LIDODERM - lidocaine patch
`
`Endo Pharmaceuticals Inc
`
`----------
`
`LIDODERM®
` (Lidocaine Patch 5%)
`
`
`Rx only
`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
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`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 Blood samples were withdrawn for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)
`
`Dose
`
`LIDODERM Application Area Absorbed
`
`Patch
`Site
`(cm2)
`(mg)
`3 patches
`Back
`420
`64 ± 32
`(2100 mg)
`
`Cmax Tmax
`
`(µg/mL) (hr)
`
`0.13 ± 11 hr
`0.06
`
`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
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`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.
`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)
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` 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.
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`Carcinogenesis, Mutagenesis, Impairment of Fertility
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`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.
`
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` 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.
`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.
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`Allergic Reactions
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`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.
`DOSAGE AND ADMINISTRATION
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`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.
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`NDC 63481-687-06
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` Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room
`
`Temperature].
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`Manufactured for:
`
`Endo Pharmaceuticals Inc.
`
`Chadds Ford, Pennsylvania 19317
`
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`LIDODERM® is a Registered Trademark of Hind Health Care, Inc.
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`© 2010 Endo Pharmaceuticals
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