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CLINICAL PHARMACOLOGY Mechanism Of Action SYNERA applied to intact skin provides local dermal analgesia by the release of lidocaine and tetracaine from the patch into the skin. Lidocaine is an amide-type local anesthetic agent and tetracaine is an ester-type local anesthetic agent. Both lidocaine and tetracaine block sodium ion channels required for the initiation and conduction of neuronal impulses, resulting in local anesthesia. Pharmacokinetics Absorption Application of one SYNERA patch for 30 minutes in adults produced peak plasma concentrations of lidocaine less than 5 ng/mL while plasma levels of tetracaine were below the limit of quantitation ( < 0.9 ng/mL) in all subjects tested (n = 12, see Table 1). SYNERA application up to 60 minutes did not significantly increase plasma levels of lidocaine or tetracaine compared to a 30-minute application. Table 1 : Absorption of Lidocaine and Tetracaine from SYNERA in Normal Adult Volunteers (n = 12) Number of SYNERA Patches Age Range (yr) Application Time (min) Drug Content (mg) Estimated Amount Absorbed (mg)* Cmax (ng/mL) Tmax (hr) 1 18-65 30 Lidocaine, 70 1.7 1.7 1.7 Tetracaine, 70 1.6

CLINICAL PHARMACOLOGY Mechanism Of Action Lidocaine is an amide-type local anesthetic agent and tetracaine is an ester-type local anesthetic agent. Both lidocaine and tetracaine block sodium ion channels required for the initiation and conduction of neuronal impulses which, in certain instances, results in local anesthesia. When applied to intact skin, PLIAGLIS Cream provides local dermal analgesia by the release of lidocaine and tetracaine from the peel into the skin. Pharmacodynamics Duration of analgesia was evaluated using a pinprick test in 40 adult volunteers. The median duration of analgesia was 11 hours. There was no difference between the 30-minute and 60-minute PLIAGLIS Cream application periods with respect to the mean for time to return of sensation. However, 55% of PLIAGLIS Cream treated subjects still reported diminished sensation at the end of the 13-hour study period. Pharmacokinetics Absorption The amount of lidocaine and tetracaine systemically absorbed from PLIAGLIS Cream is directly related to both the duration of application and the surface area over which it is applied, Table 2. Application of 59 g of PLIAGLIS Cream over 400 cm² for up to 120 minutes to adults produces peak plasma concentrations of lidocaine of 220 ng/mL. Tetracaine plasma levels were not measurable ( < 0.9 ng/mL). Systemic exposure to lidocaine, as measured by Cmax and AUC0-24, was proportional to the application area, and increased with application time up to 60 minutes. Table 2: Absorption of lidocaine and tetracaine following application of PLIAGLIS Cream PLIAGLIS Cream (g) Area (cm²) Age Range (yr) n Application Time (min) Drug Content (g) Mean Cmax (ng/mL) Mean Tmax (hr) 21 400 18-64 4 30 Lidocaine, 1.5 49 4 Tetracaine, 1.5 < 0.9 na 33 400 18-64 4 60 Lidocaine, 2.3 96 2.8 Tetracaine, 2.3 < 0.9 na 31 400 ≥ 65 6 60 Lidocaine, 2.2 48 3.8 Tetracaine, 2.2 < 0.9 na na = not applicable Distribution When lidocaine is administered intravenously to healthy volunteers, the steady-state volume of distribution is approximately 0.8 to 1.3 L/kg. At lidocaine concentrations observed following the recommended product application, approximately 75% of lidocaine is bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 mg/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. CNS toxicity may typically be observed around 5000 ng/mL of lidocaine; however, a small number of patients reportedly may show signs of toxicity at approximately 1000 ng/mL [see OVERDOSAGE]. Volume of distribution and protein binding have not been determined for tetracaine due to rapid hydrolysis in plasma. Metabolism It is not known if lidocaine or tetracaine 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. The major metabolic pathway of lidocaine, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4. The metabolite, 2,6-xylidine, has unknown pharmacologic activity. Following intravenous administration of lidocaine, MEGX and GX concentrations in serum range from 11% to 36% and from 5% to 11% of lidocaine concentrations, respectively. Serum concentrations of MEGX were about one-third the serum lidocaine concentrations. Tetracaine undergoes rapid hydrolysis by plasma esterases. Primary metabolites of tetracaine include para-aminobenzoic acid and diethylaminoethanol, both of which have an unspecified activity. Elimination The half-life of lidocaine elimination from the plasma following intravenous administration is approximately 1.8 hr. Lidocaine and its metabolites are excreted by the kidneys. More than 98% of an absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. Less than 10% of lidocaine is excreted unchanged in adults, and approximately 20% is excreted unchanged in neonates. The systemic clearance is approximately 8–10 mL/min/kg. During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours). The half-life and clearance for tetracaine has not been established for humans, but hydrolysis in the plasma is rapid. Special Populations Elderly: After application of 31g of PLIAGLIS Cream over 400 cm² for 60 minutes, mean peak plasma levels of lidocaine were 48 ng/mL for elderly patients ( > 65 years of age, mean 68.0 ± 3.2 years, n = 6). These levels are similar to or lower than those for younger patients receiving similar amounts of PLIAGLIS Cream. Cardiac, Renal and Hepatic Impairment: No specific pharmacokinetic studies were conducted. The half-life of lidocaine may be increased in patients with cardiac or hepatic dysfunction. There is no established half-life for tetracaine due to rapid