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SYNERA®
(lidocaine and tetracaine) 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:
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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:
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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.
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].
SYNERA should only be applied to intact skin. Use immediately after opening the pouch.
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.
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
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
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).
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 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 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.
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.
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.
Included as part of the PRECAUTIONS section.
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].
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.
The integrated heating component contains iron powder; therefore, the SYNERA patch must be removed before a patient undergoes magnetic resonance imaging.
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.
Lidocaine has been shown to inhibit viral and bacterial growth. The effect of SYNERA on intradermal injections of live vaccines has not been determined.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either lidocaine or tetracaine.
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.
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).
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.
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.
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].
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.
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).
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 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.
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 |
