Emla (Lidocaine and Prilocaine): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Emla

EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 1:1 by weight. This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather than as crystals. It is packaged in 5 gram and 30 gram tubes.

Lidocaine is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl), has an octanol: water partition ratio of 43 at pH 7.4, and has the following structure:

Prilocaine is chemically designated as propanamide, N-(2-methylphenyl)-2-(propylamino), has an octanol: water partition ratio of 25 at pH 7.4, and has the following structure:

Each gram of EMLA (lidocaine and prilocaine) Cream contains lidocaine 25 mg, prilocaine 25 mg, polyoxyethylene fatty acid esters (as emulsifiers), carboxypolymethylene (as a thickening agent), sodium hydroxide to adjust to a pH approximating 9, and purified water to 1 gram. EMLA (lidocaine and prilocaine) Cream contains no preservative, however it passes the USP antimicrobial effectiveness test due to the pH. The specific gravity of EMLA (lidocaine and prilocaine) Cream is 1.00.

Uses for Emla

EMLA Cream (a eutectic mixture of lidocaine 2.5% and prilocaine 2.5%) is indicated as a topical anesthetic foruse on:

• normal intact skin for local analgesia.
• genital mucous membranes for superficial minor surgery and as pretreatment for infiltration anesthesia.

EMLA Cream is not recommended in any clinical situation when penetration or migration beyond the tympanicmembrane into the middle ear is possible because of the ototoxic effects observed in animal studies (see WARNINGS).

Dosage for Emla

Adult Patients-Intact Skin

A thick layer of EMLA Cream is applied to intact skin and covered with an occlusive dressing (seeInstructions For Application).

Minor Dermal Procedures

For minor procedures such as intravenous cannulation and venipuncture, apply2.5 grams of EMLA Cream (1/2 the 5 g tube) over 20 to 25 cm² of skin surface for at least 1 hour. Incontrolled clinical trials using EMLA Cream, two sites were usually prepared in case there was a technicalproblem with cannulation or venipuncture at the first site.

Major Dermal Procedures

For more painful dermatological procedures involving a larger skin area suchas split thickness skin graft harvesting, apply 2 grams of EMLA Cream per 10 cm² of skin and allow toremain in contact with the skin for at least 2 hours.

Adult Male Genital Skin

As an adjunct prior to local anesthetic infiltration, apply a thick layer of EMLACream (1 g/10 cm²) to the skin surface for 15 minutes. Local anesthetic infiltration should be performedimmediately after removal of EMLA Cream.

Dermal analgesia can be expected to increase for up to 3 hours under occlusive dressing and persist for 1 to 2hours after removal of the cream. The amount of lidocaine and prilocaine absorbed during the period ofapplication can be estimated from the information in Table 2,

** footnote, in Individualization of Dose.

Adult Female Patients-Genital Mucous Membranes

For minor procedures on the female external genitalia, such as removal of condylomata acuminata, as well asfor use as pretreatment for anesthetic infiltration, apply a thick layer (5 to 10 grams) of EMLA Cream for 5 to10 minutes.

Occlusion is not necessary for absorption, but may be helpful to keep the cream in place. Patients should belying down during the EMLA Cream application, especially if no occlusion is used. The procedure or the localanesthetic infiltration should be performed immediately after the removal of EMLA Cream.

Pediatric Patients-Intact Skin

The following are the maximum recommended doses, application areas and application times for EMLA Creambased on a child's age and weight:

Please note: If a patient greater than 3 months old does not meet the minimum weight requirement, themaximum total dose of EMLA Cream should be restricted to that which corresponds to the patient’s weight(see Instructions For Application).

Practitioners should carefully instruct caregivers to avoid application of excessive amounts of EMLA Cream(see PRECAUTIONS).

When applying EMLA Cream to the skin of young children, care must be taken to maintain careful observationof the child to prevent accidental ingestion of EMLA Cream or the occlusive dressing. A secondary protectivecovering to prevent inadvertent disruption of the application site may be useful.

