5.1 Methemoglobinemia

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue SYNERA and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

5.2 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 ( 10)] .

5.3 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.

5.4 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.

5.5 Magnetic Resonance Imaging

The integrated heating component contains iron powder; therefore, the SYNERA patch must be removed before a patient undergoes magnetic resonance imaging.

5.6 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.

5.7 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.

5.8 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.

6.1 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).

7.1 Drugs That May Cause Methemoglobinemia When Used with SYNERA

Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:

7.2 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.

7.3 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.

8.1 Pregnancy

8.2 Lactation

8.4 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 ( 14)] . 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.

8.5 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).

12.1 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.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Superficial Venous Access

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. In all three studies pain was measured by a 100-mm VAS in which a lower VAS score corresponds to less pain. In the first study in 21 subjects, median VAS scores for SYNERA and placebo treatments were 1 mm and 9 mm, respectively. In the second study in 40 subjects, median VAS scores were 5 mm and 28 mm 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 mm and 14 mm, 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 on IV cannulation 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 an eleven-point Oucher pain scale that contained both faces and numbers. Pain scores on IV cannulation in the older children treated with SYNERA were not 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 SYNERA with heating element, prior to venipuncture. Median VAS scores for the patch with the heating element and without the heating element were 17 mm and 22 mm, respectively.

14.2 Superficial Dermatological Procedures

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. Median VAS scores for SYNERA and placebo treatments were 5 mm and 31 mm, 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 mm and 23 mm, 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 patch, 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.

16.1 How Supplied

SYNERA is available as the following:

16.2 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.