VISTABEL, 4 Allergan Units/0.1ml, powder for solution for injection

Botulinum toxin type A¹…………………4 Allergan units per 0.1ml of reconstituted solution.

¹of Clostridium botulinum

Allergan units are not interchangeable with other preparations of botulinum toxin.

Vial of 50 units.

For a full list of excipients, see section 6.1.

Powder for solution for injection.

White Powder

VISTABEL is indicated for the temporary improvement in the appearance of moderate to severe vertical lines between the eyebrows seen at frown, in adults <65 years old, when the severity of these lines has an important psychological impact for the patient.

Considering that botulinum toxin units are different depending on the medicinal products, doses of botulinum toxin are not interchangeable from one product to another.

There is limited phase 3 clinical data with VISTABEL in patients older than 65 years (see section 5.1). Until more studies have been performed in this age group, VISTABEL is not recommended in patients older than 65 years.

The safety and effectiveness of VISTABEL in the treatment of vertical lines between the eyebrows (known as glabellar lines) in individuals under 18 years of age have not been demonstrated. The use of VISTABEL is not recommended in individuals under 18 years (see section 4.4).

VISTABEL should only be administered by physicians with appropriate qualifications and expertise in this treatment and having the required equipment.

VISTABEL, after reconstitution, must be used only for one session of injection(s) per patient.

The recommended injection volume per muscle site is 0.1 ml. See also dilution table in section 6.6.

For instructions for use, handling and disposal of the vials, see section 6.6.

Care should be taken to ensure that VISTABEL is not injected into a blood vessel when it is injected in the vertical lines between the eyebrows also called Glabellar Lines.

Reconstituted VISTABEL (50 U/1.25 mL) is injected using a sterile 30 gauge needle. 0.1 mL (4 U) is administered in each of the 5 injection sites: 2 injections in each corrugator muscle and 1 injection in the procerus muscle for a total dose of 20 U.

Before injection, the thumb or index finger are to be placed firmly below the orbital rim in order to prevent extravasation below the orbital rim. The needle should be oriented superiorly and medially during the injection. In order to reduce the risk of ptosis, injections near the levator palpebrae superioris muscle must be avoided, particularly in patients with larger brow-depressor complexes (depressor supercilii). Injections in the corrugator muscle must be done in the central part of that muscle, at least 1 cm above the arch of the eyebrows.

Improvement of severity of vertical lines between the eyebrows (glabellar lines) generally occurs within one week after treatment. The effect was demonstrated for up to 4 months after injection.

Treatment intervals should not be more frequent than every three months. In the event of treatment failure or diminished effect following repeat injections, alternative treatment methods should be employed.

General information

In case of treatment failure after the first treatment session, i.e. in the absence, at one month after injection, of significant improvement from baseline, the following approaches may be considered:

• Analysis of the causes of failure, e.g. incorrect muscles injected, injection technique, formation of toxin-neutralising antibodies, insufficient dose;

• Re-evaluation of the relevance of treatment with botulinum toxin type A;

In case of insufficient dose and in the absence of any undesirable effects secondary to the first treatment session, initiate a second treatment session as follows:

i) Consider adjusting the total dose up to 40 or 50 units, taking into account the analysis of the previous treatment failure;

ii) At least a three-month interval between the two treatment sessions should be maintained.

VISTABEL is contraindicated,

- In individuals with a known hypersensitivity to botulinum toxin type A or to any of the excipients of the formulation;

- In the presence of myasthenia gravis or Eaton Lambert Syndrome;

- In the presence of infection at the proposed injection sites.

It is mandatory that VISTABEL is used for one single patient treatment only during a single session. The excess of unused product must be disposed of as detailed in section 6.6. Particular precautions should be taken for product preparation and administration as well as for the inactivation and disposal of the remaining unused solution (see section 6.6).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium free”.

The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering VISTABEL. The recommended dosage and frequency of administration of VISTABEL should not be exceeded.

An anaphylactic reaction may occur very rarely after injection of botulinum toxin. Epinephrine (adrenaline) or any other anti-anaphylactic measures should therefore be available.

Adverse reactions possibly related to the spread of toxin distant from the site of administration have been reported very rarely with botulinum toxin (see section 4.8). Patients treated with therapeutic doses may experience exaggerated muscle weakness. Injection of VISTABEL is not recommended in 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.

Too frequent or excessive dosing may enhance the risk of antibody formation. Antibody formation may lead to treatment failure of botulinum toxin type A even for other indications.

