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Mechanism of Action
EMLA Cream (lidocaine 2.5% and prilocaine 2.5%), applied to intact skin under occlusive dressing, provides dermal analgesia by the release of lidocaine and prilocaine from the cream into the epidermal and dermal layers of the skin and by the accumulation of lidocaine and prilocaine in the vicinity of dermal pain receptors and nerve endings. Lidocaine and prilocaine are amide-type local anesthetic agents. Both lidocaine and prilocaine stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action.
The onset, depth and duration of dermal analgesia on intact skin provided by EMLA (lidocaine and prilocaine) Cream depend primarily on the duration of application. To provide sufficient analgesia for clinical procedures such as intravenous catheter placement and venipuncture, EMLA (lidocaine and prilocaine) Cream should be applied under an occlusive dressing for at least 1 hour. To provide dermal analgesia for clinical procedures such as split skin graf harvesting, EMLA (lidocaine and prilocaine) Cream should be applied under occlusive dressing for at least 2 hours. Satisfactory dermal analgesia is achieved 1 hour after application, reaches maximum at 2 to 3 hours, and persists for 1 to 2 hours after removal. Absorption from the 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 (lidocaine and prilocaine) Cream to female genital mucosa, the average duration of effective analgesia to an argon laser stimulus (which produced a sharp, pricking pain) was 15 to 20 minutes (individual variations in the range of 5 to 45 minutes).
Dermal application of EMLA (lidocaine and prilocaine) Cream may cause a transient, local blanching followed by a transient, local redness or erythema.
EMLA Cream is a eutectic mixture of lidocaine 2.5% and prilocaine 2.5% formulated as an oil 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 are enhanced 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 (lidocaine and prilocaine) Cream is directly related to both the duration of application and to the area over which it is applied. In two pharmacokinetic studies, 60 g of EMLA (lidocaine and prilocaine) Cream (1.5 g lidocaine and 1.5 g prilocaine) was applied to 400 cm2 of intact skin on the lateral thigh and then covered by an occlusive dressing. The subjects were then randomized such that one-half of the subjects had the occlusive dressing and residual cream removed after 3 hours, while the remainder left the dressing in place for 24 hours. The results from these studies are summarized below.
TABLE 1: Absorption of Lidocaine and Prilocaine from EMLA (lidocaine and prilocaine)
Cream: Normal Volunteers (N=16)
|EMLA Cream (g)||Area (cm2)||Time on (hrs)||Drug Content (mg)||Absorbed (mg)||Cmax (µg/mL)||Tmax (hr)|
|* Maximum recommended duration of exposureis 4 hours.|
When 60 g of EMLA (lidocaine and prilocaine) Cream was applied over 400 cm2 for 24 hours, peak blood levels of lidocaine are approximately 1/20 the systemic toxic level. Likewise, the maximum prilocaine level is about 1/36 the toxic level. In a pharmacokinetic study, EMLA (lidocaine and prilocaine) Cream was applied to penile skin in 20 adult male patients in doses ranging from 0.5 g to 3.3 g for 15 minutes. Plasma concentrations of lidocaine and prilocaine following EMLA (lidocaine and prilocaine) Cream application in this study were consistently low (2.5-16 ng/mL for lidocaine and 2.5-7 ng/mL for prilocaine). The application of EMLA (lidocaine and prilocaine) Cream to broken or inflamed skin, or to 2,000 cm2 or more of skin where more 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 (lidocaine and prilocaine) Cream applied to genital mucous membranes was studied in two open-label clinical trials. Twenty-nine patients received 10 g of EMLA (lidocaine and prilocaine) Cream applied for 10 to 60 minutes in the vaginal fornices. Plasma concentrations of lidocaine and prilocaine following EMLA (lidocaine and prilocaine) Cream application in these studies ranged from 148 to 641 ng/mL for lidocaine and 40 to 346 ng/mL for prilocaine and time to reach maximum concentration (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 5000 ng/mL for lidocaine and prilocaine).
