Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Ferndale Pharmaceuticals Ltd, Unit 740, Thorp Arch Estate, Wetherby, West Yorkshire, LS23 7FX, United Kingdom
Anaesthetics for topical use, lidocaine
ATC Code: D04AB01
Lidocaine applied to intact skin provides dermal analgesia by a release of lidocaine from the cream into the epidermal and dermal layers of the skin, and by the accumulation of lidocaine in the vicinity of pain receptors and nerve endings. Lidocaine is an amide-type local anaesthetic agent which stabilises neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anaesthetic action. The onset, depth and duration of dermal analgesia provided by lidocaine depend primarily on the duration of application. LMX4 may cause transient peripheral vasoconstriction followed by transient vasodilation at the application site.
LMX4 has been shown to provide reliable analgesia when applied for between 30 to 60 minutes in clinical studies. The cream may remain on the skin after this time, if adequate analgesia is not achieved. There is limited data available with LMX4 and similar lidocaine-based formulations to show that application times longer than 60 minutes for cannulation procedures and large surface area topical treatments are systemically safe.
The amount of lidocaine systemically absorbed is directly related to both the duration of application and to the area over which it is applied. It is not known if it is metabolized into the skin. Lidocaine is metabolized rapidly by the liver to a number of metabolites including monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which have pharmacologic activity similar to, but less potent to that of lidocaine. The metabolite, 2,6-xylidine, has unknown pharmacologic activity but is carcinogenic in rats.
Following intravenous administration, MEGX and GX concentrations in serum range from 11 to 36% and from 5 to 11% of concentrations, respectively. The half-life of lidocaine elimination from the plasma following IV administration is approximately 65 to 150 minutes (mean 110, ±24 SD, n=13). This half-life may be increased in cardiac or hepatic dysfunction. More than 98% of an absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. The systemic clearance is 10 to 20 mL/min/kg (mean 13, ±3 SD, n=13).
When applied topically to intact skin, the absorption of lidocaine is very low. Increased absorption is therefore to be expected when applied to mucosa or previously damaged skin.
The maximum plasma level of active ingredient was very low (0.3 µ g/ml or less) in a study investigating the application of LMX4 for cannulation in children of different ages. It was well below the toxically effective plasma level of ingredients.
The mutagenic potential of lidocaine HCl has been tested in the Ames Salmonella/mammalian microsome test and by analysis of structural chromosome aberrations in human lymphocytes in vitro, and by mouse micronucleus test in vivo. There was no indication in these tests of any mutagenic effects. The mutagenicity of 2,6-xylidine, a metabolite of lidocaine, has been studied in different tests with mixed results.
The compound was found to be weakly mutagenic in the Ames test only under metabolic activation conditions. In addition, 2,6-xylidine was observed to be mutagenic at the thymidine kinase locus, with or without activation, and induced chromosome aberrations and sister chromatic exchanges at concentrations at which the drug precipitated out of the solution (1.2 mg/ml). No evidence of genotoxicity was found in the in vivo assays measuring unscheduled DNA synthesis in rat hepatocytes, chromosome damage in polychromatic erythrocytes or preferential killing of DNA repair-deficient bacteria in liver, lung, kidney, testes and blood extracts from mice. However, covalent binding studies of DNA from liver and ethmoid turbinates in rats indicate that 2,6-xylidine may be genotoxic under certain conditions in vivo.
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