hydrolysis in the plasma. Clinical Studies In four clinical trials, adult patients were treated with PLIAGLIS Cream or placebo prior to undergoing a superficial dermatologic procedure. Drug was applied for 20 or 30 minutes for dermatologic procedures such as dermal filler injection, pulsed dye laser therapy, and facial laser resurfacing. Drug was applied for 60 minutes for laser-assisted tattoo removal. Treatment with PLIAGLIS Cream resulted in statistically significantly less pain compared to placebo treatment, as measured by a 100 mm visual analog scale (VAS). Patient efficacy ratings are shown in Table 3. Table 3: Summary of patient evaluations following application of PLIAGLIS Cream and placebo Dermatologic Procedure Mean VAS score PLIAGLIS Cream Placebo 20 Min Application Pulsed Dye Laser Therapy (N=80) 16 31 30 Min Application Non-Ablative Laser Facial Resurfacing (N=54) 21 38 Dermal Filler Injections (N=70) 24 37 60 Min Application Laser-Assisted Tattoo Removal (N=62) 39 59

Find Lowest Prices on SYNERA® (lidocaine and tetracaine) Patch DESCRIPTION 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 5°C, maximum skin temperature will not exceed 40°C. The heating component is composed of iron powder, activated carbon, sodium chloride, wood flour, water and filter paper.

Find Lowest Prices on PLIAGLIS® (lidocaine and tetracaine) Cream 7%/7% DESCRIPTION PLIAGLIS (lidocaine and tetracaine) Cream 7% / 7% is a topical local anesthetic cream that forms a pliable peel on the skin when exposed to air. The drug formulation is an emulsion in which the oil phase is a 1:1 eutectic mixture of lidocaine 7% and tetracaine 7%. The eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals. The net weight of lidocaine is 2.1 g and of tetracaine is 2.1 g per 30 g tube. The net weight of lidocaine is 4.2 g and of tetracaine is 4.2 g per 60 g tube. The net weight of lidocaine is 7.0 g and of tetracaine is 7.0 g per 100 g tube. Lidocaine, an amide local anesthetic, is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl) and has an octanol:water partition ratio of 182 at pH 7.3. The molecular weight of lidocaine is 234.3, and the molecular formula is C14H22N2O. The structural formula is: Tetracaine, an ester local anesthetic, is chemically designated as 2-dimethylaminoethyl 4-n-butylaminobenzoate and has an octanol:water partition ratio of 5370 at pH 7.3. The molecular weight of tetracaine is 264.4, and the molecular formula is C15H24N2O2. The structural formula is: Each gram of PLIAGLIS Cream contains lidocaine 70 mg and tetracaine 70 mg in a 1:1 eutectic mixture and it also contains the following inactive ingredients: dibasic calcium phosphate, methylparaben, petrolatum, polyvinyl alcohol, propylparaben, purified water, and sorbitan monopalmitate.

INDICATIONS SYNERA is a combination amide and ester local anesthetic 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]. DOSAGE AND ADMINISTRATION SYNERA should only be applied to intact skin. Use immediately after opening the pouch. For adults and children 3 years of age and older Venipuncture or Intravenous Cannulation: Prior to venipuncture or intravenous cannulation, apply SYNERA to intact skin for 20 to 30 minutes. Superficial Dermatological Procedures: For superficial dermatological procedures such as superficial excision or shave biopsy, apply SYNERA to intact skin for 30 minutes prior to the procedure. While efficacy has not been established for children less than 3 years of age, safe use of SYNERA in infants 4 to 6 months of age was documented in one study. Simultaneous or sequential application of multiple SYNERA patches is not recommended. However, application of one additional patch at a new location to facilitate venous access is acceptable after a failed attempt. When SYNERA is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations should be considered, as local anesthetics are thought to have at least additive toxicities. If irritation or a burning sensation occurs during application, remove the patch. HOW SUPPLIED Dosage Forms And Strengths SYNERA topical patch contains 70 mg lidocaine and 70 mg tetracaine, has a total skin contact area of 50 cm², and an active drug-containing area of 10 cm² . SYNERA is available as the following: NDC 10885-002-01 One individually packaged SYNERA patch NDC 10885-002-10 Box of 10 individually packaged SYNERA patches Storage And Handling Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children and pets. Apply SYNERA immediately upon removal from the protective pouch. 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. 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. Manufactured for: Galen US Inc. Fretz Road Souderton PA 18964. Revised: March 2014

INDICATIONS PLIAGLIS Cream is a combination of lidocaine, an amide local anesthetic, and tetracaine, an ester local anesthetic, and is indicated for use on intact skin in adults to provide topical local analgesia for superficial dermatological procedures such as dermal filler injection, pulsed dye laser therapy, facial laser resurfacing, and laser-assisted tattoo removal. DOSAGE AND ADMINISTRATION General Dosing Information PLIAGLIS Cream should only be applied to intact skin. For use in adults only. For superficial dermatological procedures such as dermal filler injection, non-ablative laser facial resurfacing, or pulsed-dye laser therapy, apply PLIAGLIS Cream to intact skin for 20-30 minutes prior to the procedure. See Table 1 for instructions on the amount to apply. For superficial dermatological procedures such as laser-assisted tattoo removal, apply PLIAGLIS Cream to intact skin for 60 minutes prior to the procedure. See Table 1 for instructions on the amount to apply. The dose