EMLA Cream should not be used in neonates with a gestational age less than 37 weeks nor in infantsunder the age of 12 months who are receiving treatment with methemoglobin-inducing agents (seeMethemoglobinemia subsection of WARNINGS).

When EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is used concomitantly with other productscontaining local anesthetic agents, the amount absorbed from all formulations must be considered (seeIndividualization Of Dose). The amount absorbed in the case of EMLA Cream is determined by the area overwhich it is applied and the duration of application under occlusion (see Table 2, ** footnote, in Individualizationof Dose).

Although the incidence of systemic adverse reactions with EMLA Cream is very low, caution should beexercised, particularly when applying it over large areas and leaving it on for longer than 2 hours. The incidenceof systemic adverse reactions can be expected to be directly proportional to the area and time of exposure (seeIndividualization Of Dose).

Instructions For Application

To measure 1 gram of EMLA, the cream should be gently squeezed out of the tube as a narrow strip that is 1.5inches (3.8 cm) long and 0.2 inches (5 mm) wide. The strip of EMLA Cream should be contained within thelines of the diagram shown below.

Use the number of strips that equals your dose, like the examples in the table below.

For adult and pediatric patients, apply ONLY as prescribed by your physician.

If your child is below the age of 3 months or small for their age, please inform your doctor before applyingEMLA Cream, which can be harmful, if applied over too much skin at one time in young children.

When applying EMLA Cream to the intact skin of young children, it is important that they be carefullyobserved by an adult in order to prevent the accidental ingestion of or eye contact with EMLA Cream.

EMLA Cream must be applied to intact skin at least 1 hour before the start of a routine procedure and for 2hours before the start of a painful procedure. A protective covering of the cream is not necessary for absorptionbut may be helpful to keep the cream in place.

If using a protective covering, your doctor will remove it, wipe off the EMLA Cream, and clean the entire areawith an antiseptic solution before the procedure. The duration of effective skin anesthesia will be at least 1 hourafter removal of the protective covering.

Precautions

1. Do not apply near eyes or open wounds.
2. Keep out of the reach of children.
3. If your child becomes very dizzy, excessively sleepy, or develops duskiness of the face or lips after applyingEMLA Cream, remove the cream and contact the child's physician at once.

HOW SUPPLIED

EMLA Cream is available as the following:

Not For Ophthalmic Use.

KEEP CONTAINER TIGHTLY CLOSED AT ALL TIMES WHEN NOT IN USE.

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature].

Manufactured By: IGI Laboratories Inc. Buena, NJ 08310 USA. Revised Nov 2018

Side Effects for Emla

Localized Reactions

During or immediately after treatment with EMLA Cream on intact skin, the skin at thesite of treatment may develop erythema or edema or may be the locus of abnormal sensation. Rare cases ofdiscrete purpuric or petechial reactions at the application site have been reported. Rare cases ofhyperpigmentation following the use of EMLA Cream have been reported. The relationship to EMLA Cream orthe underlying procedure has not been established. In clinical studies on intact skin involving over 1,300 EMLACream-treated subjects, one or more such local reactions were noted in 56% of patients, and were generallymild and transient, resolving spontaneously within 1 or 2 hours. There were no serious reactions that wereascribed to EMLA Cream.

Two recent reports describe blistering on the foreskin in neonates about to undergo circumcision. Both neonatesreceived 1.0 g of EMLA Cream.

In patients treated with EMLA Cream on intact skin, local effects observed in the trials included: paleness(pallor or blanching) 37%, redness (erythema) 30%, alterations in temperature sensations 7%, edema 6%,itching 2% and rash, less than 1%.

In clinical studies on genital mucous membranes involving 378 EMLA Cream-treated patients, one or moreapplication site reactions, usually mild and transient, were noted in 41% of patients. The most commonapplication site reactions were redness (21%), burning sensation (17%) and edema (10%).

