- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyRefer to specific recommendations for each indication described below.Botulinum toxin units are not interchangeable from one product to another. Doses recommended in Allergan Units are different from other botulinum toxin preparations.
Elderly patientsThere is limited phase 3 clinical data with VISTABEL in patients older than 65 years (see section 5.1). No specific dose adjustment is required for use in the elderly.
Paediatric populationThe safety and effectiveness of VISTABEL in the treatment of glabellar lines seen at maximum frown or crow's feet lines seen at maximum smile 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).
Method of AdministrationVISTABEL should only be administered by physicians with appropriate qualifications and expertise in this treatment and use of the required equipment.VISTABEL, after reconstitution, must be used only for one session of injection(s) per patient. 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 4.4 and 6.6).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 seen at maximum frown (also known as glabellar lines) or in the lateral canthal lines seen at maximum smile (also known as crow's feet lines), see section 4.4.
Administration Instructions for Glabellar Lines seen at maximum frown:Reconstituted VISTABEL (50 Units/1.25 ml) is injected using a sterile 30 gauge needle. 0.1 ml (4 Units) is administered in each of the 5 injection sites (see Figure 1): 2 injections in each corrugator muscle and 1 injection in the procerus muscle for a total dose of 20 Units.Before injection, the thumb or index finger is 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 eyelid ptosis, the maximum dose of 4 Units for each injection site as well as the number of injection sites should not be exceeded. In addition, 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, a distance of at least 1 cm above the arch of the eyebrows. Figure 1: Improvement of severity of glabellar lines seen at maximum frown 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. Administration Instructions for Crow's Feet Lines seen at maximum smile: Reconstituted VISTABEL (50 Units/1.25 ml) is injected using a sterile 30 gauge needle. 0.1 ml (4 Units) is administered in each of the 3 injection sites per side (total of 6 injection sites) in the lateral orbicularis oculi muscle, for a total dose of 24 Units in a total volume of 0.6 ml (12 Units per side). In order to reduce the risk of eyelid ptosis, the maximum dose of 4 Units for each injection site as well as the number of injection sites should not be exceeded. In addition, injections should be made temporal to the orbital rim, thereby maintaining a safe distance from the muscle controlling eyelid elevation. Injections should be given with the needle tip bevel up and oriented away from the eye. The first injection (A) should be made approximately 1.5 to 2.0 cm temporal to the lateral canthus and just temporal to the orbital rim. If the lines in the crow's feet region are above and below the lateral canthus, inject as shown in Figure 2. Alternatively, if the lines in the crow's feet region are primarily below the lateral canthus, inject as shown in Figure 3. For simultaneous treatment with glabellar lines seen at maximum frown, the dose is 24 Units for crow's feet lines seen at maximum smile and 20 Units for glabellar lines (see Administration Instructions for Glabellar Lines, and Figure 1), for a total dose of 44 Units in a total volume of 1.1 ml. Improvement of severity of crow's feet lines seen at maximum smile, when assessed by the investigator, occurred within one week of treatment. The effect was demonstrated for a median of 4 months after injection. Treatment intervals should not be more frequent than every 3 months. 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 the absence of any undesirable effects secondary to the first treatment session, initiate a second treatment session with at least a three-month interval between the two treatment sessions. For glabellar lines seen at maximum frown, in case of insufficient dose, initiate a second treatment session by adjusting the total dose up to 40 or 50 Units, taking into account the analysis of the previous treatment failure. The efficacy and safety of repeat injections of VISTABEL beyond 12 months has not been evaluated.
PregnancyThere 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 is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feedingThere is no information on whether VISTABEL is excreted in human milk. The use of VISTABEL during breast-feeding cannot be recommended.
FertilityThere are no adequate data on the effects on fertility from the use of botulinum toxin type A in women of childbearing potential. Studies in male and female rats have shown fertility reductions (see section 5.3).
