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 Lidocaine Patch 5% 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 Lidocaine Patch 5% is directly related to both the duration of application and the surface area over which it is applied. In a pharmacokinetic study, three Lidocaine Patches 5% 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 Blood samples were withdrawn for determination of lidocaine concentration during the application and for 12 hours after removal of patches.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.

When Lidocaine Patch 5% 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 mcg/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 Lidocaine Patches 5% 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 Lidocaine Patch 5%, lidocaine is approximately 70% bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 mcg/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 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).

Risk of Methemoglobinemia

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Lidocaine Patch 5% and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

Accidental Exposure in Children

Even a used Lidocaine Patch 5% contains a large amount of lidocaine (at least 665 mg). The potential exists for a small child or a pet to suffer serious adverse effects from chewing or ingesting a new or used Lidocaine Patch 5%, although the risk with this formulation has not been evaluated. It is important for patients to store and dispose of Lidocaine Patch 5% out of the reach of children, pets and others. (See HANDLING AND DISPOSAL)

Excessive Dosing

Excessive dosing by applying Lidocaine Patch 5% to larger areas or for longer than the recommended wearing time could result in increased absorption of lidocaine and high blood concentrations, leading to serious adverse effects (see ADVERSE REACTIONS, Systemic Reactions). Lidocaine toxicity could be expected at lidocaine blood concentrations above 5 mcg/mL. The blood concentration of lidocaine is determined by the rate of systemic absorption and elimination. Longer duration of application, application of more than the recommended number of patches, smaller patients, or impaired elimination may all contribute to increasing the blood concentration of lidocaine. With recommended dosing of Lidocaine Patch 5%, the average peak blood concentration is about 0.13 mcg/mL, but concentrations higher than 0.25 mcg/mL have been observed in some individuals.

General

Hepatic Disease

Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations of lidocaine, because of their inability to metabolize lidocaine normally.

Allergic Reactions

Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine. However, Lidocaine Patch 5% should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain.

Non-intact Skin

Application to broken or inflamed skin, although not tested, may result in higher blood concentrations of lidocaine from increased absorption. Lidocaine Patch 5% is only recommended for use on intact skin.

External Heat Sources

MRI skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because the Lidocaine Patch 5% contains aluminum, it is recommended to remove the system before undergoing an MRI.

Placement of external heat sources, such as heating pads or electric blankets, over Lidocaine Patches 5% is not recommended as this has not been evaluated and may increase plasma lidocaine levels.

Eye Exposure

The contact of Lidocaine Patch 5% with eyes, although not studied, should be avoided based on the findings of severe eye irritation with the use of similar products in animals. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns.

Information for Patients

Methemoglobinemia

Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to stop use and seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

Drug Interactions

Antiarrhythmic Drugs

Lidocaine Patch 5% should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic.

Local Anesthetics

When Lidocaine Patch 5% is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered.

Drugs That May Cause Methemoglobinemia When Used with Lidocaine Patch 5%

Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A minor metabolite, 2, 6-xylidine, has been found to be carcinogenic in rats. The blood concentration of this metabolite is negligible following application of Lidocaine Patch 5%.

Mutagenesis

Lidocaine HCl is not mutagenic in Salmonella/mammalian microsome test nor clastogenic in chromosome aberration assay with human lymphocytes and mouse micronucleus test.

Impairment of Fertility

The effect of Lidocaine Patch 5% on fertility has not been studied.

Pregnancy

Teratogenic Effects

Pregnancy Category B.

Lidocaine Patch 5% has not been studied in pregnancy. Reproduction studies with lidocaine have been performed in rats at doses up to 30 mg/kg subcutaneously and have revealed no evidence of harm to the fetus due to lidocaine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Lidocaine Patch 5% should be used during pregnancy only if clearly needed.

Labor and Delivery

Lidocaine Patch 5% has not been studied in labor and delivery. Lidocaine is not contraindicated in labor and delivery. Should Lidocaine Patch 5% be used concomitantly with other products containing lidocaine, total doses contributed by all formulations must be considered.

Nursing Mothers

Lidocaine Patch 5% has not been studied in nursing mothers. Lidocaine is excreted in human milk, and the milk: plasma ratio of lidocaine is 0.4. Caution should be exercised when Lidocaine Patch 5% is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Application Site Reactions

During or immediately after treatment with Lidocaine Patch 5%, the skin at the site of application may develop blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours.

Allergic Reactions

Allergic and anaphylactoid reactions associated with lidocaine, although rare, can occur. They are characterized by angioedema, bronchospasm, dermatitis, dyspnea, hypersensitivity, laryngospasm, pruritus, shock, and urticaria. If they occur, they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value.

Other Adverse Events

Due to the nature and limitation of spontaneous reports in postmarketing surveillance, causality has not been established for additional reported adverse events including:

Asthenia, confusion, disorientation, dizziness, headache, hyperesthesia, hypoesthesia, lightheadedness, metallic taste, nausea, nervousness, pain exacerbated, paresthesia, somnolence, taste alteration, vomiting, visual disturbances such as blurred vision, flushing, tinnitus, and tremor.

Systemic (Dose-Related) Reactions

Systemic adverse reactions following appropriate use of Lidocaine Patch 5% are unlikely, due to the small dose absorbed (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Systemic adverse effects of lidocaine are similar in nature to those observed with other amide local anesthetic agents, including CNS excitation and/or depression (light headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest). Excitatory CNS reactions may be brief or not occur at all, in which case the first manifestation may be drowsiness merging into unconsciousness. Cardiovascular manifestations may include bradycardia, hypotension and cardiovascular collapse leading to arrest.