Distribution: When each drug is administered intravenously, the steady-state volume of distribution is 1.1 to 2.1 L/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 observed when equal amounts of prilocaine and lidocaine are administered. At concentrations produced by application of EMLA (lidocaine and prilocaine) 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 is concentration dependent. Prilocaine is 55% bound to plasma proteins. Both lidocaine and prilocaine cross the placental and blood brain barrier, presumably by passive diffusion.
Metabolism: It is not known if lidocaine or prilocaine are 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 metabolite, 2,6-xylidine, has unknown pharmacologic activity. Following intravenous administration, MEGX and GX concentrations in serum range from 11 to 36% and from 5 to 11% of lidocaine concentrations, respectively. Prilocaine is metabolized in both the liver and kidneys by amidases to various metabolites including ortho-toluidine and N-n-propylalanine. It is not metabolized by plasma esterases. The ortho-toluidine metabolite has been shown to be carcinogenic in several animal models (see Carcinogenesis subsection of PRECAUTIONS). In addition, ortho-toluidine can produce methemoglobinemia following systemic 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 as antimalarials 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 is approximately 65 to 150 minutes (mean 110, ±24 SD, n=13). More than 98% of an absorbed dose of lidocaine can 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 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). No studies are available on the intravenous pharmacokinetics of prilocaine in elderly patients.
Pediatrics: Some pharmacokinetic (PK) data are available in infants (1 month to < 2 years old) and children (2 to < 12 years old). One PK study was conducted in 9 full-term neonates (mean age: 7 days and mean gestational age: 38.8 weeks). The study results show that neonates had comparable plasma lidocaine and prilocaine concentrations and blood methemoglobin concentrations as those found in previous pediatric PK studies and clinical trials. There was a tendency towards an increase in methemoglobin formation. However, due to assay limitations and very little amount of blood that could be collected from neonates, large variations in the above reported concentrations were found.
Special Populations: No specific PK studies were conducted. The half-life may be increased in cardiac or hepatic dysfunction. Prilocaine's half-life also may be increased in hepatic or renal dysfunction since both of these organs are involved in prilocaine metabolism.
EMLA (lidocaine and prilocaine) Cream application in adults prior to IV cannulation or venipuncture was studied in 200 patients in four clinical studies in Europe. Application for at least 1 hour provided significantly more dermal analgesia than placebo cream or ethyl chloride. EMLA (lidocaine and prilocaine) Cream was comparable to subcutaneous lidocaine, but was less efficacious than intradermal lidocaine. Most patients found EMLA (lidocaine and prilocaine) Cream treatment preferable to lidocaine infiltration or ethyl chloride spray.
EMLA (lidocaine and prilocaine) Cream was compared with 0.5% lidocaine infiltration prior to skin graft harvesting in one open label study in 80 adult patients in England. Application of EMLA (lidocaine and prilocaine) Cream for 2 to 5 hours provided dermal analgesia comparable to lidocaine infiltration.
EMLA (lidocaine and prilocaine) 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 (lidocaine and prilocaine) Cream for at least 1 hour with or without presurgical medication prior to needle insertion provided significantly more pain reduction than placebo. In children under the age of seven years, EMLA (lidocaine and prilocaine) Cream was less effective than in older children or adults.
EMLA (lidocaine and prilocaine) Cream was compared with placebo in the laser treatment of facial port-wine stains in 72 pediatric patients (ages 5-16). EMLA (lidocaine and prilocaine) Cream was effective in providing pain relief during laser treatment.
EMLA (lidocaine and prilocaine) Cream alone was compared with EMLA (lidocaine and prilocaine) Cream followed by lidocaine infiltration and lidocaine infiltration alone prior to cryotherapy for the removal of male genital warts. The data from 121 patients demonstrated that EMLA (lidocaine and prilocaine) Cream was not effective as a sole anesthetic agent in managing the pain from the surgical procedure. The administration of EMLA (lidocaine and prilocaine) Cream prior to lidocaine infiltration provided significant relief of discomfort associated with local anesthetic infiltration and thus was effective in the overall reduction of pain from the procedure only when used in conjunction with local anesthetic infiltration of lidocaine.
