A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Emla Pharmacology, Pharmacokinetics, Studies, Metabolism - Lidocaine and Prilocaine
Emla Pharmacology, Pharmacokinetics, Studies, Metabolism - Lidocaine and Prilocaine
CLINICAL PHARMACOLOGY
Mechanism of Action
EMLA (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 provided by EMLA
depends primarily on the duration
of application. To provide sufficient analgesia
for clinical procedures
such as intravenous catheter
placement and venipuncture, EMLA
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
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.
Dermal application of EMLA
may cause a transient, local
blanching followed by a transient, local
redness or erythema.
Pharmacokinetics
EMLA 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.
The amount of lidocaine
and prilocaine systemically absorbed from EMLA
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
(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 |
*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 (2.5-16 ng/mL
for lidocaine and
2.5-7 ng/mL for prilocaine). The application of EMLA 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. 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
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
but is carcinogenic
in rats (see PRECAUTIONS:
Carcinogenesis, Mutagenesis, Impairment of Fertility). 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 PRECAUTIONS: Carcinogenesis,
Mutagenesis, Impairment of Fertility). 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 deficiencies
and patients
taking oxidizing drugs such
as antimalarials and sulfonamides are more susceptible to methemoglobinemia
(see WARNINGS: Methemoglobinemia).
The half-life of
lidocaine elimination
from the plasma following
IV administration
is approximately 65 to 150 minutes (mean 110, ±24 SD, n=13).
This half-life may
be increased in cardiac
or hepatic dysfunction.
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). Prilocaine's
half-life also may
be increased in hepatic
or renal dysfunction
since both of these 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 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 516). EMLA
Cream was effective in providing pain
relief during laser treatment.
EMLA Cream alone was compared to 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.
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).
Individualization of Dose
The dose of EMLA
which 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 (12
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. Although a thinner application may be efficacious, such
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 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 which produce toxicity. Table 2 which follows gives
maximum recommended
doses and application areas for infants and children.
TABLE 2
EMLA MAXIMUM RECOMMENDED DOSE
AND APPLICATION AGE
BY AGE AND WEIGHT*
For Infants and Children
Based on Application to Intact Skin
Age and Body Weight
Requirements |
Maximum Total
Dose of EMLA |
Maximum
Application Area** |
| 1 to 3 months or < 5 kg |
1 g |
10 cm2 |
| 4 to 12 months and > 5 kg |
2 g |
20 cm2 |
| 1 to 6 years and >10 kg |
10 g |
100 cm2 |
| 7 to 12 years and >20 kg |
20 g |
200 cm2 |
Please note: If a patient
greater than 3 months old does not meet the minimum
weight requirement,
the maximum total dose
of EMLA should be restricted
to that which corresponds to the patient's weight.
* These are broad guidelines for avoiding systemic toxicity
in applying EMLA 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 IV 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.
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