1.0 NAME OF THE MEDICINAL PRODUCT
VISTABEL®,4 Allergan Units/0.1ml, powder for solution for injection
2.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Botulinum toxin type A1…………………4 Allergan units in 0.1ml of reconstituted solution.
1of Clostridium botulinum
Vial of 50 units VISTABEL®, BOTOX® Vial of 100 units.
For excipients, see section 6.1.
3.0 PHARMACEUTICAL FORM
Powder for solution for injection.
4.0 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONS
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.
4.2 POSOLOGY AND METHOD OF ADMINISTRATION
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 0.1ml. See also dilution table in section 6.6.
For instructions for use, handling and disposal of the vials, please refer to section 6.6.
Vertical lines between the eyebrows also called Glabellar Lines
Reconstituted VISTABEL® (50 U/1.25 mL, 100 U/2.5 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, place the thumb or index finger 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, avoid injections near the levator palpebrae superioris muscle, particularly in
patients with larger brow- depressor complexes (depressor supercilii). Injections
in the corrugator muscle must be made into the central part of that muscle, at
least 1cm above the arch of the eyebrows.
Improvement of severity of vertical lines between the eyebrows (glabellar lines) generally occurs within one week after treatment.
Efficacy was demonstrated for up to 4 months after injection. Treatment 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. selection of muscles injected, insufficient dose, injection technique,
formation of toxin-neutralising antibodies;
• Re-evaluation of the relevance of treatment with botulinum toxin type A;
• In the absence of any undesirable effects secondary to the first treatment session, initiate a second treatment session as follows: i) adjust the dose, taking into account the analysis of the previous treatment failure;
ii) maintain a three-month interval between the two treatment sessions.
4.3 CONTRA-INDICATIONS
VISTABEL® is contraindicated
a) In individuals with a known hypersensitivity to botulinum toxin type A or to any of the excipients of
the formulation;
b) In the presence of myasthenia gravis or Eaton Lambert Syndrome.
4.4 SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE
It is mandatory that VISTABEL® is used for one single patient treatment only during a single session. The excessof unused product must be disposed of as detailed in section 6.6 (Instructions for use, handling and disposal).
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).
The relevant anatomy, and any alterations to the anatomy due to prior surgical procedures, must be understood prior to administering VISTABEL®. The recommended dosages and frequencies 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.
Rare spontaneous reports of death have been reported in the treatment of large dystonic muscles, where
botulinum toxin type A is injected in high doses into the neck area, sometimes associated with dysphagia,
pneumonia and/or other significant debility (see section 4.8).
Patients should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
Too frequent or excessive dosing can result in antibody formation, which may lead to resistance to treatment.
This may reduce the efficacy of subsequent treatments with botulinum toxin type A 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 use of VISTABEL® is not recommended in individuals under 18 years and in patients older than 65 years.
4.5 INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION
Theoretically, the effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or 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.
4.6 PREGNANCY AND LACTATION
Pregnancy
VISTABEL® is not recommended during 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.
Lactation
There is no information on whether VISTABEL® is excreted in human milk. The use of VISTABEL® during lactation cannot be recommended.
4.7 EFFECTS ON THE ABILITY TO DRIVE AND USE MACHINES
Attention is drawn in vehicle drivers and users of machines to the risks of asthenia and muscle weakness linked with the use of this medicinal product, which could make driving or using machines dangerous.
4.8 UNDESIRABLE EFFECTS
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
Common: headache, blepharoptosis, face pain, erythema, local muscle weakness
Uncommon: skin tightness, paresthesia, nausea, dizziness, twitch, blepharitis, eye pain, flu syndrome, oedema (face, eyelid, periorbital), asthenia, fever, photosensitivity reaction, pruritus, dry skin, visual disturbance, anxiety,oral dryness, infection.
c) Additional information
The following adverse reactions have been reported rarely since the drug has been marketed for other clinical indications; skin rash (including erythema multiforme, urticaria and psoriasiform eruption), pruritus, and allergic reaction.
Rare spontaneous reports of death have been reported in the treatment of large dystonic muscles,
where botulinum toxin type A is injected in high doses into the neck area, sometimes associated with dysphagia, pneumonia and/or other significant debility (see section 4.4).
4.9 OVERDOSE
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).
5.0 PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
Muscle relaxants, peripherally acting agents, ATC class M03A X01. (M: Musculoskeletal system)
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 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.