Caution should be taken when VISTABEL is used in the presence of inflammation at the proposed injection site(s) or when the targeted muscle shows excessive weakness or atrophy. Caution should also be exercised when VISTABEL is used for treatment of patients with amyotrophic lateral sclerosis or with peripheral neuromuscular disorders.

The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

The use of VISTABEL is not recommended in individuals under 18 years and in patients older than 65 years.

Theoretically, the effect of botulinum toxin may be potentiated by aminoglycoside antibiotics, spectinomycin, or other medicinal products that interfere with neuromuscular transmission (e.g. tubocurarine-type muscle relaxants).

No specific tests have been carried out to establish the possibility of clinical interaction with other medicinal products. No other interactions of clinical significance have been reported in this indication.

Pregnancy

There are no adequate data from the use of botulinum toxin type A in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. VISTABEL should not be used during pregnancy unless clearly necessary.

Lactation

There is no information on whether VISTABEL is excreted in human milk. The use of VISTABEL during lactation cannot be recommended.

Attention is drawn in vehicle drivers and users of machines to the potential risks of asthenia, muscle weakness, dizziness and visual disturbance linked with the use of this medicinal product, which could make driving or using machines dangerous.

a) General

Based on controlled clinical trial data, the proportion of patients that would be expected to experience an adverse reaction after treatment with VISTABEL is 23.5% (placebo: 19.2%). These adverse reactions may be related to treatment, injection technique or both.

In general, adverse reactions occur within the first few days following injection and are transient. Most adverse events reported were of mild to moderate severity.

The expected pharmacological action of botulinum toxin is a local muscle weakness. Blepharoptosis, which may be technique-related, is consistent with the pharmacological action of VISTABEL. As is expected for any injection procedure, pain/burning/stinging, oedema and/or bruising may be observed in association with the injection.

b) Adverse reactions - frequency

The frequency is 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).

Infections and infestations

Psychiatric disorders

Nervous system disorders

Eye disorders

Gastrointestinal disorders

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

General disorders and administration site conditions

c) Post-Marketing data (frequency not known)

The following adverse reactions have been reported rarely since the drug has been marketed for the treatment of Glabellar Lines and other clinical indications: rash, urticaria, pruritus, erythema multiforme, psoriasiform eruption, anaphylactic reaction (angiodema, bronchospasm), alopecia, madarosis, tinnitus and hypoacousia.

Adverse reactions possibly related to the spread of toxin distant from the site of administration have been reported very rarely with botulinum toxin (e.g. muscle weakness, dysphagia, or aspiration pneumonia which can be fatal) (see section 4.4).

No cases of systemic toxicity resulting from accidental injection of botulinum toxin type A have been observed. No cases of ingestion of botulinum toxin type A have been reported. Signs of overdose are not apparent immediately post-injection. Should accidental injection or ingestion occur, the patient should be medically supervised for several days for signs and symptoms of general weakness or muscle paralysis.

Admission to hospital should be considered in patients presenting symptoms of botulinum toxin type A poisoning (generalised weakness, ptosis, diplopia, swallowing and speech disorders, or paresis of the respiratory muscles).

Pharmacotherapeutic group: Muscle relaxants, peripherally acting agents, ATC code: M03A X01.

Botulinum toxin type A (Clostridium botulinum neurotoxin) blocks peripheral acetylcholine release at presynaptic cholinergic nerve terminals by cleaving SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within the nerve endings leading to denervation of the muscle and therefore to a paralysis.

After injection, there is an initial rapid high-affinity binding of toxin to specific cell surface receptors. This is followed by transfer of the toxin across the plasma membrane by receptor-mediated endocytosis. Finally, the toxin is released into the cytosol. This latter process is accompanied by progressive inhibition of acetylcholine release, clinical signs are manifest within 2-3 days, with peak effect seen within 5-6 weeks of injection.

Recovery after intramuscular injection takes place normally within 12 weeks of injection as nerve terminals sprout and reconnect with the endplates.

Clinical data:

537 patients with moderate to severe vertical lines between the eyebrows (glabellar lines) at maximum frown have been included in clinical studies.

VISTABEL injections significantly reduced the severity of glabellar lines for up to 4 months, as measured by the investigator assessment of glabellar line severity at maximum frown and by subject's global assessment of change in appearance of his/her vertical lines between the eyebrows (glabellar lines). None of the clinical endpoints included an objective evaluation of the psychological impact. Thirty days after injection 80% (325/405) of VISTABEL-treated patients were considered by investigators as treatment responders (none or mild severity at maximum frown), compared to 3% (4/132) of placebo-treated patients. At this same timepoint, 89% (362/405) of VISTABEL-treated patients felt they had a moderate or better improvement, compared to 7% (9/132) of placebo-treated patients.

