FDA Label for Lidothol Es

Description:

Lidothol® ES is a prescription drug-in-adhesive system, packaged with 15 systems:

1 per pouch, 15 pouches. Lidocaine is present in a 4% concentration (w/w). It is chemically designated as 2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide and has an empirical formula of C14H22N2O. The molecular weight of lidocaine is 234.34 g/mol. Menthol is present in a 5% concentration (w/w). The chemical name is (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol. The empirical formula for menthol is C10H20O with a molecular weight of 156.27 g/mol.

Lidothol® ES consists of a Drug-in-Adhesive System containing lidocaine 4% and menthol 5%, applied to flexible woven polyester backing and protected by a plastic film. The protective film is removed prior to application to the skin. The size of the system is 10 cm x 14 cm.

Lidocaine is chemically designated as 2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide, has an octanol: water partition ratio of 43 at pH 7.4, and has the following structure:

Menthol is chemically designated as 2-Isopropyl-5-methylcyclohexanol. It contains colorless, hexagonal crystals, usually needle-like; fused masses or crystalline powder with a pleasant, peppermint-like odor. It has a melting point between 31°C to 36°C. Menthol has the following structure:

Each system contains:Lidocaine: 373.5 mg (45 mg per gram adhesive) in an anhydrous base. Menthol: 415 mg (50 mg per gram adhesive) in an anhydrous base. It also contains the following inactive ingredients: acrylate copolymer PSA adhesives, alpha-tocopherol (vitamin E)

Indications And Usage

Lidothol® ES is a formulation used to assist patients in the treatment of mild to moderate acute or chronic aches or pain. Muscle or joint pain can be due to muscle or ligament strains, simple backache, tendonitis, osteoarthritis, rheumatoid arthritis, peripheral neuropathies such as diabetic neuropathy or post-herpetic neuralgia, and other complex regional pains. It can also be used to help with certain types of headaches, but use with caution when applying in order to avoid eye contact. Other uses may be considered if deemed clinically relevant.

Dosage And Administration

Apply Lidothol® ES to intact skin to cover the most painful area. Apply no more than two systems per day. Each system should not be applied for more than 12 hours in a given 24-hour period. Lidothol® ES may be cut into smaller sizes with scissors prior to the removal of the protective film. Clothing may be worn over the area of application. Smaller treatment areas are recommended for debilitated patients or those with impaired elimination. If irritation or a burning sensation occurs during application, remove the system and do not reapply until the irritation subsides. When Lidothol® ES is used concurrently with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered.

Contraindications

Lidothol® ES is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product.

Warnings And Precautions

Excessive dosage or short intervals between doses can result in high plasma levels and serious adverse effects. Patients should be instructed to strictly adhere to the recommended dosage and administration guidelines set forth in this literature and on their prescription label. The management of serious adverse reactions may require the use of resuscitative equipment, oxygen, or other resuscitative drugs.

Adverse Reactions

The most common adverse reactions occur at the application site, including dermatitis, itching, or scaling. These tend to be dose-limiting and diminish with time. Serious adverse experiences following the administration of Lidothol® ES are similar in nature to those observed in other amide local anesthetic-containing agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption, or may result from hypersensitivity, idiosyncrasy, or a diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. During or immediately after treatment with Lidothol® ES, the skin at the site of application may develop redness, blisters, bruising, burning sensation, depigmentation, dermatitis, or mild irritation.

Drug Interactions

Antiarrhythmic Drugs

Lidothol® ES should be used with caution in patients receiving Class 1 antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic.

Local Anesthetics

When Lidothol® ES is used concurrently with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered.

Methemoglobinemia

Patients that are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following oxidizing agents:

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Use In Specific Populations

Pregnancy

The safety of Lidothol® ES has not been established during pregnancy. There are no well-controlled studies in pregnant women. Discuss with a physician prior to using Lidothol® ES during pregnancy.

Lactation

The effect of Lidothol® ES on breastfed infants has not been evaluated. Lidothol® ES has not been studied during lactation. Discuss with a physician prior to using Lidothol® ES while breastfeeding.

Pediatric/Geriatric Use

Safety and effectiveness in pediatric and geriatric patients have not been established.

Overdosage

There have been no reports of overdosage with Lidothol® ES. Signs of overdosage would include vomiting, drowsiness, coma, respiratory depression, and seizures. In the case of overdosage, discontinue the product immediately, treat the patient symptomatically, and institute supportive measures.

Clinical Pharmacology

Pharmacodynamics

Menthol works by targeting the κ-opioid receptor on the TRPM8 neuron. The TRPM8 neuron is normally activated at temperatures between 46.4–82.4 °F (8–28 °C). Menthol causes the neuron to fire at temperatures above normal activation, which triggers the characteristic cooling sensation. Also, because of menthol’s specific targeting of the κ-opioid receptor, it is endowed with analgesic properties.

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 Lidothol® ES 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 and menthol systemically absorbed is directly related to both the duration of application and the surface area over which it is applied. In a pharmacokinetic study, three lidocaine 5% 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 a determination of lidocaine concentration during the application and for 12 hours after the removal of the patches.

The results are summarized in Table 1: When lidocaine 5% patch is used according to the recommended dosing instructions, only 3 ± 2% of the dose applied is expected to be absorbed.

table1 - table1

At least 95% (665 mg) of lidocaine will remain in a used patch. The 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 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 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 4µg/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.

Humans rapidly metabolize menthol primarily in the liver by the microsomes, using the enzyme CYP2A6. Cytochrome P450-mediated oxidation occurs in humans, yielding various alcohol and hydroxy acid derivatives. These are eliminated in the urine unchanged or conjugated with glucuronic acid.

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 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).

Menthol is largely eliminated as glucuronides. In an experiment, 79% of a 1g (Quick, 1928) and 78% of a 10-20 mg (Aitz et al., 1972) oral dose of menthol was eliminated as the glucuronic acid conjugate within 6 h after administration to volunteers. Of a dose of 47 mg/kg body weight [3-3H]-(-)-menthol, 62% was eliminated in the urine 17 hours after administration.

Smaller amounts were distributed in the feces and ileum; only 1% of the activity remained in the liver (Clegg et al., 1982).

Nonclinical Toxicology

Carcinogenesis

A minor metabolite, 2,6-xylidine, has been found to be carcinogenic in rats. The blood concentration of metabolite is negligible following application of Lidothol® ES.

Mutagenesis

Lidocaine 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 Lidothol® ES on fertility has not been studied.

How Supplied

Lidothol® ES is supplied in the following dosage form:
15 Systems: 1 per pouch, 15 pouches  |  NDC 83881-445-15

Storage

Store at 68–77 °F (20–25 °C); excursions permitted to 59–86 °F (15–30 °C). Keep away from heat or sunlight. Protect from excessive moisture. The product can be considered safe and effective to use when maintained under these recommended conditions within the posted expiration date.

Handling And Disposal

Wash hands immediately after applying or removing Lidothol® ES. Eye contact with Lidothol® ES should be avoided. Do not store the system outside the pouch. Apply immediately after removal from the protective film. Fold used systems so the adhesive side sticks to itself, then safely discard used systems or pieces of cut systems where children and pets cannot access them. Lidothol® ES should be kept out of reach of children.

Box Label