of PLIAGLIS Cream that provides effective local dermal analgesia depends on the duration of the application. Although not specifically studied, a shorter duration of application may result in a less complete dermal analgesia or a shorter duration of adequate dermal analgesia. Dosage Information Determine the amount of drug to apply. The amount (length) of PLIAGLIS Cream that should be dispensed is determined by the size of the area to be treated (see Table 1). Using the ruler supplied on the carton, squeeze out and measure the amount of PLIAGLIS Cream that approximates the amount required to achieve proper coverage. Spread PLIAGLIS Cream evenly and thinly (approximately 1 mm or the thickness of a dime) across the treatment area using a flat-surfaced tool such as a metal spatula or tongue depressor. After waiting the required application time, remove the PLIAGLIS Cream by grasping a free-edge with your fingers and pulling it away from the skin. Table 1: Amount of PLIAGLIS Cream According to Treatment Site Surface Area Surface Area of Treatment Site (cm²) Length of PLIAGLIS Cream for 1 mm Thickness (cm) Weight of PLIAGLIS Cream Dispensed (g) 10 3 1 20 6 3 40 12 5 80 24 11 100 30 13 150 46 20 200 61 26 250 76 33 300 91 40 350 106 46 400 121 53 Important Dosage and Administration Instructions Important Dosage and Administration instructions include: Remove PLIAGLIS Cream if skin irritation or a burning sensation occurs during application. In order to minimize the risk of systemic toxicity, do not exceed the recommended amount of drug to apply or the duration of the application [see OVERDOSAGE]. Avoid eye contact with PLIAGLIS Cream. Wash hands after handling PLIAGLIS Cream. Upon removal from the treatment site, discard the used PLIAGLIS Cream in a location that is out of the reach of children and pets. Access to PLIAGLIS Cream by children or pets should be prevented during usage and storage of the product [see WARNINGS AND PRECAUTIONS]. HOW SUPPLIED Dosage Forms And Strengths Each gram of PLIAGLIS Cream contains lidocaine 70 mg and tetracaine 70 mg and is a smooth, white to off-white, viscous cream. Storage And Handling PLIAGLIS (lidocaine and tetracaine) Cream (70 mg of lidocaine and 70 mg of tetracaine in 1 gram), 7% / 7%, appears smooth and white to off-white and is available as the following: NDC 0299-6100-30 30 gram tube (with Child Resistant Cap) NDC 0299-6100-35 30 gram tube NDC 0299-6100-60 60 gram tube NDC 0299-6100-10 100 gram tube Refrigerate at 2 -8°C (36 -46°F). Do not freeze. PLIAGLIS can be stored at room temperature for up to 3 months. Discard PLIAGLIS after storing at room temperature for 3 months. Marketed by: Galderma Laboratories, L.P. Fort Worth, Texas 76177 USA. Manufactured by: G Production Inc., Baie d'Urfé, QC, H9X 3S4 Canada. Made in Canada. Revised: Nov 2013.

PATIENT INFORMATION Leave the patch in the foil pouch until you read this leaflet WHAT THE PATCH DOES: The medicine on this patch is used to numb the skin that it covers. The safety and effectiveness of SYNERA® have been established in adults and children 3 years of age and older. FOLLOW THE INSTRUCTIONS BELOW, AND THESE SAFETY TIPS: Do not put the patch on your lips or near your eyes. If you get medicine from the patch in your eye, rinse your eye with water and protect it until the numbness goes away. Do not cut or tear the patch. Do not get water on the patch. Keep the patch away from children and pets at all times. STEP 1: Check the skin where the patch will be worn Keep the patch in the unopened foil pouch until you are ready to put it on. Check the skin where your doctor or health care professional told you to wear it. Do not put the patch on skin that is cut, scratched or red (like a rash). Do not shave the area or you may hurt the skin. STEP 2: Open the foil pouch and remove the patch. Save the foil pouch. TO TEAR OPEN THE FOIL POUCH - fold the upper right corner toward you. (See picture A) Press the corner flat to form a small triangle. Tear the foil pouch in the middle of the fold along the pre-cut slit. (See picture B) TO CUT OPEN WITH SCISSORS - cut carefully along the edge of the package. SAVE THE FOIL POUCH. STEP 3: Put the patch on your skin DO NOT TOUCH THE MEDICINE IN THE MIDDLE - touch only the sticky edges of the patch. Never touch the center area. Peel the patch off of the hard plastic backing. Put the sticky side of the patch on your skin, where you were told to wear it. Press the edges to make sure the patch will stick to your skin. Wash your hands. STEP 4: IMPORTANT — How to remove and discard the patch Do not leave the patch on the skin for longer than 30 minutes. Carefully peel the patch off your skin, touching only the sticky edges of the patch - DO NOT TOUCH THE MEDICINE IN THE MIDDLE. PRESS THE STICKY SIDE OF THE USED PATCH ONTO THE FOIL POUCH. THROW FOIL POUCH WITH PATCH ATTACHED, AND HARD PLASTIC BACKING, IN THE GARBAGE so children and pets cannot reach it. Wash your hands. While Wearing the Patch: Do not put the patch on your lips or near your eyes. If you get medicine from the patch in your eye, rinse it with water until the numbness goes away. Do not cut or tear the patch. Do not get water on the patch. Keep the patch dry. Do not cover the small holes on the outside of the patch. If you applied the patch to the back of your hand, wash your hands carefully. If your skin hurts or burns too much, you should take the patch off. It is normal for the skin to feel warm, but it should not burn. After the patch is removed: Be careful with your skin after the patch is removed. The skin that was covered by the patch stays numb and you won't be able to feel pain right away. Do not scratch or let this skin touch hot or cold things.

