LIDODERM

Aidarex Pharmaceuticals LLC

FULL PRESCRIBING INFORMATION: CONTENTS*

• LIDODERM DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Pharmacodynamics
  • Pharmacokinetics
• CLINICAL STUDIES
• INDICATION AND USAGE
• LIDODERM CONTRAINDICATIONS
• WARNINGS
  • Accidental Exposure in Children
  • Excessive Dosing
• PRECAUTIONS
  • General
  • Drug Interactions
  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Pregnancy
  • Labor and Delivery
  • Nursing Mothers
  • Pediatric Use
• LIDODERM ADVERSE REACTIONS
  • Application Site Reactions
  • Allergic Reactions
  • Other Adverse Events
  • Systemic (Dose-Related) Reactions
• OVERDOSAGE
• LIDODERM DOSAGE AND ADMINISTRATION
• HANDLING AND DISPOSAL
• HOW SUPPLIED
• PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

LIDODERM DESCRIPTION

LIDODERM (lidocaine patch 5%) is comprised of an adhesive material containing 5% lidocaine, which is applied to a non-woven polyester felt backing and covered with a polyethylene terephthalate (PET) film release liner. The release liner is removed prior to application to the skin. The size of the patch is 10 cm × 14 cm.

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

Each adhesive patch contains 700 mg of lidocaine (50 mg per gram adhesive) in an aqueous base. It also contains the following inactive ingredients: dihydroxyaluminum aminoacetate, disodium edetate, gelatin, glycerin, kaolin, methylparaben, polyacrylic acid, polyvinyl alcohol, propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, D-sorbitol, tartaric acid, and urea.

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 Blood samples were withdrawn for determination of lidocaine concentration during the application and for 12 hours after removal of patches.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.

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).

CLINICAL STUDIES

Single-dose treatment with LIDODERM was compared to treatment with vehicle patch (without lidocaine), and to no treatment (observation only) in a double-blind, crossover clinical trial with 35 post-herpetic neuralgia patients. Pain intensity and pain relief scores were evaluated periodically for 12 hours. LIDODERM performed statistically better than vehicle patch in terms of pain intensity from 4 to 12 hours.

Multiple-dose, two-week treatment with LIDODERM was compared to vehicle patch (without lidocaine) in a double-blind, crossover clinical trial of withdrawal-type design conducted in 32 patients, who were considered as responders to the open-label use of LIDODERM prior to the study. The constant type of pain was evaluated but not the pain induced by sensory stimuli (dysesthesia). Statistically significant differences favoring LIDODERM were observed in terms of time to exit from the trial (14 versus 3.8 days at p-value <0.001), daily average pain relief, and patient's preference of treatment. About half of the patients also took oral medication commonly used in the treatment of post-herpetic neuralgia. The extent of use of concomitant medication was similar in the two treatment groups.

INDICATION AND USAGE

LIDODERM is indicated for relief of pain associated with post-herpetic neuralgia. It should be applied only to intact skin.

LIDODERM CONTRAINDICATIONS

LIDODERM 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

Accidental Exposure in Children

Even a used LIDODERM patch 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 LIDODERM patch, although the risk with this formulation has not been evaluated. It is important for patients to store and dispose of LIDODERM out of the reach of children, pets and others. (See HANDLING AND DISPOSAL)

Excessive Dosing

Excessive dosing by applying LIDODERM 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 µg/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 LIDODERM, the average peak blood concentration is about 0.13 µg/mL, but concentrations higher than 0.25 µg/mL have been observed in some individuals.

PRECAUTIONS

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, LIDODERM 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. LIDODERM is only recommended for use on intact skin.

External Heat Sources: Placement of external heat sources, such as heating pads or electric blankets, over LIDODERM patches is not recommended as this has not been evaluated and may increase plasma lidocaine levels.

Eye Exposure: The contact of LIDODERM 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.

Drug Interactions

Antiarrhythmic Drugs: LIDODERM 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 LIDODERM is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered.

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 LIDODERM.

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 LIDODERM on fertility has not been studied.

Pregnancy

Teratogenic Effects: Pregnancy Category B. LIDODERM (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, LIDODERM should be used during pregnancy only if clearly needed.

Labor and Delivery

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

Nursing Mothers

LIDODERM 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 LIDODERM is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

LIDODERM ADVERSE REACTIONS

Application Site Reactions

During or immediately after treatment with LIDODERM (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 LIDODERM 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.

OVERDOSAGE

Lidocaine overdose from cutaneous absorption is rare, but could occur. If there is any suspicion of lidocaine overdose (see ADVERSE REACTIONS, Systemic Reactions), drug blood concentration should be checked. The management of overdose includes close monitoring, supportive care, and symptomatic treatment. Dialysis is of negligible value in the treatment of acute overdose with lidocaine.

In the absence of massive topical overdose or oral ingestion, evaluation of symptoms of toxicity should include consideration of other etiologies for the clinical effects, or overdosage from other sources of lidocaine or other local anesthetics.

The oral LD₅₀ of lidocaine HCl is 459 (346-773) mg/kg (as the salt) in non-fasted female rats and 214 (159-324) mg/kg (as the salt) in fasted female rats, which are equivalent to roughly 4000 mg and 2000 mg, respectively, in a 60 to 70 kg man based on the equivalent surface area dosage conversion factors between species.

LIDODERM DOSAGE AND ADMINISTRATION

Apply LIDODERM to intact skin to cover the most painful area. Apply up to three patches, only once for up to 12 hours within a 24-hour period. Patches may be cut into smaller sizes with scissors prior to removal of the release liner. (See HANDLING AND DISPOSAL) Clothing may be worn over the area of application. Smaller areas of treatment are recommended in a debilitated patient, or a patient with impaired elimination.

If irritation or a burning sensation occurs during application, remove the patch(es) and do not reapply until the irritation subsides.

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

HANDLING AND DISPOSAL

Hands should be washed after the handling of LIDODERM, and eye contact with LIDODERM should be avoided. Do not store patch outside the sealed envelope. Apply immediately after removal from the protective envelope. Fold used patches so that the adhesive side sticks to itself and safely discard used patches or pieces of cut patches where children and pets cannot get to them. LIDODERM should be kept out of the reach of children.

HOW SUPPLIED

LIDODERM (lidocaine patch 5%) is available as the following:

Carton of 30 patches, packaged into individual child-resistant envelopes.
NDC 33261-672-30

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].

Manufactured for:
Endo Pharmaceuticals Inc.
Chadds Ford, Pennsylvania 19317

Repackaged By:
Aidarex Pharmaceuticals, LLC.
Corona, CA 92880

LIDODERM^® is a Registered Trademark of Hind Health Care, Inc.

© 2010 Endo Pharmaceuticals

6524-12/March 2010

PRINCIPAL DISPLAY PANEL