Versatis 5%e solution for injection should not be mixed with other preparations unless compatibility is known.
Not applicable.
No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.
Effects in non-clinical general toxicity studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Lidocaine HCl has shown no genotoxicity when investigated in vitro or in vivo. Its hydrolysis product and metabolite, 2,6-xylidine, showed mixed genotoxic activity in several assays particularly after metabolic activation.
Carcinogenicity studies have not been performed with lidocaine. Studies performed with the metabolite 2,6-xylidine mixed in the diet of male and female rats resulted in treatment-related cytotoxicity and hyperplasia of the nasal olfactory epithelium and carcinomas and adenomas in the nasal cavity were observed. Tumorigenic changes were also found in the liver and subcutis. Because the risk to humans is unclear, long-term treatment with high doses of lidocaine should be avoided.
Lidocaine had no effect on general reproductive performance, female fertility or embryo-foetal development/teratogenicity in rats at plasma concentrations up to more than 50-fold those observed in patients.
Animal studies are incomplete with respect to male fertility, parturition or postnatal development.
ATC Code:N01BB02
Versatis 5%e is a local anaesthetic of the amide type. It is used to provide local anaesthesia by nerve blockade at various sites in the body and in the control of dysrhythmias. It acts by inhibiting the ionic refluxes required for the initiation and conduction of impulses, thereby stabilising the neuronal membrane. In addition to blocking conduction in nerve axons in the peripheral nervous system, Versatis 5%e has important effects on the central nervous system and cardiovascular system. After absorption, Versatis 5%e may cause stimulation of the CNS followed by depression and in the cardiovascular system, it acts primarily on the myocardium where it may produce decreases in electrical excitability, conduction rate and force of contraction. It has a rapid onset of action (about one minute following intravenous injection and fifteen minutes following intramuscular injection) and rapidly spreads through the surrounding tissues. The effect lasts about ten to twenty minutes and about sixty to ninety minutes following intravenous and intramuscular injection respectively.
Pharmacotherapeutic group: local anaesthetics, amides
ATC code: N01 BB02
Mechanism of action
Versatis 5% 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 5% 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 efficacy
Pain management in PHN is difficult. There is evidence of efficacy with Versatis 5% in the symptomatic relief from the allodynic component of PHN in some cases.
Efficacy of Versatis 5% has been shown in post-herpetic neuralgia studies.
There were two main controlled studies carried out to assess the efficacy of the lidocaine 700 mg 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 700 mg 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 700 mg 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 700 mg 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 5% suggested comparable efficacy to pregabalin in 98 patients with PHN with a favourable safety profile.
The concentration of Versatis 5%e in the blood will be determined by its rate of absorption from the site of injection, the rate of tissue distribution and the rate of metabolism and excretion.
The systemic absorption of Versatis 5%e is determined by the site of injection, the dosage and its pharmacological profile. The maximum blood concentration occurs following intercostal nerve blockade followed in order of decreasing concentration, the lumbar epidural space, brachial plexus site and subcutaneous tissue. The total dose injected regardless of the site is the primary determinant of the absorption rate and blood levels achieved. There is a linear relationship between the amount of Versatis 5%e injected and the resultant peak anaesthetic blood levels.
The lipid solubility and vasodilator activity will also influence its rate of absorption. This is seen in the epidural space where Versatis 5%e is absorbed more rapidly than prilocaine.
Versatis 5%e is distributed throughout the total body water. Its rate of disappearance from the blood can be described by a two or three compartment model. There is a rapid disappearance (alpha) phase which is believed to be related to uptake by rapidly equilibrating tissues (i.e. tissues with a high vascular perfusion). The slower phase is related to distribution, to slowly equilibrating tissues (Betaphase) and to its metabolism and excretion (Gamma phase).
Versatis 5%e is distributed less rapidly than prilocaine (an amide drug of similar potency and duration of action) but equally as with mepivacaine. Its distribution is throughout all body tissues. In general, the more highly perfused organs will show higher concentrations of Versatis 5%e. The highest percentage of this drug will be found in skeletal muscle. This is because of the mass of muscle rather than an affinity.
Versatis 5%e undergoes enzymatic degradation primarily in the liver. Some degradation may take in tissues other than liver. The main pathway involves oxidative de-ethylation to monoethylglycinexylidide followed by a subsequent hydrolysis to xylidine.
The excretion occurs via the kidney with less than 5% in the unchanged form appearing in the urine. The renal clearance is inversely related to its protein binding affinity and the pH of the urine. This suggests by the latter that excretion of Versatis 5%e occurs by non-ionic diffusion..
Absorption
When lidocaine 700 mg 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.
Distribution
After 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.
Biotransformation
Lidocaine 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. 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.
Elimination
Lidocaine 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.
For single use only.
Use immediately after opening.
If only part of an ampoule is used, discard the remaining solution.
The injection should not be used if particles are present.
After use the plaster still contains active substance. After removal, the used plasters should be folded in half, adhesive side inwards so that the self-adhesive layer is not exposed, and the plaster should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