Allergic Reactions

Allergic and anaphylactoid reactions associated with lidocaine or prilocaine can occur.They are characterized by urticaria, angioedema, bronchospasm, and shock. If they occur they should bemanaged by conventional means. The detection of sensitivity by skin testing is of doubtful value.

Systemic (Dose Related) Reactions

Systemic adverse reactions following appropriate use of EMLA Creamare unlikely due to the small dose absorbed (see Pharmaco*kinetics subsection of CLINICALPHARMACOLOGY). Systemic adverse effects of lidocaine and/or prilocaine are similar in nature to thoseobserved with other amide local anesthetic agents including CNS excitation and/or depression (lightheadedness,nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or doublevision, 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 thefirst manifestation may be drowsiness merging into unconsciousness. Cardiovascular manifestations mayinclude bradycardia, hypotension and cardiovascular collapse leading to arrest.

Drug Interactions for Emla

EMLA Cream should be used with caution in patients receiving Class I antiarrhythmicdrugs (such as tocainide and mexiletine) since the toxic effects are additive and potentially synergistic.

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

Examples of Drugs Associated with Methemoglobinemia:

Specific interaction studies with lidocaine/prilocaine and class III anti-arrhythmic drugs (e.g., amiodarone,bretylium, sotalol, dofetilide) have not been performed, but caution is advised (see WARNINGS).

Should EMLA Cream be used concomitantly with other products containing lidocaine and/or prilocaine,cumulative doses from all formulations must be considered.

Warnings for Emla

Application of EMLA Cream to larger areas or for longer times than those recommended could result insufficient absorption of lidocaine and prilocaine resulting in serious adverse effects (see Individualization OfDose).

Patients treated with class III anti-arrhythmic drugs (e.g., amiodarone, bretylium, sotalol, dofetilide) should beunder close surveillance and ECG monitoring considered, because cardiac effects may be additive.

Studies in laboratory animals (guinea pigs) have shown that EMLA Cream has an ototoxic effect when instilledinto the middle ear. In these same studies, animals exposed to EMLA Cream only in the external auditory canal,showed no abnormality. EMLA Cream should not be used in any clinical situation when its penetration ormigration beyond the tympanic membrane into the middle ear is possible.

Methemoglobinemia

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

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

Precautions for Emla

General

Repeated doses of EMLA Cream may increase blood levels of lidocaine and prilocaine. EMLACream should be used with caution in patients who may be more sensitive to the systemic effects of lidocaineand prilocaine including acutely ill, debilitated, or elderly patients.

EMLA Cream should not be applied to open wounds.

Care should be taken not to allow EMLA Cream to come in contact with the eye because animal studies havedemonstrated severe eye irritation. Also the loss of protective reflexes can permit corneal irritation and potentialabrasion. Absorption of EMLA Cream in conjunctival tissues has not been determined. If eye contact occurs,immediately wash out the eye with water or saline and protect the eye until sensation returns.

Patients allergic to paraaminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not showncross sensitivity to lidocaine and/or prilocaine, however, EMLA Cream should be used with caution in patientswith a history of drug sensitivities, especially if the etiologic agent is uncertain.

Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are atgreater risk of developing toxic plasma concentrations of lidocaine and prilocaine.

Lidocaine and prilocaine have been shown to inhibit viral and bacterial growth. The effect of EMLA Cream onintradermal injections of live vaccines has not been determined.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies in animals designed to evaluate the carcinogenic potential of lidocaine andprilocaine have not been conducted.

Metabolites of prilocaine have been shown to be carcinogenic in laboratory animals. In the animal studiesreported below, doses or blood levels are compared with the Single Dermal Administration (SDA) of 60 g ofEMLA Cream to 400 cm² for 3 hours to a small person (50 kg). The typical application of EMLA Cream forone or two treatments for venipuncture sites (2.5 or 5 g) would be 1/24 or 1/12 of that dose in an adult or aboutthe same mg/kg dose in an infant.