SIDE EFFECTS Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 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). Most common adverse events in clinical trials Localized Reactions During or immediately after treatment with SYNERA, the skin at the site of treatment may develop erythema, blanching, edema, or abnormal sensation. In clinical studies involving 1449 SYNERA-treated subjects, the most common local reactions were erythema (71%), blanching (12%) and edema (12%). These reactions were generally mild, resolving spontaneously soon after patch removal. There were no treatment-related serious adverse events. Other application site reactions of various types (contact dermatitis, rash, skin discoloration) occurred in less than 4% of SYNERA-treated patients during clinical trials. Of these adverse events, 75% were mild, resolving spontaneously soon after patch removal. Application site-related adverse events that occurred in 1% or less of SYNERA-treated subjects included rash, pruritus, pain, contact dermatitis, infection, skin discoloration, allergic reaction, blister, paresthesia, urticaria, and vesiculobullous rash. Allergic Reactions Allergic or anaphylactoid reactions can occur with the active or inactive components of SYNERA. They may be characterized by urticaria, angioedema, bronchospasm, and shock. Allergic reactions to the patch should be managed by conventional means. Systemic (Dose-Related) Reactions Systemic adverse reactions that occurred in 1% or less of SYNERA-treated subjects included dizziness, headache, nausea, somnolence, and vomiting. Systemic adverse effects of lidocaine and tetracaine are similar in nature to those observed with other amide and ester 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. Signs of CNS toxicity may start at plasma concentrations of lidocaine as low as 1000 ng/mL. The plasma concentrations at which tetracaine toxicity may occur are less well characterized; however, systemic toxicity with tetracaine is thought to occur with much lower plasma concentrations compared with lidocaine. The toxicity of co-administered local anesthetics is thought to be at least additive. Cardiovascular manifestations may include bradycardia, hypotension and cardiovascular collapse leading to arrest. DRUG INTERACTIONS Antiarrhythmic Drugs SYNERA should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the systemic toxic effects are thought to be additive and potentially synergistic with lidocaine and tetracaine. Local Anesthetics When SYNERA is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations should be considered since the systemic toxic effects are thought to be additive and potentially synergistic with lidocaine and tetracaine.

SIDE EFFECTS Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. However, the adverse reaction information from clinical trials does provide a basis for identifying the adverse events that appear to be related to drug use and for approximating their incidence in clinical practice. PLIAGLIS Cream has been evaluated for safety in 2159 persons undergoing a superficial dermal procedure. PLIAGLIS Cream was studied in 11 placebo-controlled and 1 active-controlled trials, and in open-label safety trials. All 2159 persons were exposed to only a single application of PLIAGLIS Cream. Adverse reactions were assessed by collecting spontaneously reported adverse events, and observations made on formal evaluation of the skin for specific reactions. Most common adverse events in clinical trials Localized Reactions: During or immediately after treatment with PLIAGLIS Cream, the skin at the site of treatment may develop erythema, blanching or edema. In clinical studies, the most common local reactions were erythema (47%), skin discoloration (e.g., blanching, ecchymosis, and purpura) (16%), and edema (14%). There were no serious adverse events. However, one patient withdrew due to burning pain at the treatment site. Other Localized Reactions: The following dermal adverse events occurred in 1% or less of PLIAGLIS Cream -treated patients: ecchymosis, petechial rash, vesiculobullous rash, perifollicular erythema, perifollicular edema, pruritus, rash, maculopapular rash, dry skin, contact dermatitis, and acne. Systemic (Dose-Related) Reactions: Across all trials, 19 subjects experienced a systemic adverse event, 15 of who were treated with PLIAGLIS Cream and 4 with placebo. The frequency of systemic adverse events was greater for the PLIAGLIS Cream group (1%) than the placebo group (0.3%). The most common systemic adverse events were headache, vomiting, dizziness, and fever, all of which occurred with a frequency of < 1%. Other systemic reactions were syncope, nausea, confusion, dehydration, hyperventilation, hypotension, nervousness, paresthesia, pharyngitis, stupor, pallor, and sweating. Systemic adverse effects of lidocaine and tetracaine are similar in nature to those observed with other amide and ester local anesthetic agents, including CNS excitation and/or depression (light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensation 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. Signs of CNS toxicity may start at plasma concentrations of lidocaine at 1000 ng/mL. The plasma concentrations at which tetracaine toxicity may occur are less well characterized; however, systemic toxicity with tetracaine is thought to occur with much lower plasma concentrations compared with lidocaine. The toxicity of co-administered local anesthetics is thought to be at least additive. Cardiovascular manifestations may include bradycardia, hypotension and cardiovascular collapse leading to arrest. Postmarketing Experience The following adverse reactions have been identified during post-approval use of PLIAGLIS Cream. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Eye disorders: Eyelid swelling Skin: Pruritus, Rash, Skin Burning Sensation, Erythema, Urticaria Other: Drug ineffective DRUG INTERACTIONS Antiarrhythmic Drugs PLIAGLIS Cream should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the systemic toxic effects are thought to be additive and potentially synergistic with lidocaine and tetracaine. Local Anesthetics When PLIAGLIS Cream is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations should be considered since the systemic toxic effects are thought to be additive and potentially synergistic with lidocaine and tetracaine.