Synera_TM
(lidocaine 70 mg and tetracaine 70 mg) topical patch

Synera™ consists of a thin, uniform layer of a local anesthetic formulation with an integrated, oxygen-activated heating component that is intended to enhance the delivery of the local anesthetic. The drug formulation is an emulsion in which the oil phase is a eutectic mixture of lidocaine 70 mg and tetracaine 70 mg. The eutectic mixture has a melting point below room temperature and therefore exists as a liquid oil rather than as crystals. The surface area of the entire Synera patch is approximately 50 cm², 10 cm² of which is active.

Lidocaine is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl), has an octanol:water partition ratio of 182 at pH 7.3 and has the following structure:

Tetracaine is chemically designated as 2-(dimethylamino) ethyl p-(butylamino) benzoate, has an octanol: water partition ratio of 5370 at pH 7.3 and has the following structure:

Each Synera patch contains lidocaine 70 mg and tetracaine 70 mg in a eutectic mixture. The Synera formulation also contains the following inactive ingredients: polyvinyl alcohol, sorbitan monopalmitate, water, methylparaben and propylparaben.

The Synera heating component generates a mild warming that is intended to enhance the delivery of the local anesthetic. Synera begins to heat once the patch is removed from the pouch and is exposed to oxygen in the air. Although the patch may increase skin temperature by up to approximately 5ºC, maximum skin temperature will not exceed 40ºC. The heating component is composed of iron powder, activated carbon, sodium chloride, wood flour, water and filter paper.

Three randomized, double-blind, placebo controlled clinical trials in adult and geriatric subjects evaluated the degree of dermal analgesia upon venipuncture following a 20-minute treatment with Synera™ or a placebo patch (patch with heating component but no drug). In each trial, subjects received Synera on one arm and placebo patch on the other. Less pain was reported following Synera treatment compared to placebo in all three studies as measured by a 100 mm visual analog scale (VAS). In the first study in 21 subjects, median VAS scores for Synera and placebo treatments were 1 and 9, respectively. In the second study in 40 subjects, median VAS scores were 5 and 28 for Synera and placebo treatments, respectively. In the third study, in 40 subjects over the age of 65 years, median VAS scores for Synera and placebo treatments were 8 and 14, respectively.

In a randomized, double-blind, placebo controlled study, 61 pediatric patients received either Synera or placebo for 20 minutes prior to venipuncture or IV cannulation in the antecubital fossa or dorsum of the hand. Subjects were stratified by age group (3 to 6 years and 7 to 17 years). Children in the younger group reported less pain with Synera than with placebo, as rated using a six-point Oucher pain scale with faces. Children in the older group rated their pain using a different instrument; an eleven-point Oucher pain scale that contained both faces and numbers. Pain scores in the older children treated with Synera were not statistically significantly different from pain scores in those treated with placebo.

In a double-blind trial in 250 adults, subjects were randomized to receive either Synera without heating element or intact, heated Synera, prior to venipuncture. Less pain was reported following treatment with the heated Synera compared to the non-heated patch. Median VAS scores for the patch with the heating component and without the heating component were 17 and 22, respectively.

In one randomized, double-blind, placebo controlled study, 94 adult subjects received either Synera or placebo patch for 30 minutes prior to a superficial dermatological procedure such as superficial excision, shave biopsy or electrodessication. Less pain was reported following Synera treatment compared to placebo. Median VAS scores for Synera and placebo treatments were 5 and 31, respectively. In a similarly designed study in 74 subjects over the age of 65 years, less pain was reported following Synera treatment compared to placebo with median VAS scores for Synera and placebo treatments of 10 and 23, respectively.

In a randomized, double-blind, placebo controlled study, 88 pediatric patients were stratified by age group (3 to 6 years and 7 to 17 years) to receive a 30-minute application of either Synera or placebo, prior to lidocaine injection. In younger children who used the Oucher pain scale with faces, those receiving Synera reported less pain from lidocaine injection than those receiving placebo. Older children used the numerical Oucher pain scale to report pain intensity. There was no difference between treatments observed in the older children.