Chronic oral toxicity studies of ortho-toluidine, a metabolite of prilocaine, in mice (450 to 7200 mg/m²; 60 to960 times SDA) and rats (900 to 4,800 mg/m²; 60 to 320 times SDA) have shown that ortho-toluidine is acarcinogen in both species. The tumors included hepatocarcinomas/adenomas in female mice, multipleoccurrences of hemangiosarcomas/ hemangiomas in both sexes of mice, sarcomas of multiple organs,transitional-cell carcinomas/ papillomas of urinary bladder in both sexes of rats, subcutaneousfibromas/fibrosarcomas and mesotheliomas in male rats, and mammary gland fibroadenomas/adenomas infemale rats. The lowest dose tested (450 mg/m² in mice, 900 mg/m² in rats; 60 times SDA) was carcinogenic inboth species. Thus the no-effect dose must be less than 60 times SDA. The animal studies were conducted at150 to 2,400 mg/kg in mice and at 150 to 800 mg/kg in rats. The dosages have been converted to mg/m² for theSDA calculations above.

Mutagenesis

The mutagenic potential of lidocaine HCl has been tested in a bacterial reverse (Ames) assay inSalmonella, an in vitro chromosomal aberration assay using human lymphocytes and in an in vivo micronucleustest in mice. There was no indication of mutagenicity or structural damage to chromosomes in these tests.

Ortho-toluidine, a metabolite of prilocaine, at a concentration of 0.5 μg/mL, was genotoxic in Escherichia coliDNA repair and phage-induction assays. Urine concentrates from rats treated with ortho-toluidine (300 mg/kgorally; 300 times SDA) were mutagenic when examined in Salmonella typhimurium in the presence ofmetabolic activation. Several other tests on ortho-toluidine, including reverse mutations in five differentSalmonella typhimurium strains in the presence or absence of metabolic activation and a study to detect singlestrand breaks in DNA of V79 Chinese hamster cells, were negative.

Impairment Of Fertility

See Use In Pregnancy.

Use In Pregnancy

Teratogenic Effects

Pregnancy Category B.

Reproduction studies with lidocaine have been performed in rats and have revealed no evidence of harm to thefetus (30 mg/kg subcutaneously; 22 times SDA). Reproduction studies with prilocaine have been performed inrats and have revealed no evidence of impaired fertility or harm to the fetus (300 mg/kg intramuscularly; 188times SDA). There are, however, no adequate and well-controlled studies in pregnant women. Because animalreproduction studies are not always predictive of human response, EMLA Cream should be used duringpregnancy only if clearly needed.

Reproduction studies have been performed in rats receiving subcutaneous administration of an aqueous mixturecontaining lidocaine HCl and prilocaine HCl at 1:1 (w/w). At 40 mg/kg each, a dose equivalent to 29 timesSDA lidocaine and 25 times SDA prilocaine, no teratogenic, embryotoxic or fetotoxic effects were observed.

Labor And Delivery

Neither lidocaine nor prilocaine are contraindicated in labor and delivery. Should EMLACream be used concomitantly with other products containing lidocaine and/or prilocaine, cumulative doses fromall formulations must be considered.

Nursing Mothers

Lidocaine, and probably prilocaine, are excreted in human milk. Therefore, caution shouldbe exercised when EMLA Cream is administered to a nursing mother since the milk:plasma ratio of lidocaine is0.4 and is not determined for prilocaine.

Pediatric Use

Controlled studies of EMLA Cream in children under the age of seven years have shown lessoverall benefit than in older children or adults. These results illustrate the importance of emotional andpsychological support of younger children undergoing medical or surgical procedures.

EMLA Cream should be used with care in patients with conditions or therapy associated withmethemoglobinemia (see Methemoglobinemia subsection of WARNINGS).