EMLA (lidocaine and prilocaine) Cream was studied in 105 full term neonates (gestational age: 37 weeks) for blood drawing and circumcision procedures. When considering the use of EMLA (lidocaine and prilocaine) Cream in neonates, the primary concerns are the systemic absorption of the active ingredients and the subsequent formation of methemoglobin. In clinical studies performed in neonates, the plasma levels of lidocaine, prilocaine, and methemoglobin were not reported in a range expected to cause clinical symptoms.
Local dermal effects associated with EMLA (lidocaine and prilocaine) 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 (lidocaine and prilocaine) Cream on genital mucous membranes for minor, superficial surgical procedures (eg, removal of condylomata acuminata) was studied in 80 patients in a placebo-controlled clinical trial (60 patients received EMLA (lidocaine and prilocaine) Cream and 20 patients received placebo). EMLA (lidocaine and prilocaine) Cream (5 to 10 g) applied between 1 and 75 minutes before surgery, with a median time of 15 minutes, provided effective local anesthesia for minor superficial surgical procedures. The greatest extent of analgesia, as measured by VAS scores, was attained after 5 to 15 minutes' application. The application of EMLA (lidocaine and prilocaine) Cream to genital mucous membranes as pretreatment for local anesthetic infiltration was studied in a double-blind, placebo-controlled study in 44 female patients (21 patients received EMLA (lidocaine and prilocaine) Cream and 23 patients received placebo) scheduled for infiltration prior to a surgical procedure of the external vulva or genital mucosa. EMLA (lidocaine and prilocaine) Cream applied to the genital mucous membranes for 5 to 10 minutes resulted in adequate topical anesthesia for local anesthetic injection.
Individualization of Dose: The dose of EMLA (lidocaine and prilocaine) Cream that provides effective analgesia depends on the duration of the application over the treated area.
All pharmacokinetic and clinical studies employed a thick layer of EMLA (lidocaine and prilocaine) Cream (1-2 g/10 cm2). The duration of application prior to venipuncture was 1 hour. The duration of application prior to taking split thickness skin grafts was 2 hours. A thinner application has not been studied and may result in less complete analgesia 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 of drug absorbed depends on surface area and duration of application. The systemic blood levels depend on the amount absorbed and patient size (weight) and the rate of systemic drug elimination. Long duration of application, large treatment area, small patients, or impaired elimination may result in high blood levels. The systemic 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 and children.
TABLE 2: EMLA (lidocaine and prilocaine) CREAM MAXIMUM RECOMMENDED DOSE, APPLICATION
AREA, AND APPLICATION TIME BY AGE AND WEIGHT* For Infants and Children Based
on Application to Intact Skin
|Age and Body Weight Requirements||Maximum Total Dose of EMLA Cream||Maximum Application Area**||Maximum Application Time|
|0 up to 3 months or < 5 kg||1 g||10 cm2||1 hour|
|3 up to 12 months and > 5 kg||2 g||20 cm2||4 hours|
|1 to 6 years and > 10 kg||10 g||100 cm2||4 hours|
|7 to 12 years and > 20 kg||20 g||200 cm2||4 hours|
|Please note: If a patient greater than 3 months old does
not meet the minimum weight requirement, the maximum total dose of EMLA (lidocaine and prilocaine)
Cream should be restricted to that which corresponds to the patient's
* These are broad guidelines for avoiding systemic toxicity in applying EMLA (lidocaine and prilocaine) Cream to patients with normal intact skin and with normal renal and hepatic function.
** For more individualized calculation of how much lidocaine and prilocaine may be absorbed, physicians can use the following estimates of lidocaine and prilocaine absorption for children and adults:
The estimated mean (±SD) absorption of lidocaine is 0.045 (±0.016) mg/cm2/hr.
The estimated mean (±SD) absorption of prilocaine is 0.077 (±0.036) mg/cm2/hr.
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 a debilitated patient, a small child or a patient with impaired elimination. Decreasing the duration of application is likely to decrease the analgesic effect.
Last reviewed on RxList: 8/13/2008
This monograph has been modified to include the generic and brand name in many instances.
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