(lidocaine and tetracaine)
[Galderma Laboratories, L.P.]
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 tube.
Lidocaine 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 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 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, sorbitan monopalmitate and water.
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 provides local dermal analgesia by the release of lidocaine and tetracaine from the peel into the skin.
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 application periods with respect to the mean for time to return of sensation. However, 55% of PLIAGLIS treated subjects still reported diminished sensation at the end of the 13-hour study period.
Absorption: The amount of lidocaine and tetracaine systemically absorbed from PLIAGLIS is directly related to both the duration of application and the surface area over which it is applied, Table 1. Application of 59 g of PLIAGLIS 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 (< 0.9ng/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.
|PLIAGLIS (g)||Area (cm2)||Age Range (yr)||n||Application Time (min)||Drug Content (g)||
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. 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 810 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.
Elderly: After application of 31g of PLIAGLIS 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.
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
In four clinical trials, adult patients were treated with PLIAGLIS and/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 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 2.
|Mean VAS score|
|20 Min Application
Pulsed Dye Laser Therapy (N=80)
|30 Min Application
Non-Abrasive Laser Facial Resurfacing (N=54)
Dermal Filler Injections (N=70)
|60 Min Application
Laser-Assisted Tattoo Removal (N=62)
In a trial of PLIAGLIS in pediatric patients aged 5-17 years undergoing venipuncture (blood draw or intravenous line placement), PLIAGLIS applied for 30 minutes failed to show efficacy over placebo in reducing the pain associated with the procedure.
PLIAGLIS 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.
PLIAGLIS is contraindicated in patients with a known history of sensitivity to lidocaine or tetracaine, or local anesthetics of the amide or ester type. PLIAGLIS is also contraindicated in patients with para-aminobenzoic acid (PABA) hypersensitivity and in patients with a known history of sensitivity to any other component of the product.
Application of PLIAGLIS for longer times than those recommended or application of PLIAGLIS 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 section).
Even used PLIAGLIS may contain a large amount of lidocaine and tetracaine. The potential exists for a small child or pet to suffer serious adverse effects from chewing or ingesting new or used PLIAGLIS, although this risk with PLIAGLIS has not been evaluated. After use, the cap should be put back securely on the tube. It is important to store and dispose of PLIAGLIS out of the reach of children and pets (see HANDLING AND DISPOSAL section).
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 are more susceptible to methemoglobinemia.
Patients taking 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. However, providers are cautioned to carefully apply PLIAGLIS to ensure that the doses, areas of application, and duration of application are consistent with those recommended for the intended population.
PLIAGLIS should be used with caution in patients who may be more sensitive to the systemic effects of lidocaine and tetracaine, including the acutely ill or debilitated.
When PLIAGLIS 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.
Allergic or anaphylactoid reactions associated with lidocaine, tetracaine, or other components of PLIAGLIS can occur. They are characterized by urticaria, angioedema, bronchospasm, and shock. If an allergic reaction occurs, it should be managed by conventional means.
Contact of PLIAGLIS 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.
PLIAGLIS 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.
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.
Lidocaine has been shown to inhibit viral and bacterial growth. The effect of PLIAGLIS on intradermal injections of live vaccines has not been determined.
Patients should be advised that topical application of local anesthetics such as PLIAGLIS may lead to diminished or blocked sensation in the treated skin. For this reason, patients should be instructed to avoid trauma to the treated area. Trauma can result from scratching or rubbing before complete sensation has returned, or from exposure to extreme temperatures or to excessive sunlight.
Antiarrhythmic Drugs: PLIAGLIS 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 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.
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 2-fold higher than the single dermal administration [SDA]). Although lidocaine treatment of male rats increased the copulatory interval and led 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 <1-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 1 g of PLIAGLIS applied to 10 cm2 for 60 minutes to a 60 kg person (645 mg/m2).
Teratogenic Effects: Pregnancy Category B. Lidocaine was not teratogenic in rats at doses up to 60 mg/kg (360 mg/m2 or <1-fold the SDA), nor in rabbits at doses up to 15 mg/kg (180 mg/m2 or <1-fold the SDA). Tetracaine was not teratogenic in rats given subcutaneous doses up to 10 mg/kg (60 mg/m2), nor in rabbits at doses up to 5 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). PLIAGLIS active components (lidocaine and tetracaine given as a 1:1 eutectic mixture) was not teratogenic in rats (60 mg/m2 or <1-fold the SDA) or rabbits (120 mg/m2 or <1- fold the SDA).
Lidocaine containing 1:100,000 epinephrine at a dose of 6 mg/kg (<1-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, 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 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, PLIAGLIS should be used during pregnancy only if the potential benefit justifies risk to the fetus.