When using EMLA Cream in young children, especially infants under the age of 3 months, care must be takento insure that the caregiver understands the need to limit the dose and area of application, and to preventaccidental ingestion (see DOSAGE AND ADMINISTRATION and Methemoglobinemia).

In neonates (minimum gestation age: 37 weeks) and children weighing less than 20 kg, the area andduration of application should be limited (see TABLE 2 in Individualization of Dose).

Studies have not demonstrated the efficacy of EMLA Cream for heel lancing in neonates.

Geriatric Use

Of the total number of patients in clinical studies of EMLA Cream, 180 were age 65 to 74 and138 were 75 and over. No overall differences in safety or efficacy were observed between these patients andyounger patients. Other reported clinical experience has not identified differences in responses between theelderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Plasma levels of lidocaine and prilocaine in geriatric and non-geriatric patients following application of a thicklayer of EMLA Cream are very low and well below potentially toxic levels. However, there are no sufficientdata to evaluate quantitative differences in systemic plasma levels of lidocaine and prilocaine between geriatricand non-geriatric patients following application of EMLA Cream.

Consideration should be given for those elderly patients who have enhanced sensitivity to systemic absorption(see PRECAUTIONS).

After intravenous dosing, the elimination half-life of lidocaine is significantly longer in elderly patients (2.5hours) than in younger patients (1.5 hours). (see CLINICAL PHARMACOLOGY).

Overdose Information for Emla

Peak blood levels following a 60 g application to 400 cm² of intact skin for 3 hours are 0.05 to 0.16 μg/mL forlidocaine and 0.02 to 0.10 μg/mL for prilocaine. Toxic levels of lidocaine (>5 μg/mL) and/or prilocaine (>6μg/mL) cause decreases in cardiac output, total peripheral resistance and mean arterial pressure. These changesmay be attributable to direct depressant effects of these local anesthetic agents on the cardiovascular system. Inthe absence of massive topical overdose or oral ingestion, evaluation should include evaluation of otheretiologies for the clinical effects or overdosage from other sources of lidocaine, prilocaine or other localanesthetics. Consult the package inserts for parenteral Xylocaine (lidocaine HCl) or Citanest (prilocaine HCl)for further information for the management of overdose.

Contraindications for Emla

EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is contraindicated in patients with a known history ofsensitivity to local anesthetics of the amide type or to any other component of the product.

Clinical Pharmacology for Emla

Mechanism Of Action

EMLA Cream (lidocaine 2.5% and prilocaine 2.5%), applied to intact skin underocclusive dressing, provides dermal analgesia by the release of lidocaine and prilocaine from the cream into theepidermal and dermal layers of the skin and by the accumulation of lidocaine and prilocaine in the vicinity ofdermal pain receptors and nerve endings. Lidocaine and prilocaine are amide-type local anesthetic agents. Bothlidocaine and prilocaine stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiationand conduction of impulses, thereby effecting local anesthetic action.

The onset, depth and duration of dermal analgesia on intact skin provided by EMLA Cream depend primarilyon the duration of application. To provide sufficient analgesia for clinical procedures such as intravenouscatheter placement and venipuncture, EMLA Cream should be applied under an occlusive dressing for at least 1hour. To provide dermal analgesia for clinical procedures such as split skin graft harvesting, EMLA Creamshould be applied under occlusive dressing for at least 2 hours. Satisfactory dermal analgesia is achieved 1 hourafter application, reaches maximum at 2 to 3 hours, and persists for 1 to 2 hours after removal. Absorption fromthe genital mucosa is more rapid and onset time is shorter (5 to 10 minutes) than after application to intact skin.After a 5 to 10 minute application of EMLA Cream to female genital mucosa, the average duration of effectiveanalgesia to an argon laser stimulus (which produced a sharp, pricking pain) was 15 to 20 minutes (individualvariations in the range of 5 to 45 minutes).