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Overexposure Application of a SYNERA 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]. Storage And Disposal Used SYNERA patches contain 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. Avoidance Of Exposure To Eyes And Mucous Membranes Contact of SYNERA with the eyes should be avoided based on the findings of severe eye irritation with the use of similar products in animals. Also, the loss of protective reflexes may predispose to corneal irritation and potential abrasion. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns. SYNERA is not recommended for use on mucous membranes or on areas with a compromised skin barrier because these uses have not been studied. Application to broken or inflamed skin may result in toxic blood concentrations of lidocaine and tetracaine from increased absorption. Magnetic Resonance Imaging The integrated heating component contains iron powder; therefore, the SYNERA patch must be removed before a patient undergoes magnetic resonance imaging. Methemoglobinemia Several local anesthetics, including tetracaine, have been associated with methemoglobinemia. The risk of methemoglobinemia is greatest for patients with congenital or idiopathic methemoglobinemia, and infants under the age of twelve months who are receiving treatment with methemoglobin-inducing agents. Very young patients or patients with glucose-6-phosphate dehydrogenase deficiencies have an increased risk of methemoglobinemia. Patients taking concomitant drugs associated with drug-induced methemoglobinemia such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para-aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine are also at greater risk for developing methemoglobinemia. There have been no reports of methemoglobinemia with SYNERA. However, providers are cautioned to carefully apply SYNERA to ensure that the areas of application and duration of application are consistent with those recommended for the intended population. Allergic Reactions Allergic or anaphylactoid reactions associated with lidocaine, tetracaine, or other components of SYNERA can occur. They are characterized by urticaria, angioedema, bronchospasm, and shock. If an allergic reaction occurs, it should be managed by conventional means. Special Patient Populations SYNERA should be used with caution in patients who may be more sensitive to the systemic effects of lidocaine and tetracaine particularly the acutely ill or debilitated. Patients with severe hepatic disease or pseudocholinesterase deficiency, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations of lidocaine and tetracaine. Vaccinations Lidocaine has been shown to inhibit viral and bacterial growth. The effect of SYNERA on intradermal injections of live vaccines has not been determined. Patient Counseling Information Advise patients to read the FDA-approved patient labeling (Instructions for Use). Advise patients that SYNERA is a patch containing two medicines (lidocaine and tetracaine) that are known as local anesthetics, and a heating component. These medicines are used to lessen the pain associated with superficial venous access and superficial dermatological procedures such as excision, electrodessication and shave biopsy of skin lesions. Advise patients that SYNERA should be applied immediately after opening the pouch. Instruct patients to not cut or remove the top cover of the patch as this could result in thermal injury. Advise patients that keeping a patch on longer than recommended or applying multiple patches simultaneously or sequentially could result in systemic absorption sufficient to result in serious adverse effects that are typical of drugs in this class. Advise patients that the patch must be removed before magnetic resonance imaging. Advise patients that SYNERA is contraindicated in patients with a known history of sensitivity to lidocaine, tetracaine, local anesthetics of the amide or ester type, or any other component of the product and in patients with para-aminobenzoic acid (PABA) hypersensitivity. Advise patients that SYNERA should be used with caution in patients who may be more sensitive to the systemic effects of lidocaine and tetracaine, including the acutely ill, the debilitated, and those with compromised hepatic function. Patients with severe hepatic disease or pseudocholinesterase deficiency are at greater risk of developing toxic plasma concentrations. Advise patients that SYNERA should be used with caution in patients receiving class I antiarrhythmics and/or other local anesthetics, because the systemic toxic effects may be additive and potentially synergistic with lidocaine and tetracaine. Advise patients not to use SYNERA if they have a history of methemoglobinemia. Advise patients to avoid contact of SYNERA with the eyes due to potential irritation or abrasion. If contact occurs, immediately wash the eye with water or saline, and protect it until sensation returns. Advise patients that SYNERA should only be applied to intact skin. Inform patients that exposure of the skin to SYNERA may result in erythema, blanching and edema; these reactions are generally mild, resolving spontaneously soon after the patch is removed. Advise patients that SYNERA is not for use on mucous membranes or on areas with broken skin. Advise patients that if skin irritation or a burning sensation occurs during application, the product should be removed. Inform patients of the signs of an allergic or anaphylactoid reaction (urticaria, angioedema, bronchospasm, and shock). Instruct patients to seek immediate emergency help if these occur. Advise patients that SYNERA may lead to diminished or blocked sensation in the treated skin; therefore, patients should avoid inadvertent trauma (rubbing, scratching, or exposure to heat or cold) before complete sensation returns. Advise patients to contact their healthcare professional if they don't recall where to apply the patch. Instruct patients to store SYNERA and to discard used patches out of the reach of children and pets. The effect of SYNERA on intradermal injections of live vaccines has not been determined. