- 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
Adults and elderly patientsThe painful area should be covered with the plaster once daily for up to 12 hours within a 24 hours period. Only the number of plasters that are needed for an effective treatment should be used. When needed, the plasters may be cut into smaller sizes with scissors prior to removal of the release liner. In total, not more than three plasters should be used at the same time.The plaster must be applied to intact, dry, non-irritated skin (after healing of the shingles).Each plaster must be worn no longer than 12 hours. The subsequent plaster-free interval must be at least 12 hours. The plaster can be applied during the day or during the night.The plaster must be applied to the skin immediately after removal from the sachet and following removal of the release liner from the gel surface. Hairs in the affected area must be cut off with a pair of scissors (not shaved). Treatment outcome should be re-evaluated after 2-4 weeks. If there has been no response to Versatis after this period (during the wearing time and/or during the plaster-free interval), treatment must be discontinued as potential risks may outweigh benefits in this context (see sections 4.4 and 5.1). Long-term use of Versatis in clinical studies showed that the number of plasters used decreased over time. Therefore treatment should be reassessed at regular intervals to decide whether the amount of plasters needed to cover the painful area can be reduced, or if the plaster-free period can be extended.
Renal impairmentIn patients with mild or moderate renal impairment a dosage adjustment is not required.Versatis should be used with caution in patients with severe renal impairment (see section 4.4).
Hepatic impairmentIn patients with mild or moderate hepatic impairment a dosage adjustment is not required. Versatis should be used with caution in patients with severe hepatic impairment (see section 4.4).
Paediatric populationThe safety and efficacy of Versatis in children below 18 years has not been established. No data are available.
PregnancyLidocaine crosses the placenta. However, there are no adequate data from the use of lidocaine in pregnant women.Animal studies do not indicate a teratogenic potential for lidocaine (see section 5.3).The potential risk for humans is unknown. Therefore, Versatis should not be used during pregnancy unless clearly necessary.
Breast-feedingLidocaine is excreted in breast milk. However, there are no studies of the plaster in breast-feeding women. Since the metabolism of lidocaine occurs relatively fast and almost completely in the liver, only very low levels of lidocaine are expected to be excreted into human milk.
FertilityNo clinical data regarding fertility are available. Animal studies have not shown effects on female fertility.
|Body system||Adverse drug reaction|
|Skin and subcutaneous tissues disorders|
|Injury, poisoning and procedural complications|
|General disorders and administration site conditions|
|Very common||Administration site reactions|
|Body system||Adverse drug reaction|
|Injury, poisoning and procedural complications|
|Very rare||Open wound|
|Immune system disorders|
|Very rare||Anaphylactic reaction, hypersensitivity|
Mechanism of actionVersatis has a dual mode of action: the pharmacological action of lidocaine diffusion and the mechanical action of the hydrogel plaster that protects the hypersensitive area.The lidocaine contained in the Versatis plaster diffuses continuously into the skin, providing a local analgesic effect. The mechanism by which this occurs is due to stabilisation of neuronal membranes, which is thought to cause down regulation of sodium channels resulting in pain reduction.
Clinical efficacyPain management in PHN is difficult. There is evidence of efficacy with Versatis in the symptomatic relief from the allodynic component of PHN in some cases (see section 4.2).Efficacy of Versatis has been shown in post-herpetic neuralgia studies.There were two main controlled studies carried out to assess the efficacy of the lidocaine 5% medicated plaster.In the first study, patients were recruited from a population who were already considered to respond to the product. It was a cross over design of 14 days treatment with lidocaine 5% medicated plaster followed by placebo, or vice versa. The primary endpoint was the time to exit, where patients withdrew because their pain relief was two points lower than their normal response on a six point scale (ranging from worse to complete relief). There were 32 patients, of whom 30 completed. The median time to exit for placebo was 4 days and for active was 14 days (p value < 0.001); none of those on active discontinued during the two week treatment period.In the second study 265 patients with post-herpetic neuralgia were recruited and allocated eight weeks of open label active treatment with lidocaine 5% medicated plaster. In this uncontrolled setting approximately 50% of patients responded to treatment as measured by at least four points on a six point scale (ranging from worse to complete relief). A total of 71 patients were randomised to receive either placebo or lidocaine 5% medicated plaster given for 2-14 days. The primary endpoint was defined as lack of efficacy on two consecutive days because their pain relief was two points lower than their normal response on a six point scale (ranging from worse to complete relief) leading to withdrawal of treatment. There were 9/36 patients on active and 16/35 patients on placebo who withdrew because of lack of treatment benefit.Post hoc analyses of the second study showed that the initial response was independent of the duration of pre-existing PHN. However, the notion that patients with longer duration of PHN (> 12 months) do benefit more from active treatment is supported by the finding that this group of patients was more likely to drop out due to lack of efficacy when switched to placebo during the double-blind withdrawal part of this study.In a controlled open-label study Versatis suggested comparable efficacy to pregabalin in 98 patients with PHN with a favourable safety profile.
AbsorptionWhen lidocaine 5% medicated plaster is used according to the maximum recommended dose (3 plasters applied simultaneously for 12 h) about 3 ± 2% of the total applied lidocaine dose is systemically available and similar for single and multiple administrations. A population kinetics analysis of the clinical efficacy studies in patients suffering from PHN revealed a mean maximum concentration for lidocaine of 45 ng/ml after application of 3 plasters simultaneously 12 h per day after repeated application for up to one year. This concentration is in accordance with the observation in pharmacokinetic studies in PHN patients (52 ng/ml) and in healthy volunteers (85 ng/ml and 125 ng/ml). For lidocaine and its metabolites MEGX, GX, and 2,6-xylidine no tendency for accumulation was found, steady state concentrations were reached within the first four days.The population kinetic analysis indicated that when increasing the number from 1 to 3 plasters worn simultaneously, the systemic exposure increased less than proportionally to the number of used plasters.
DistributionAfter intravenous administration of lidocaine to healthy volunteers, the volume of distribution was found to be 1.3 ± 0.4 l/kg (mean ± S.D., n = 15). The lidocaine distribution volume showed no age-dependency, it is decreased in patients with congestive heart failure and increased in patients with liver disease. At plasma concentrations produced by application of the plaster approximately 70 % of lidocaine is bound to plasma proteins. Lidocaine crosses the placental and blood brain barriers presumably by passive diffusion.
BiotransformationLidocaine is metabolised rapidly in the liver to a number of metabolites. The primary metabolic route for lidocaine is N-dealkylation to monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which are less active than lidocaine and available in low concentrations. These are hydrolyzed to 2,6-xylidine, which is converted to conjugated 4-hydroxy-2,6-xylidine. The metabolite, 2,6-xylidine, has unknown pharmacological activity but shows carcinogenic potential in rats (see section 5.3). A population kinetics analysis revealed a mean maximum concentration for 2,6-xylidine of 9 ng/ml after repeated daily applications for up to one year. This finding is confirmed by a phase I pharmacokinetic study. Data on lidocaine metabolism in the skin are not available.
EliminationLidocaine and its metabolites are excreted by the kidneys. More than 85 % of the dose is found in the urine in the form of metabolites or active substance. Less than 10 % of the lidocaine dose is excreted unchanged. The main metabolite in urine is a conjugate of 4-hydroxy-2,6-xylidine, accounting for about 70 to 80% of the dose excreted in the urine. 2,6-xylidine is excreted in the urine in man at a concentration of less than 1% of the dose. The elimination half-life of lidocaine after plaster application in healthy volunteers is 7.6 hours. The excretion of lidocaine and its metabolites may be delayed in cardiac, renal or hepatic insufficiency.
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