Dermal application of EMLA Cream may cause a transient, local blanching followed by a transient, localredness or erythema.

Pharmaco*kinetics

EMLA Cream is a eutectic mixture of lidocaine 2.5% and prilocaine 2.5% formulated as anoil in water emulsion. In this eutectic mixture, both anesthetics are liquid at room temperature (see DESCRIPTION) and the penetration and subsequent systemic absorption of both prilocaine and lidocaine areenhanced over that which would be seen if each component in crystalline form was applied separately as a 2.5%topical cream.

Absorption

The amount of lidocaine and prilocaine systemically absorbed from EMLA Cream is directlyrelated to both the duration of application and to the area over which it is applied. In two pharmaco*kineticstudies, 60 g of EMLA Cream (1.5 g lidocaine and 1.5 g prilocaine) was applied to 400 cm² of intact skin on thelateral thigh and then covered by an occlusive dressing. The subjects were then randomized such that one-halfof the subjects had the occlusive dressing and residual cream removed after 3 hours, while the remainder left thedressing in place for 24 hours. The results from these studies are summarized below.

TABLE 1: Absorption of Lidocaine and Prilocaine from EMLA Cream: Normal Volunteers (N=16)

When 60 g of EMLA Cream was applied over 400 cm² for 24 hours, peak blood levels of lidocaine areapproximately 1/20 the systemic toxic level. Likewise, the maximum prilocaine level is about 1/36 the toxiclevel. In a pharmaco*kinetic study, EMLA Cream was applied to penile skin in 20 adult male patients in dosesranging from 0.5 g to 3.3 g for 15 minutes. Plasma concentrations of lidocaine and prilocaine following EMLACream application in this study were consistently low (2.5 to 16 ng/mL for lidocaine and 2.5 to 7 ng/mL forprilocaine). The application of EMLA Cream to broken or inflamed skin, or to 2,000 cm² or more of skin wheremore of both anesthetics are absorbed, could result in higher plasma levels that could, in susceptible individuals,produce a systemic pharmacologic response.

The absorption of EMLA Cream applied to genital mucous membranes was studied in two open-label clinicaltrials. Twenty-nine patients received 10 g of EMLA Cream applied for 10 to 60 minutes in the vagin*l fornices.Plasma concentrations of lidocaine and prilocaine following EMLA Cream application in these studies rangedfrom 148 to 641 ng/mL for lidocaine and 40 to 346 ng/mL for prilocaine and time to reach maximumconcentration (tmax) ranged from 21 to 125 minutes for lidocaine and from 21 to 95 minutes for prilocaine.These levels are well below the concentrations anticipated to give rise to systemic toxicity (approximately 5000ng/mL for lidocaine and prilocaine).

Distribution

When each drug is administered intravenously, the steady-state volume of distribution is 1.1 to 2.1L/kg (mean 1.5, ±0.3 SD, n=13) for lidocaine and is 0.7 to 4.4 L/kg (mean 2.6, ±1.3 SD, n=13) for prilocaine.

The larger distribution volume for prilocaine produces the lower plasma concentrations of prilocaine observedwhen equal amounts of prilocaine and lidocaine are administered. At concentrations produced by application ofEMLA Cream, lidocaine is approximately 70% bound to plasma proteins, primarily alpha-1-acid glycoprotein.At much higher plasma concentrations (1 to 4 μg/mL of free base) the plasma protein binding of lidocaine isconcentration dependent. Prilocaine is 55% bound to plasma proteins. Both lidocaine and prilocaine cross theplacental and blood brain barrier, presumably by passive diffusion.

