CLINICAL PHARMACOLOGY
Pharmacodynamics
Lidocaine is an amide-type local anesthetic agent and is suggested to stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses.
The penetration of lidocaine into intact skin after application of LIDODERM is sufficient to produce an analgesic effect, but less than the amount necessary to produce a complete sensory block.
Pharmacokinetics
Absorption
The amount of lidocaine systemically absorbed from LIDODERM is directly related to both the duration of application and the surface area over which it is applied. In a pharmacokinetic study, three LIDODERM patches were applied over an area of 420 cm2 of intact skin on the back of normal volunteers for 12 hours. Blood samples were withdrawn for determination of lidocaine concentration during the application and for 12 hours after removal of patches. The results are summarized in Table 1.
Table 1 Absorption of lidocaine from LIDODERM Normal volunteers (n= 15, 12-hour wearing time) LIDODERM
Patch | Application
Site | Area
(cm2) | Dose
Absorbed
(mg) | Cmax
(µg/mL) | Tmax
(hr) |
|---|
3 patches
(2100 mg) | Back | 420 | 64 ± 32 | 0.13 ± 0.06 | 11 hr |
When LIDODERM is used according to the recommended dosing instructions, only 3 ± 2% of the dose applied is expected to be absorbed. At least 95% (665 mg) of lidocaine will remain in a used patch. Mean peak blood concentration of lidocaine is about 0.13 µg/mL (about 1/10 of the therapeutic concentration required to treat cardiac arrhythmias). Repeated application of three patches simultaneously for 12 hours (recommended maximum daily dose), once per day for three days, indicated that the lidocaine concentration does not increase with daily use. The mean plasma pharmacokinetic profile for the 15 healthy volunteers is shown in Figure 1.
Figure 1
Mean lidocaine blood concentrations after three consecutive daily applications of three LIDODERM patches simultaneously for 12 hours per day in healthy volunteers (n = 15).
Distribution
When lidocaine is administered intravenously to healthy volunteers, the volume of distribution is 0.7 to 2.7 L/kg (mean 1.5 ± 0.6 SD, n=15). At concentrations produced by application of LIDODERM, lidocaine is approximately 70% bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 µg/mL of free base), the plasma protein binding of lidocaine is concentration dependent. Lidocaine crosses the placental and blood brain barriers, presumably by passive diffusion.
Metabolism
It is not known if lidocaine is metabolized in 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 than that of lidocaine. A minor metabolite, 2, 6-xylidine, has unknown pharmacologic activity but is carcinogenic in rats. The blood concentration of this metabolite is negligible following application of LIDODERM (lidocaine patch 5%). Following intravenous administration, MEGX and GX concentrations in serum range from 11 to 36% and from 5 to 11% of lidocaine concentrations, respectively.
Excretion
Lidocaine and its metabolites are excreted by the kidneys. Less than 10% of lidocaine is excreted unchanged. The half-life of lidocaine elimination from the plasma following IV administration is 81 to 149 minutes (mean 107 ± 22 SD, n = 15). The systemic clearance is 0.33 to 0.90 L/min (mean 0.64 ± 0.18 SD, n = 15).
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