
There are limited clinical data from phase 3 studies of BOCOUTURE in patients over 65 years of age. Until further studies have been conducted in this age group, BOCOUTURE is not recommended for use in patients over 65 years of age.
The safety and efficacy of BOCOUTURE for the treatment of vertical lines between the eyebrows or lateral periorbital lines seen at maximum smile has not been studied in individuals younger than 18 years old. Therefore, the use of BOCOUTURE in individuals under the age of 18 is not recommended.
If no treatment effect occurs within one month of the initial injection, the following measures should be taken:
• analysis of the reasons for non-response, e.g. injected into the wrong muscles, injection method, insufficient dosage, formation of neurotoxin-neutralising antibodies
• recheck Botulinum neurotoxin type A as an adequate therapy
• if no adverse reactions have occurred during the initial treatment, an additional treatment can be performed under the following conditions: 1.) dose adjustment with regard to the analysis of the most recent therapy failure, 2.) compliance with the minimum interval of 3 months between the initial and repeat treatment.
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)
Presence of infection or inflammation at the proposed injection site
BOCOUTURE may only be applied for its intended use to treat one patient for one session. Special care must be taken when preparing and administering the product, and when inactivating and disposing of unused solution (see section 6.6).
Care should be taken to ensure that BOCOUTURE is not injected into a blood vessel.
There have been very rare reports of undesirable effects that might be related to the spread of the toxin to sites far from the injection site (see section 4.8). Patients treated with therapeutic doses may experience exaggerated muscle weakness. The injection of BOCOUTURE is not recommended for patients with a history of dysphagia and aspiration.
Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
Rarely, an anaphylactic reaction may occur 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 BOCOUTURE, the physician must familiarise himself/herself with the patient’s anatomy and any alterations to the anatomy due to prior surgical procedures.
BOCOUTURE should be used with caution:
• if bleeding disorders of any type occur
• in patients receiving anticoagulant therapy or taking other substances in anticoagulant doses
• 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.
Too frequent or too high doses may increase the risk of antibody formation, which can result in treatment failure even if the product is being used to treat other indications (see section 4.2).
BOCOUTURE 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 implementation 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 according to the specifications of the European Pharmacopoeia using established procedures.
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 BOCOUTURE 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 BOCOUTURE.
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, BOCOUTURE should not be used during pregnancy unless clearly necessary.
It is unknown whether Botulinum neurotoxin type A is excreted in human milk. Therefore, BOCOUTURE should not be used during breast-feeding.
There are no clinical data from the use of Botulinum neurotoxin type A. In an animal study no adverse effects on male or female fertility were detected (see section 5.3).
BOCOUTURE has a minor or moderate influence on the ability to drive and use machines. There is a potential risk of localised muscle weakness or visual disturbances linked with the use of this medicinal product which may temporarily impair the ability to drive or operate machinery.
Individuals who drive vehicles and operate machines should be informed of the possible risks of asthenia, muscle weakness, dizziness and vision disorders, which could be caused by this medicinal product and could make it dangerous to drive vehicles or operate machinery.
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.
Localised muscle weakness is one expected pharmacological effect of Botulinum toxin. Blepharoptosis, which can be caused by injection technique, is associated with the pharmacological effect of BOCOUTURE.
Localised pain, tenderness, itching, swelling and/or haematoma can occur in conjunction with the injection. Temporary vasovagal reactions associated with pre-injection anxiety, such as syncope, circulatory problems, nausea or tinnitus, may occur.
Frequency of occurrence
Based on clinical experience, information on the frequency of undesirable effects 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).