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either lidocaine or tetracaine. Mutagenesis The mutagenic potential of lidocaine base and tetracaine base has been determined in the in vitro Ames Bacterial Reverse Mutation Assay, the in vitro chromosome aberration assay using Chinese hamster ovary cells, and the in vivo mouse micronucleus assay. Lidocaine was negative in all three assays. Tetracaine was negative in the in vitro Ames assay and the in vivo mouse micronucleus assay. In the in vitro chromosome aberration assay, tetracaine was negative in the absence of metabolic activation, and equivocal in the presence of metabolic activation. Impairment of Fertility Lidocaine did not affect fertility in female rats when given via continuous subcutaneous infusion via osmotic minipumps up to doses of 250 mg/kg/day (1500 mg/m² or 43-fold higher than the SDA). Although lidocaine treatment of male rats increased the copulatory interval and lead to a dose-related decreased homogenization resistant sperm head count, daily sperm production, and spermatogenic efficiency, the treatment did not affect overall fertility in male rats when given subcutaneous doses up to 60 mg/kg (360 mg/m² or 8-fold the SDA). Tetracaine did not affect fertility in male or female rats when given subcutaneous doses up to 7.5 mg/kg (45 mg/m² or 1-fold the SDA). Multiples of exposure are based on an SDA of 70 mg each of lidocaine and tetracaine in SYNERA patch for 30 minutes to a 60 kg person (43 mg/m²). Use In Specific Populations Pregnancy Pregnancy Category B Lidocaine was not teratogenic in rats given subcutaneous doses up to 60 mg/kg (360 mg/m² or 8-fold the Single Dermal Administration (SDA)) or in rabbits up to 15 mg/kg (180 mg/m² or 4-fold the SDA). Tetracaine was not teratogenic in rats given subcutaneous doses up to 10 mg/kg (60 mg/m² or 1-fold the SDA) or in rabbits up to 5 mg/kg (60 mg/m² or 1-fold the SDA). SYNERA components (lidocaine and tetracaine) given as a 1:1 eutectic mixture were not teratogenic in rats (60 mg/m² or 1-fold the SDA) or rabbits (120 mg/m² or 3-fold the SDA). Lidocaine, contained 1:100,000 epinephrine, at a dose of 6 mg/kg (2-fold the SDA) injected into the masseter muscle of the jaw or into the gum of the lower jaw of Long-Evans hooded pregnant rats on Gestation Day 11 led to developmental delays in neonatal behavior among offspring. Developmental delays were observed for negative geotaxis, static righting reflex, visual discrimination response, sensitivity and response to thermal and electrical shock stimuli, and water maze acquisition. The developmental delays of the neonatal animals were transient with responses becoming comparable to untreated animals later in life. The clinical relevance of the animal data is uncertain. Pre-and postnatal maturational, behavioral, or reproductive development was not affected by maternal subcutaneous administration of tetracaine during gestation and lactation up to doses of 7.5 mg/kg (45 mg/m² or 1-fold the SDA). No adequate and well-controlled studies have been conducted in pregnant women. Because animal studies are not always predictive of human response, SYNERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor And Delivery Neither lidocaine nor tetracaine is contraindicated in labor and delivery. In humans, the use of lidocaine for labor neuraxial analgesia has not been associated with an increased incidence of adverse fetal effects either during delivery or during the neonatal period. Tetracaine has also been used as a neuraxial anesthetic for cesarean section without apparent adverse effects on offspring. Should SYNERA be used concomitantly with other products containing lidocaine and/or tetracaine, total doses contributed by all formulations must be considered. Nursing Mothers Lidocaine is excreted into human milk and it is not known if tetracaine is excreted into human milk. Therefore, caution should be exercised when SYNERA is administered to a nursing mother since the milk:plasma ratio of lidocaine is 0.4 and is not determined for tetracaine. In a prior report, when lidocaine was used as an epidural anesthetic for cesarean section in 27 women, a milk:plasma ratio of 1.07 ±0.82 was found by using AUC values. Following single dose administration of 20 mg of lidocaine for a dental procedure, the point value milk: plasma ratio was similarly reported as 1.1 at five to six hours after injection. Thus, the estimated maximum total daily dose of lidocaine delivered to the infant via breast milk would be approximately 36 μg/kg. Based on these data and the low concentrations of lidocaine and tetracaine found in the plasma after topical administration of SYNERA in recommended doses, the small amount of these primary compounds and their metabolites that would be ingested orally by a suckling infant is unlikely to cause adverse effects [see CLINICAL PHARMACOLOGY]. Pediatric Use The safety and effectiveness of SYNERA have been established in pediatric patients 3 years and older based on adequate and well-controlled studies [see Clinical Studies]. While efficacy has not been established for children less than 3 years of age, the safety of SYNERA in infants has been evaluated in one study in which 34 infants 4 to 6 months of age received SYNERA. The recommended application time for the patch for pediatric patients is the same as for adults. Simultaneous or sequential application of more than two SYNERA patches to children is not recommended as it has not been adequately studied. Use In Geriatric Patients In the controlled clinical studies, 139 patients over 65 years of age, including 41 patients over 75 years of age, received SYNERA. Visual Analog Scale (VAS) pain score differences between SYNERA and placebo were considerably lower in the geriatric subjects than in the rest of the adult population. No overall differences in safety were observed between geriatric subjects and younger subjects. However, increased sensitivity in individual patients greater than 65 years of age cannot be ruled out. After intravenous dosing, the elimination half-life of lidocaine is significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours).