5.2 PHARMACOKINETIC PROPERTIES
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 radio-labeled 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.
5.3 PRECLINICAL SAFETY DATA
Acute toxicity in rats with intramuscular administration occurred at around 39 U/kg. Repeated administrations in rats and monkeys caused muscle atrophy and degeneration and respiratory paralysis. The No Observed
Adverse Effect Levels (NOAEL), expressed in U/kg, are estimated at 16 (rat, 6 monthly injections), 4 (adult
monkey, 7 monthly x 1 injection every other month), and 8 (juvenile monkey, 3 x 1 injection every 8 weeks).
In rats, decreased fertility was observed at 8 to 16 U/kg, probably related to paralysis of the male’s hindquarters and to alteration of the ovulation cycle in females. The NOAEL was 4 U/kg for males and 8 U/kg for females.
Administration during the organogenesis period in rats and mice, resulted in delayed ossification and reduced foetal bodyweight at maternotoxic doses. No malformative effects nor effects on foetal viability were observed.
In a peri-post natal study, low birth weight and reduced newborn viability were observed. The dose with no toxic
effect on development was 4 U/kg and < 4 U/kg for maternotoxic effects.
After administration during the organogenesis period in rabbits, 0.5 U/kg/day caused maternal death and
abortion but no teratogenic effects. The developmental NOAEL was 0.25 U/kg/day.
There is no mutagenic or clastogenic potential.
6.0 PHARMACEUTICAL PARTICULARS
6.1 LIST OF EXCIPIENTS
Human albumin
Sodium chloride
6.2 INCOMPATIBILITIES
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
2 years.
After reconstitution, immediate use of the solution is recommended; however, stability has been demonstrated
for 4 hours at 2°C - 8°C.
6.4 Special precautions for storage
Store in a refrigerator (at 2°C - 8°C).
6.5 Nature and contents of container
Powder in a vial (Type I glass) fitted with a stopper (rubber) and a seal (aluminium);
Vial of 50 Allergan Units
Vial of 100 Allergan Units
Pack of one.
NOT ALL PACK SIZES MAY BE MARKETED
6.6 Instructions for use and handling, and disposal
Reconstitute VISTABEL® with a 0.9% preservative free sodium chloride solution for injection, draw up the required amount of 0.9% sodium chloride solution for injection into a syringe in order to obtain a reconstituted solution at a concentration of 4U/0.1 ml;
Clean the central part of the rubber cap 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. Discard the vial 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 2ml of dilute sodium hypochlorite solution at 0.5% or 1%.
Used vials, syringes and materials should not be emptied and must be discarded into appropriate containers
and disposed of in accordance with local requirements.
1.25 ml
Resulting dose
(Units per 0.1 ml)
Amount of solvent added
(0.9% sodium chloride solution)
to a 50 U vial
4.0 U
2.5 ml
Resulting dose
(Units per 0.1 ml)
Amount of solvent added
(0.9% sodium chloride solution)
to a 100 U vial
4.0 U
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.
• The toxin is very sensitive to heat and certain chemical agents
• Any spillage must be wiped up: either with an absorbent material soaked in a solution of sodium
hypochlorite (Javel solution) in the case of the vacuum-dried product, or with a dry absorbent material in the
case of the reconstituted product.
• Contaminated surfaces must be cleaned with an absorbent material soaked in a solution of sodium
hypochlorite (Javel solution) and then dried.
• If a vial is broken, carefully collect up the pieces of glass and wipe up the product as stated above, avoiding
cutting the skin.
• If splashed, wash with a solution of sodium hypochlorite and then rinse thoroughly with plenty of water.
• If splashed into the eyes, flush thoroughly with plenty of water or with an ophthalmic eyewash solution.
• If the operator injures himself (cuts, pricks himself), proceed as above and take the appropriate medical
steps according to the dose injected.
This instruction for use and handling, and disposal should be strictly followed.
7.0 MARKETING AUTHORISATION HOLDER
Allergan Pharmaceuticals Ireland, Westport, County Mayo, Ireland
8.0 MARKETING AUTHORISATION NUMBER(S)
PL 05179/0010
9.0 DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
12th January 2006
10.0 DATE OF REVISION OF THE TEXT
12th January 2006
ACA 32/2006
This information is for reference only and we cannot ensure accuracy please contact your Botox provider for current information. |
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