CLINICAL PHARMACOLOGY
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.
Pharmacokinetics:
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 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) |
Area
(cm2) |
Time
on (hrs) |
Drug
Content (mg) |
Absorbed (mg) |
Cmax
(µg/mL) |
Tmax
(hr) |
60 |
400
|
3
|
lidocaine 1500
|
54
|
0.12
|
4
|
| prilocaine
1500
|
92
|
0.07
|
4
|
60
|
400
|
24
|
lidocaine
1500
|
243
|
0.28
|
10
|
| prilocaine
1500
|
503
|
0.14
|
10
|
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).
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
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.
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