Synera™ is indicated for use on intact skin to provide local dermal analgesia for superficial venous access and superficial dermatological procedures such as excision, electrodessication and shave biopsy of skin lesions (see CLINICAL STUDIES section).

Synera™ is contraindicated in patients with a known history of sensitivity to lidocaine, tetracaine, or local anesthetics of the amide or ester type. Synera is also contraindicated in patients with paraaminobenzoic acid (PABA) hypersensitivity and in patients with a known history of sensitivity to any other component of the product.

Application of Synera™ (lidocaine 70 mg and tetracaine 70 mg) topical patch for longer duration than recommended, or the simultaneous or sequential application of multiple Synera patches, could result in sufficient absorption of lidocaine and tetracaine to result in serious adverse effects (see Overdosage).

Even a used Synera patch contains a large amount of lidocaine and tetracaine (at least 90% of the initial amount). The potential exists for a child or pet to suffer serious adverse effects from chewing or ingesting a new or used Synera patch. It is important for patients to store and dispose of Synera out of the reach of children and pets.

Three different formulations were studied during clinical development of Synera™: Developmental A (n=138), Developmental B (n=30), and the Synera final formulation (n=1281). The developmental patch formulations each contained the same amount of the active drug (70 mg each of lidocaine and tetracaine) as the final patch formulation, but varying amounts of excipients, principally polyvinyl alcohol and water. Data obtained from studies utilizing the developmental patches have been included in the overall evaluation of Synera safety (calculation of adverse event incidence).

In adults the maximum peak plasma concentrations of lidocaine and tetracaine following application of two to four Synera™ patches for 30-60 minutes were less than 9 ng/mL and tetracaine levels were not detectable. In children, the maximum observed peak plasma concentrations of lidocaine were 63 ng/mL and 331 ng/mL after the application of one or two Synera patches, respectively. Higher maximum concentrations of lidocaine were observed for younger children when compared to older children. The maximum concentration of tetracaine observed in children was 65 ng/mL, and most values obtained were <0.9 ng/mL. Signs of CNS toxicity may start at plasma concentrations of lidocaine as low as 1000 ng/mL, and the risk of seizures generally increases with increasing plasma levels. Very high levels of lidocaine can cause respiratory arrest, coma, decreases in cardiac output, total peripheral resistance and mean arterial pressure, ventricular arrhythmias and cardiac arrest. Tetracaine is associated with a profile of systemic CNS and cardiovascular adverse events similar to lidocaine, although toxicity associated with tetracaine is thought to occur at lower doses compared to lidocaine. The toxicity of co-administered local anesthetics is thought to be at least additive. In the absence of massive topical overdose or oral ingestion, other etiologies for the clinical effects or overdosage from other sources of lidocaine, tetracaine or other local anesthetics should be considered. The management of overdosage includes close monitoring, supportive care and symptomatic treatment. Dialysis is of negligible value in the treatment of acute overdosage of lidocaine.

Synera™ should only be applied to intact skin.

Use immediately after opening the pouch.

For adults and children 3 years of age and older:

Hands should be washed after handling Synera™, and eye contact with Synera should be avoided. The used patch should be disposed of immediately. The adhesive sides of the patch should be folded together and the patch should then be thrown away in a location that is out of the reach of children and pets.

Do not cut the patch or otherwise remove the top cover as this could cause the patch to heat to temperatures that could cause thermal injury. Do not cover the holes on the top side of the patch as this could cause the patch not to heat.

Access to Synera by children or pets should be prevented during usage and storage of the product.

Synera™ is available as the following:

NDC 63481-864-10 box of 10 individually packaged Synera patches

Store at 25^oC (77^oF); excursions permitted to 15-30^oC (59-86^oF) [see USP Controlled Room Temperature].

Not for home use by patient.

R_x Only.

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

Manufactured by:
Tapemark Company
West St. Paul, MN 55118

Copyright © Endo Pharmaceuticals Inc. 2006

Rev. 7/06
# 308498