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 Cream depend primarily
on the duration of application. To provide sufficient analgesia for clinical procedures such as intravenous
catheter placement and venipuncture, EMLA Cream should be applied under an occlusive dressing for at least 1
hour. To provide dermal analgesia for clinical procedures such as split skin graft harvesting, EMLA 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 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 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%
The amount of lidocaine and prilocaine systemically absorbed from EMLA 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 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 Cream: Normal Volunteers (N=16)
|EMLA Cream (g)
|*Maximum recommended duration of exposure is 4 hours.
When 60 g of EMLA 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 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
Cream application in this study were consistently low (2.5 to 16 ng/mL for lidocaine and 2.5 to 7 ng/mL for
prilocaine). The application of EMLA 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 Cream applied to genital mucous membranes was studied in two open-label clinical
trials. Twenty-nine patients received 10 g of EMLA Cream applied for 10 to 60 minutes in the vaginal fornices.
Plasma concentrations of lidocaine and prilocaine following EMLA 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).
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 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.
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).
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.
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.
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 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 Cream was comparable to subcutaneous lidocaine, but was less
efficacious than intradermal lidocaine. Most patients found EMLA Cream treatment preferable to lidocaine
infiltration or ethyl chloride spray.
EMLA 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 Cream for 2 to 5 hours provided dermal analgesia
comparable 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 presurgical
medication prior to needle insertion provided significantly more pain reduction than placebo. In children under
the 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 pediatric
patients (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 lidocaine
infiltration alone prior to cryotherapy for the removal of male genital warts. The data from 121 patients
demonstrated that EMLA Cream was not effective as a sole anesthetic agent in managing the pain from the
surgical procedure. The administration of EMLA 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 Cream was studied in 105 full term neonates (gestational age: 37 weeks) for blood drawing and
circumcision procedures. When considering the use of EMLA 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 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 patients
received EMLA Cream and 20 patients received placebo). EMLA 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 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 Cream and 23 patients received placebo) scheduled for infiltration prior to a surgical
procedure of the external vulva or genital mucosa. EMLA 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 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 Cream (1 to 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
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
|Age and Body Weight
Dose of EMLA Cream
|0 up to 3 months or < 5 kg
|3 up to 12 months and > 5 kg
|1 to 6 years and > 10 kg
|7 to 12 years and > 20 kg
|Please note: If a patient greater than 3 months old does not meet the minimum weight requirement, the
maximum total dose of EMLA Cream should be restricted to that which corresponds to the patient’s weight.
* These are broad guidelines for avoiding systemic toxicity in applying EMLA 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.