Bocouture 4 units/0.1 ml powder for solution for injection

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 a full list of excipients, see Section 6.1.

Powder for solution for injection

White powder

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) 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.

Bocouture may only be administered by physicians with suitable qualifications and the requisite experience with this therapy, and who have the necessary equipment.

Posology

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. 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.

Special populations

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.

Paediatric population

The safety and efficacy of Bocouture for the treatment of vertical lines between the eyebrows 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.

Method of administration

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).

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.

General information

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 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 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.

There is limited experience with the long-term application of Bocouture for this indication.

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

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 ( 1/1000, < 1/100); rare ( 1/10,000, < 1/1000); very rare (< 1/10,000).

The following table lists adverse reactions as reported with Bocouture. In addition, adverse reactions are presented which were reported with the comparator product containing conventional Botulinum toxin type A complex used in some clinical studies of Bocouture. These adverse reactions are highlighted with an asterisk. It is possible that these adverse reactions can also occur with Bocouture:

General

In rare cases, localised allergic reactions, such as swelling, oedema, erythema, pruritus or rash, have been reported after treating vertical lines between the eyebrows (glabellar frown lines) and other indications.

When treating other indications with Botulinum toxins, undesirable effects related to spread of the toxin far from the site of administration have been reported very rarely (excessive muscle weakness, dysphagia, aspiration pneumonia with a fatal outcome in some cases) (see Section 4.4). Undesirable effects such as these cannot be completely ruled out with the use of Bocouture.

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, speech difficulties, paralysis of the respiratory muscles and swallowing difficulties which may result 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: 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 at the motor endplates is prevented (chemical denervation). Recovery of impulse transmission is re-established by the formation of new nerve terminals and reconnection with the motor endplates.

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

A total of 447 subjects with moderate to severe glabellar frown lines at maximum frown participated in studies relevant to the efficacy of Bocouture in the indication glabellar frown lines. Of these, 169 subjects ( 18 years) were treated with Bocouture in the Main Period of the pivotal Phase III double-blind placebo controlled trial and 236 subjects were treated in the Open-label Extension (OLEX) of that study. The study demonstrated a statistically significant and clinically relevant efficacy of 20 U Bocouture when compared to placebo. This was validated by the higher number of responders at Day 30 according to the Facial Wrinkle Scale at maximum frown by both the investigator and the patient's assessment showing a significantly higher proportion of responders among the patients receiving 20 U Bocouture compared to placebo.

Subgroup analysis showed that efficacy in patients older than 50 years is lower compared to younger patients. Of those, 113 subjects were in the age of 50 years or younger and 56 subjects were older than 50 years of age. Efficacy in men is lower compared to women. Of those, 33 subjects were male and 136 subjects were female.

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 binds rapidly and irreversibly to the 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, Bocouture contains pure (150 kD) neurotoxin because it is free from complexing proteins.

Like many other proteins, Botulinum neurotoxin type A has been shown to undergo retrograde axonal transport after intramuscular injection. However, retrograde transsynaptic passage of active Botulinum neurotoxin type A into the central nervous system 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 then degraded intracellularly. Freely circulating Botulinum neurotoxin type A molecules, which have not bound to presynaptic cholinergic nerve terminal receptors, are phagocytosed or pinocytosed and degraded like any other freely circulating protein.

Distribution of the active substance in patients

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

Non-clinical data reveal no special hazard based on studies of cardiovascular safety pharmacology.

The findings from repeated-dose toxicity studies on the systemic toxicity of Bocouture in animals were mainly related to its pharmacodynamic properties, i.e. signs of local muscle atony, such as reduced motility and decreased muscle tone.

No evidence of local intolerability was noted. Reproductive toxicity studies with Bocouture performed in rabbits did not show adverse effects on male or female fertility nor direct effects on embryonic development. However, the administration of Bocouture at dose levels exhibiting maternal toxicity at weekly to biweekly intervals increased the number of abortions in a prenatal study in rabbits. Continuous systemic exposure of the dams during the (unknown) sensitive phase of 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 Bocouture.

Human albumin

Sucrose

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

Unopened vial:

3 years

Reconstituted solution:

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

Unopened vial: Do not store above 25°C.

Storage conditions for the reconstituted solution: See Section 6.3.

Vial (type 1 glass) with a stopper (bromobutyl rubber) and tamper-proof seal (aluminium). Pack sizes of 1, 2, 3 or 6 vials.

Not all pack sizes may be marketed.

50 units of Bocouture are reconstituted prior to use in 1.25 ml unpreserved sodium chloride 9 mg/ml (0.9%) solution for injection. This corresponds to a concentration of 40 units/ml. Reconstitution and dilution should be performed in accordance with good clinical practice guidelines, particularly with respect to asepsis.

It is good practice to reconstitute the vial contents and prepare the syringe over plastic-lined paper towels to catch any spillage. An appropriate amount of sodium chloride solution is drawn up into a syringe. The sodium chloride solution must be injected gently into the vial. The vial must be discarded if the vacuum does not pull the solvent into the vial. Reconstituted Bocouture is a clear, colourless solution free of particulate matter.

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

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

PROCEDURE TO FOLLOW FOR A SAFE DISPOSAL OF VIALS, SYRINGES AND MATERIALS USED

For safe disposal, unreconstituted Bocouture should be reconstituted in the vial with a small amount of water and then autoclaved. Any empty vials, vials containing residual solution, syringes or spillage should be autoclaved. Alternatively, the remaining Bocouture can be inactivated with diluted sodium hydroxide solution (0.1 N NaOH) or with diluted sodium hypochlorite solution (0.5% or 1% NaOCl).

After inactivation used vials, syringes and materials should not be emptied and must be discarded into appropriate containers and disposed of in accordance with local requirements.

RECOMMENDATIONS SHOULD ANY INCIDENT OCCUR DURING THE HANDLING OF BOTULINUM TOXIN

• Any spills of the product must be wiped up: either using absorbent material impregnated with a solution of sodium hydroxide or sodium hypochlorite (bleach) in case of the powder, or with dry, absorbent material in case of reconstituted product.

• The contaminated surfaces should be cleaned using absorbent material impregnated with a solution of sodium hydroxide or sodium hypochlorite (bleach), then dried.

• If a vial is broken, proceed as mentioned above by carefully collecting the pieces of broken glass and wiping up the product, avoiding any cuts to the skin.

• If the product comes into contact with the skin, wash the affected area with a solution of sodium hydroxide or sodium hypochlorite (bleach) then rinse abundantly with water.

• If product enters into contact with the eyes, rinse thoroughly with plenty of water or with an ophthalmic eyewash solution.

• If product enters into contact with a wound, cut or broken skin, rinse thoroughly with plenty of water and take the appropriate medical steps according to the dose injected.

These instructions for use handling and disposal should be strictly followed.

Merz Pharmaceuticals GmbH

Eckenheimer Landstraße 100

60318 Frankfurt/Main

Germany

PL 29978/0002

29/06/2010

06/03/2012