|System Organ Class||Preferred Term||Frequency|
|Infections and infestations||Infection||Uncommon|
|Nervous system disorders||Headache, paraesthesia||Common|
|Eye disorders||Eyelid ptosis||Common|
|Blepharitis, eye pain, visual disturbance (includes vision blurred)||Uncommon|
|Skin and subcutaneous tissue disorders||Erythema, skin tightness||Common|
|Oedema (face, eyelid, periorbital), photosensitivity reaction, pruritus, dry skin||Uncommon|
|Musculoskeletal and connective tissue disorders||Localised muscle weakness||Common|
|General disorders and administration site conditions||Face pain, injection site oedema, ecchymosis, injection site pain, injection site irritation||Common|
|Flu syndrome, asthenia, fever||Uncommon|
Crow's Feet LinesThe following adverse drug reactions were reported in the double-blind, placebo-controlled clinical studies following injection of VISTABEL 24 Units for crow's feet lines alone:
|System organ class||Preferred term||Frequency|
|Eye disorders||Eyelid oedema||Common|
|General disorders and administration site conditions||Injection site haemorrhage*, injection site haematoma*||Common|
|Injection site pain*, injection site paraesthesia||Uncommon|
*procedure-related adverse reactions
Crow's Feet Lines and Glabellar LinesThe following adverse drug reactions were reported in double-blind, placebo-controlled clinical studies following injection of VISTABEL 44 Units (simultaneous treatment of crow's feet lines and glabellar lines):
|System organ class||Preferred term||Frequency|
|General disorders and administration site conditions||Injection site haematoma*||Common|
|Injection site haemorrhage*, injection site pain*||Uncommon|
*procedure-related adverse reactionsNo change was observed in the overall safety profile following repeat dosing.c) Post-Marketing data (frequency not known)The following adverse reactions or medically relevant adverse events have been reported since the drug has been marketed for the treatment of glabellar lines, crow's feet lines and other clinical indications:
|System organ class||Preferred term|
|Immune system disorders||Anaphylaxis, angioedema, serum sickness, urticaria|
|Metabolism and nutrition disorders||Anorexia|
|Nervous system disorders||Brachial plexopathy, dysphonia, dysarthria, facial paresis, hypoaesthesia, muscle weakness, myasthenia gravis, peripheral neuropathy, paraesthesia, radiculopathy, syncope, facial palsy|
|Eye disorders||Angle-closure glaucoma (for treatment of blepharospasm), lagophthalmos, strabismus, vision blurred, visual disturbance|
|Ear and labyrinth disorders||Hypoacusis, tinnitus, vertigo|
|Respiratory, thoracic and mediastinal disorders||Aspiration pneumonia, dyspnoea, bronchospasm, respiratory depression, respiratory failure|
|Gastrointestinal disorders||Abdominal pain, diarrhoea, dry mouth, dysphagia, nausea, vomiting|
|Skin and subcutaneous tissue disorders||Alopecia, dermatitis psoriasiform, erythema multiforme, hyperhidrosis, madarosis, pruritus, rash|
|Musculoskeletal and connective tissue disorders||Muscle atrophy, myalgia|
|General disorders and administration site conditions||Denervation atrophy, malaise, pyrexia|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
Glabellar Lines537 patients with moderate to severe glabellar lines seen at maximum frown have been included in clinical studies.VISTABEL injections significantly reduced the severity of glabellar lines seen at maximum frown 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 glabellar lines seen at maximum frown. 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.
Crow's Feet Lines1362 patients with moderate to severe crow's feet lines seen at maximum smile, either alone (N=445, Study 191622-098) or also with moderate to severe glabellar lines seen at maximum frown (N=917, Study 191622-099), were enrolled.VISTABEL injections significantly reduced the severity of crow's feet lines seen at maximum smile compared to placebo at all timepoints (p <0.001) for up to 5 months. This was measured by the proportion of patients achieving a crow's feet lines severity rating of none or mild at maximum smile in both pivotal studies; until day 150 (end of study) in Study 191622-098 and day 120 (end of first treatment cycle in Study 191622-099). For both investigator and subject assessments, the proportion of subjects achieving none or mild crow's feet lines severity seen at maximum smile was greater in patients with moderate crow's feet lines seen at maximum smile at baseline, compared to patients with severe crow's feet lines seen at maximum smile at baseline. Table 1 summarises results at day 30, the timepoint of the primary efficacy endpoint.In Study 191622-104 (extension to Study 191622-099), 101 patients previously randomised to placebo were enrolled to receive their first treatment at the 44 Units dose. Patients treated with VISTABEL had a statistically significant benefit in the primary efficacy endpoint compared to placebo at day 30 following their first active treatment. The response rate was similar to the 44 Units group at day 30 following first treatment in Study 191622-099. A total of 123 patients recieved 4 cycles of 44 Units VISTABEL for combined crow's feet and glabellar lines treatment.Table 1. Day 30: Investigator and Patient Assessment of Crow's Feet Lines Seen at Maximum Smile - Responder Rates (% of Patients Achieving Crow's Feet Lines Severity Rating of None or Mild)
|Investigator Assessment||Patient Assessment|
|191622-098||24 Units (crow's feet lines)||66.7%* (148/222)||6.7% (15/223)||58.1%* (129/222)||5.4% (12/223)|
|191622-099||24 Units (crow's feet lines)||54.9%* (168/306)||3.3% (10/306)||45.8%* (140/306)||3.3% (10/306)|
|44 Units (24 Units crow's feet lines; 20 Units glabellar lines)||59.0%* (180/305)||3.3% (10/306)||48.5%* (148/305)||3.3% (10/306)|
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.
|Amount of solvent added (0.9% sodium chloride solution) to a 50 Units vial||Resulting dose (Units per 0.1 ml)|
|1.25 ml||4.0 Units|
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.• 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, rinse one's eyes thoroughly with plenty of water or with an eye wash 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.
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