Neither lidocaine nor tetracaine is contraindicated in labor and delivery. In humans, the use of lidocaine for labor conduction 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 conduction anesthetic for cesarean section without apparent adverse effects on offspring. Should PLIAGLIS 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 PLIAGLIS 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 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, Pharmacokinetics).
Of the total number of subjects treated with PLIAGLIS 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.
PLIAGLIS has been evaluated for safety in 2159 persons undergoing a superficial dermal procedure. PLIAGLIS 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.
Adverse reactions were assessed by collecting spontaneously reported adverse events, and observations made on formal evaluation of the skin for specific reactions. Because clinical trials are conducted under widely varying conditions, the frequencies of adverse reactions observed in the clinical trials of a drug may not reflect the frequencies 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.
Most common adverse events in clinical trials
Localized Reactions: During or immediately after treatment with PLIAGLIS, 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%). These reactions were generally mild and transient, resolving spontaneously soon after treatment. 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-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 and 4 with placebo. The frequency of systemic adverse events was greater for the PLIAGLIS 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.
Overall, systemic adverse reactions following appropriate use of PLIAGLIS are unlikely, due to the small dose absorbed (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
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 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.
Application of 59 g of PLIAGLIS over 400 cm2 for up to 120 minutes to adults produces peak plasma concentrations of lidocaine of 220 ng/mL. Toxic levels of lidocaine (>5000 ng/mL) cause CNS toxicity, including the risk of seizure. 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 or tetracaine.
PLIAGLIS should only be applied to intact skin.
For use in adults only.
• For superficial dermatological procedures such as dermal filler injection or facial laser ablation, apply PLIAGLIS to intact skin for 20-30 minutes prior to the procedure. See Table 3 for instructions on the amount to apply.
• For superficial dermatological procedures such as laser-assisted tattoo removal, apply PLIAGLIS to intact skin for 60 minutes prior to the procedure. See Table 3 for instructions on the amount to apply.
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 section). The dose of PLIAGLIS 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.
Determine the amount of drug to apply
The amount (length) of PLIAGLIS that should be dispensed is determined by the size of the area to be treated (see Table 3). Using the ruler supplied on the carton and in the DOSAGE AND ADMINISTRATION section, squeeze out and measure the amount of PLIAGLIS that approximates the amount required to achieve proper coverage. Then spread PLIAGLIS 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 by grasping a free-edge with your fingers and pulling it away from the skin.
|Surface Area of Treatment Site (cm2)||Length of PLIAGLIS for 1 mm Thickness (cm)||Weight of PLIAGLIS Dispensed (g)|
If skin irritation or a burning sensation occurs during application, remove PLIAGLIS.
Upon removal from the treatment site, discard the used PLIAGLIS in a location that is out of the reach of children and pets.
Hands should be washed after handling PLIAGLIS, and eye contact with PLIAGLIS should be avoided. Access to PLIAGLIS by children or pets should be prevented during usage and storage of the product.
Used PLIAGLIS tubes should be disposed of immediately. Discard used PLIAGLIS in a location that prevents accidental ingestion by children or pets.
PLIAGLIS (lidocaine and tetracaine) Cream 7% / 7% 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°C to 8°C (36° to 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.
GALDERMA LABORATORIES, L.P. Fort Worth, Texas 76177 USA
G Production Inc., Baie d’Urfé, QC, H9X 3S4 Canada
Made in Canada.
GALDERMA and PLIAGLIS are registered trademarks.
© Copyright 2012 Galderma www.pliaglis.com P50805-1 Revised 08/12
Rx only NDC 0299-6100-30
Pliaglis® (lidocaine and tetracaine) Cream 7% / 7% For topical use only.
Net Wt. 30 g
Ruler to be used for Pliaglis dosing. See Dosage and Administration for directions.
Usual Dosage: Apply to intact skin. See package insert for full prescribing information and directions for use. Use the supplied ruler on the carton for dosing.
Contains: Each gram of cream contains 70 mg of lidocaine (net weight: 2.1 g) and 70 mg of tetracaine (net weight: 2.1 g) and the following inactive ingredients: dibasic calcium phosphate, methylparaben, petrolatum, polyvinyl alcohol, propylparaben, purified water, and sorbitan monopalmitate.
GALDERMA LABORATORIES, L.P.
Fort Worth, Texas 76177 USA
G Production Inc. Baie d’Urfé, QC, H9X 3S4 Canada
Made in Canada.
GALDERMA and PLIAGLIS are registered trademarks.
To Open Tube: Push cap in and turn clockwise.
Not for home use by patient.
Warning: Keep used and unused product out of reach of children.
Wash hands after use. Avoid contact with eyes.
Refrigerate at 2°C to 8°C (36°F to 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.
lidocaine and tetracaine cream
|Labeler - Galderma Laboratories, L.P. (047350186)|
|G Production Inc.||251676961||manufacture(0299-6100)|