Metabolism

It is not known if lidocaine or prilocaine are metabolized in the skin. Lidocaine is metabolizedrapidly by the liver to a number of metabolites including monoethylglycinexylidide (MEGX) andglycinexylidide (GX), both of which have pharmacologic activity similar to, but less potent than that oflidocaine. The metabolite, 2,6-xylidine, has unknown pharmacologic activity. Following intravenousadministration, MEGX and GX concentrations in serum range from 11 to 36% and from 5 to 11% of lidocaineconcentrations, respectively. Prilocaine is metabolized in both the liver and kidneys by amidases to variousmetabolites including ortho-toluidine and N-n-propylalanine. It is not metabolized by plasma esterases. Theortho-toluidine metabolite has been shown to be carcinogenic in several animal models (see Carcinogenesis subsection of PRECAUTIONS). In addition, ortho-toluidine can produce methemoglobinemia followingsystemic doses of prilocaine approximating 8 mg/kg (see ADVERSE REACTIONS). Very young patients,patients with glucose-6-phosphate dehydrogenase deficiencies and patients taking oxidizing drugs such asantimalarials and sulfonamides are more susceptible to methemoglobinemia (see Methemoglobinemia subsection of PRECAUTIONS).

Elimination

The terminal elimination half-life of lidocaine from the plasma following IV administration isapproximately 65 to 150 minutes (mean 110, ±24 SD, n=13). More than 98% of an absorbed dose of lidocainecan be recovered in the urine as metabolites or parent drug. The systemic clearance is 10 to 20 mL/min/kg(mean 13, ±3 SD, n=13). The elimination half-life of prilocaine is approximately 10 to 150 minutes (mean 70,±48 SD, n=13). The systemic clearance is 18 to 64 mL/min/kg (mean 38, ±15 SD, n=13). During intravenousstudies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours)than in younger patients (1.5 hours). No studies are available on the intravenous pharmaco*kinetics of prilocainein elderly patients.

Pediatrics

Some pharmaco*kinetic (PK) data are available in infants (1 month to <2 years old) and children (2to <12 years old). One PK study was conducted in 9 full-term neonates (mean age: 7 days and mean gestationalage: 38.8 weeks). The study results show that neonates had comparable plasma lidocaine and prilocaineconcentrations and blood methemoglobin concentrations as those found in previous pediatric PK studies andclinical trials. There was a tendency towards an increase in methemoglobin formation. However, due to assaylimitations and very little amount of blood that could be collected from neonates, large variations in the abovereported concentrations were found.

Special Populations

No specific PK studies were conducted. The half-life may be increased in cardiac orhepatic dysfunction. Prilocaine's half-life also may be increased in hepatic or renal dysfunction since both ofthese organs are involved in prilocaine metabolism.

Clinical Studies

EMLA Cream application in adults prior to IV cannulation or venipuncture was studied in 200 patients in fourclinical studies in Europe. Application for at least 1 hour provided significantly more dermal analgesia thanplacebo cream or ethyl chloride. EMLA Cream was comparable to subcutaneous lidocaine, but was lessefficacious than intradermal lidocaine. Most patients found EMLA Cream treatment preferable to lidocaineinfiltration or ethyl chloride spray.

EMLA Cream was compared with 0.5% lidocaine infiltration prior to skin graft harvesting in one open labelstudy in 80 adult patients in England. Application of EMLA Cream for 2 to 5 hours provided dermal analgesiacomparable to lidocaine infiltration.

EMLA Cream application in children was studied in seven non-US studies (320 patients) and one US study(100 patients). In controlled studies, application of EMLA Cream for at least 1 hour with or without presurgicalmedication prior to needle insertion provided significantly more pain reduction than placebo. In children underthe age of seven years, EMLA Cream was less effective than in older children or adults.

EMLA Cream was compared with placebo in the laser treatment of facial port-wine stains in 72 pediatricpatients (ages 5 to 16). EMLA Cream was effective in providing pain relief during laser treatment.