VISTABEL injections also significantly reduced the severity of glabellar lines at rest. Of the 537 patients enrolled, 39% (210/537) had moderate to severe glabellar lines at rest (15% had no lines at rest). Of these, 74% (119/161) of VISTABEL-treated patients were considered treatment responders (none or mild severity) thirty days after injection, compared with 20% (10/49) of placebo-treated patients.

There is limited phase 3 clinical data with VISTABEL in patients older than 65 years. Only 6.0% (32/537) of subjects were >65 years old and efficacy results obtained were lower in this population.

a) General characteristics of the active substance:

Distribution studies in rats indicate slow muscular diffusion of ¹²⁵I-botulinum neurotoxin A complex in the gastrocnemius muscle after injection, followed by rapid systemic metabolism and urinary excretion. The amount of radiolabeled material in the muscle declined with a half-life of approximately 10 hours. At the injection site, the radioactivity was bound to large protein molecules, whereas in the plasma it was bound to small molecules, suggesting rapid systemic metabolism of the substrate. Within 24 hours of dosing, 60% of the radioactivity was excreted in the urine. Toxin is probably metabolised by proteases and the molecular components recycled through normal metabolic pathways.

Classical absorption, distribution, biotransformation and elimination (ADME) studies on the active substance have not been performed due to the nature of this product.

b) Characteristics in patients:

It is believed that at therapeutic doses, low systemic distribution of VISTABEL occurs. Clinical studies using single fibre electromyographic techniques have shown increased electrophysiologic neuromuscular activity in muscles distant to the injection site, with no associated clinical signs or symptoms.

In reproductive studies in mice, rats, and rabbits, embryo toxicity was observed with high doses (delayed ossification and reduced foetal bodyweight). No teratogenic effects were observed in these species. In rats adverse effects on male fertility and female estrous cycling and fertility occurred only at high doses.

Studies on acute toxicity, repeated dose toxicity, local tolerance, mutagenicity, antigenicity and blood compatibility did not show unusual adverse local or systemic effects at clinically relevant dose levels.

Human albumin

Sodium chloride

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.

3 years.

After reconstitution, immediate use of the solution is recommended; However, physicochemical stability for 24 hours between +2°C and 8°C has been demonstrated.

Store in a refrigerator (2°C - 8°C).

For storage conditions of the reconstituted medicinal product, see section 6.3.

Powder in a vial (Type I glass) fitted with a stopper (chlorobutyl rubber) and a seal (aluminium);

Vial of 50 Allergan Units of Botulinum toxin type A – pack of one or pack of two

NOT ALL PACK SIZES MAY BE MARKETED

Reconstitution should be performed in accordance with good practices rules, particularly for the respect of asepsis. VISTABEL has to be reconstituted with a 0.9% preservative free sodium chloride solution for injection. As per the dilution table below, the requested amount of sodium chloride 9mg/ml (0.9%) solution for injection has to be drawn up into a syringe in order to obtain a reconstituted solution at a concentration of 4U/0.1 ml;

The central part of the rubber cap has to be cleaned with alcohol.

To avoid VISTABEL denaturation, the solution is prepared by injecting the solvent slowly into the vial and by gently rotating the vial avoiding bubble formation. The vial has to be discarded if the vacuum does not pull the solvent into the vial. Once reconstituted, the solution should be visually inspected prior to use. Only clear, colourless to slightly yellow solution without particles should be used.

It is mandatory that VISTABEL is used for one single patient treatment only during a single session.

Procedure to follow for a safe disposal of vials, syringes and materials used:

Immediately after use, and prior to disposal, unused reconstituted VISTABEL solution in the vial and/or the syringe must be inactivated, with 2 ml of dilute sodium hypochlorite solution at 0.5% or 1 % and should be disposed of in accordance with local requirements.

Used vials, syringes and materials should not be emptied and must be discarded into appropriate containers and disposed of as a Medical Biohazardous Waste in accordance with local requirements.

Recommendations in the event of an accident when handling botulinum toxin.

In the event of an accident when handling the product, whether in the vacuum-dried state or reconstituted, the appropriate measures described below must be initiated immediately.

This instruction for use and handling, and disposal should be strictly followed.

ALLERGAN PHARMACEUTICALS IRELAND

Castlebar Road

Westport

County Mayo

Ireland

PL 05179/0010

Date of first authorisation: 12 January 2006

Date of last renewal: 16 May 2008

12^th August 2010