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Overexposure Application of PLIAGLIS Cream for longer times than those recommended or application of PLIAGLIS Cream over larger surface areas than those recommended could result in absorption of lidocaine and tetracaine at doses that could lead to serious adverse effects [see OVERDOSAGE]. When PLIAGLIS Cream is used concomitantly with other products containing local anesthetic agents, consider the amount absorbed from all formulations since the systemic toxic effects are thought to be additive and potentially synergistic with lidocaine and tetracaine. PLIAGLIS Cream is not recommended for use on mucous membranes or on areas with a compromised skin barrier because these uses have not been adequately studied. Application to broken or inflamed skin may result in toxic blood concentrations of lidocaine and tetracaine from increased absorption. Use PLIAGLIS Cream with caution in patients who may be more sensitive to the systemic effects of lidocaine and tetracaine, including the acutely ill or debilitated. Risks of Secondary Exposure to Children and Pets Used PLIAGLIS Cream contains a large amount of lidocaine and tetracaine. The potential exists for a small child or pet to suffer serious adverse effects from ingesting PLIAGLIS Cream, although this risk with PLIAGLIS Cream has not been evaluated. After use, replace the child-proof cap securely on the tube. It is important to store and dispose of PLIAGLIS Cream out of the reach of children and pets. Methemoglobinemia Several local anesthetics, including tetracaine, have been associated with methemoglobinemia. The risk of methemoglobinemia is greatest for patients with congenital or idiopathic methemoglobinemia, and infants under the age of twelve months who are receiving treatment with methemoglobininducing agents. Very young patients or patients with glucose-6-phosphate dehydrogenase deficiencies are more susceptible to methemoglobinemia. Patients taking concomitant drugs associated with drug-induced methemoglobinemia such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para-aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine are also at greater risk for developing methemoglobinemia. There were no reports of methemoglobinemia in the trials of PLIAGLIS Cream; however, providers are cautioned to carefully apply PLIAGLIS Cream to ensure that the doses, areas of application, and duration of application are consistent with those recommended for the intended population. Allergic Reactions Allergic or anaphylactoid reactions associated with lidocaine, tetracaine, or other components of PLIAGLIS Cream can occur. They are characterized by urticaria, angioedema, bronchospasm, and shock. If an allergic reaction occurs, it should be managed by conventional means. PLIAGLIS is contraindicated in patients with known hypersensitivity reactions to lidocaine, tetracaine, or local anesthetics of the amide or ester type. Eye Irritation Avoid contact of PLIAGLIS Cream with the eyes based on the findings of severe eye irritation with the use of similar products in animals. Also, the loss of protective reflexes may predispose to corneal irritation and potential abrasion. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns. Vaccinations Lidocaine has been shown to inhibit viral and bacterial growth. The effect of PLIAGLIS Cream on intradermal injections of live vaccines has not been determined. Special patient populations Use PLIAGLIS Cream with caution in patients who may be more sensitive to the systemic effects of lidocaine and tetracaine particularly the acutely ill or debilitated. Patients with severe hepatic disease or pseudocholinesterase deficiency, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations of lidocaine and tetracaine. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either lidocaine or tetracaine. Mutagenesis The mutagenic potential of lidocaine base and tetracaine base has been determined in the in vitro Ames bacterial reverse mutation assay, the in vitro chromosome aberration assay using Chinese hamster ovary cells, and the in vivo mouse micronucleus assay. Lidocaine was negative in all three assays. Tetracaine was negative in the in vitro Ames assay and the in vivo mouse micronucleus assay. In the in vitro chromosome aberration assay, tetracaine was negative in the absence of metabolic activation, and equivocal in the presence of metabolic activation. Impairment Of Fertility Lidocaine did not affect fertility in female rats when given via continuous subcutaneous infusion via osmotic minipumps up to doses of 250 mg/kg/day (35-fold higher than the level of lidocaine contained in the lowest approved dose of PLIAGLIS Cream based on a mg/m² body surface area comparison). Lidocaine treatment did not affect overall fertility in male rats when given as subcutaneous doses up to 60 mg/kg (8-fold higher than the level of lidocaine contained in the lowest approved dose of PLIAGLIS Cream based on a mg/m² basis), although the treatment caused an increased copulatory interval and led to a dose-related decrease in homogenization resistant sperm head count, daily sperm