EMLA Cream alone was compared with EMLA Cream followed by lidocaine infiltration and lidocaineinfiltration alone prior to cryotherapy for the removal of male genital warts. The data from 121 patientsdemonstrated that EMLA Cream was not effective as a sole anesthetic agent in managing the pain from thesurgical procedure. The administration of EMLA Cream prior to lidocaine infiltration provided significant reliefof discomfort associated with local anesthetic infiltration and thus was effective in the overall reduction of painfrom the procedure only when used in conjunction with local anesthetic infiltration of lidocaine.

EMLA Cream was studied in 105 full term neonates (gestational age: 37 weeks) for blood drawing andcircumcision procedures. When considering the use of EMLA Cream in neonates, the primary concerns are thesystemic absorption of the active ingredients and the subsequent formation of methemoglobin. In clinicalstudies performed in neonates, the plasma levels of lidocaine, prilocaine, and methemoglobin were not reportedin a range expected to cause clinical symptoms.

Local dermal effects associated with EMLA Cream application in these studies on intact skin included paleness,redness and edema and were transient in nature (see ADVERSE REACTIONS).

The application of EMLA Cream on genital mucous membranes for minor, superficial surgical procedures (e.g.,removal of condylomata acuminata) was studied in 80 patients in a placebo-controlled clinical trial (60 patientsreceived EMLA Cream and 20 patients received placebo). EMLA Cream (5 to 10 g) applied between 1 and 75minutes before surgery, with a median time of 15 minutes, provided effective local anesthesia for minorsuperficial surgical procedures. The greatest extent of analgesia, as measured by VAS scores, was attained after5 to 15 minutes’ application. The application of EMLA Cream to genital mucous membranes as pretreatmentfor local anesthetic infiltration was studied in a double-blind, placebo-controlled study in 44 female patients (21patients received EMLA Cream and 23 patients received placebo) scheduled for infiltration prior to a surgicalprocedure of the external vulva or genital mucosa. EMLA Cream applied to the genital mucous membranes for5 to 10 minutes resulted in adequate topical anesthesia for local anesthetic injection.

Individualization Of Dose

The dose of EMLA Cream that provides effective analgesia depends on theduration of the application over the treated area.

All pharmaco*kinetic and clinical studies employed a thick layer of EMLA Cream (1 to 2 g/10 cm²). Theduration of application prior to venipuncture was 1 hour. The duration of application prior to taking splitthickness skin grafts was 2 hours. A thinner application has not been studied and may result in less completeanalgesia or a shorter duration of adequate analgesia.

The systemic absorption of lidocaine and prilocaine is a side effect of the desired local effect. The amount ofdrug absorbed depends on surface area and duration of application. The systemic blood levels depend on theamount absorbed and patient size (weight) and the rate of systemic drug elimination. Long duration ofapplication, large treatment area, small patients, or impaired elimination may result in high blood levels. Thesystemic blood levels are typically a small fraction (1/20 to 1/36) of the blood levels that produce toxicity.Table 2 below gives maximum recommended doses, application areas and application times for infants andchildren.

TABLE 2: EMLA CREAM MAXIMUM RECOMMENDED DOSE, APPLICATION AREA, AND APPLICATION TIME BY AGE AND WEIGHT*
For Infants and Children Based on Application to Intact Skin

An I.V. antiarrhythmic dose of lidocaine is 1 mg/kg (70 mg/70 kg) and gives a blood level of about 1 μg/mL.Toxicity would be expected at blood levels above 5 μg/mL. Smaller areas of treatment are recommended in adebilitated patient, a small child or a patient with impaired elimination. Decreasing the duration of application islikely to decrease the analgesic effect.

Patient Information for Emla

Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must betreated promptly. Advise patients or caregivers to stop use and seek immediate medical attention if they orsomeone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis);headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

When EMLA Cream is used, the patient should be aware that the production of dermal analgesia may beaccompanied by the block of all sensations in the treated skin. For this reason, the patient should avoidinadvertent trauma to the treated area by scratching, rubbing, or exposure to extreme hot or cold temperaturesuntil complete sensation has returned.

EMLA Cream should not be applied near the eyes or on open wounds.