production, and spermatogenic efficiency. Tetracaine did not affect fertility in male or female rats when given as subcutaneous doses up to 7.5 mg/kg (equivalent to the level of tetracaine in the lowest approved dose of PLIAGLIS Cream on a mg/m²basis). Use In Specific Populations Pregnancy Pregnancy Category B No adequate and well-controlled studies have been conducted in pregnant women. PLIAGLIS Cream should be used during pregnancy only if the potential benefit justifies risk to the fetus. Lidocaine was not teratogenic in rats at doses up to 60 mg/kg (8-fold higher than the level of lidocaine contained in the lowest approved dose of PLIAGLIS Cream based on a mg/m² body surface area comparison). Lidocaine was not teratogenic in rabbits at doses up to 15 mg/kg (4-fold higher than the level of lidocaine in the lowest approved dose of PLIAGLIS Cream on a mg/m²basis). Tetracaine was not teratogenic in rats given subcutaneous doses up to 10 mg/kg or in rabbits up to 5 mg/kg (equivalent to the level of tetracaine in the lowest approved dose of PLIAGLIS Cream on a mg/m² basis). Lidocaine and tetracaine given as a 1:1 eutectic mixture of 10 mg/kg each was not teratogenic in rats (equivalent to the level of the active components in the lowest approved dose of PLIAGLIS Cream on a mg/m² basis. Lidocaine and tetracaine given as a 1:1 eutectic mixture of 5 mg/kg each was not teratogenic in rabbits (equivalent to the level of the active components in the lowest approved dose of PLIAGLIS Cream on a mg/m² basis). Lidocaine containing 1:100,000 epinephrine at a dose of 6 mg/kg (approximately equivalent to the level of lidocaine in the lowest approved dose PLIAGLIS Cream on a mg/m² basis) injected into the masseter muscle of the jaw or into the gum of the lower jaw of pregnant Long-Evans hooded rats on gestation day 11, lead to developmental delays in neonatal behavior among offspring. Developmental delays were observed for negative geotaxis, static righting reflex, visual discrimination response, sensitivity and response to thermal and electrical shock stimuli, and water maze acquisition. The developmental delays of the neonatal animals were transient with responses becoming comparable to untreated animals later in life. The clinical relevance of the animal data is uncertain. Pre-and post-natal maturational, behavioral, or reproductive development was not affected by maternal subcutaneous administration of tetracaine during gestation and lactation up to doses of 7.5 mg/kg (equivalent to the level of tetracaine in the lowest approved dose of PLIAGLIS Cream on a mg/m² basis). Labor And Delivery Neither lidocaine nor tetracaine is contraindicated in labor and delivery. In humans, the use of lidocaine for labor neuraxial analgesia has not been associated with an increased incidence of adverse fetal effects either during delivery or during the neonatal period. Tetracaine has also been used as a neuraxial anesthetic for cesarean section without apparent adverse effects on offspring. Should PLIAGLIS Cream be used concomitantly with other products containing lidocaine and/or tetracaine, total doses contributed by all formulations must be considered. Nursing Mothers Lidocaine is excreted into human milk and it is not known if tetracaine is excreted into human milk. Therefore, caution should be exercised when PLIAGLIS Cream is administered to a nursing mother since the milk:plasma ratio of lidocaine is 0.4 and is not determined for tetracaine. In a prior report, when lidocaine was used as an epidural anesthetic for cesarean section in 27 women, a milk:plasma ratio of 1.07 ±0.82 was found by using AUC values. Following single dose administration of 20 mg of lidocaine for a dental procedure, the point value milk:plasma ratio was similarly reported as 1.1 at five to six hours after injection. Thus, the estimated maximum total daily dose of lidocaine delivered to the infant via breast milk would be approximately 36 mcg/kg. Based on these data and the low concentrations of lidocaine and tetracaine found in the plasma after topical administration of PLIAGLIS Cream in recommended doses, the small amount of these primary compounds and their metabolites that would be ingested orally by a suckling infant is unlikely to cause adverse effects [see CLINICAL PHARMACOLOGY]. Pediatric Use Safety and effectiveness of PLIAGLIS Cream in pediatric patients have not been established. Unintended exposure in pediatric patients could possibly lead to serious adverse effects [see WARNINGS AND PRECAUTIONS]. In a trial of PLIAGLIS Cream in pediatric patients aged 5-17 years undergoing venipuncture (blood draw or intravenous line placement), PLIAGLIS Cream applied for 30 minutes failed to show efficacy over placebo in reducing the pain associated with the procedure. Geriatric Use Of the total number of subjects treated with PLIAGLIS Cream in controlled clinical studies, 161 subjects were 65 years and older, while 50 subjects were over 75 years of age. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. However, increased sensitivity in individual patients aged 65 years and older cannot be ruled out [see CLINICAL PHARMACOLOGY].