LIDOCAINE AND PRILOCAINE cream

United States - English - NLM (National Library of Medicine)

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Active ingredient:
LIDOCAINE (UNII: 98PI200987) (LIDOCAINE - UNII:98PI200987), PRILOCAINE (UNII: 046O35D44R) (PRILOCAINE - UNII:046O35D44R)
Available from:
NuCare Pharamceuticals,Inc.
INN (International Name):
LIDOCAINE
Composition:
LIDOCAINE 25 mg in 1 g
Administration route:
TOPICAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Lidocaine 2.5% and prilocaine 2.5% cream (a eutectic mixture of lidocaine 2.5% and prilocaine 2.5%) is indicated as a topical anesthetic for use on: - normal intact skin for local analgesia. - genital mucous membranes for superficial minor surgery and as pretreatment for infiltration anesthesia. Lidocaine 2.5% and prilocaine 2.5% cream is not recommended in any clinical situation when penetration or migration beyond the tympanic membrane into the middle ear is possible because of the ototoxic effects observed in animal studies (see WARNINGS). lidocaine 2.5% and prilocaine 2.5% cream (lidocaine 2.5% and prilocaine 2.5%) is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type or to any other component of the product.
Product summary:
Lidocaine 2.5% and Prilocaine 2.5% Cream is available as the following: NDC 68071-1625-3 Box of 30g NOT FOR OPHTALMIC USE. KEEP CONTAINER TIGHTLY CLOSED AT ALL TIMES WHEN NOT IN USE. Store at controlled room temperature 15° to 30°C (59° to 86°F) [see USP]. Manufactured by: Hi-Tech Pharmacal Co., Inc. Amityville, NY 11701 Rev. 667:02 7/09 MG #16518
Authorization status:
Abbreviated New Drug Application
Authorization number:
68071-1625-3

LIDOCAINE AND PRILOCAINE- lidocaine and prilocaine cream

NuCare Pharamceuticals,Inc.

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Lidocaine 2.5% and Prilocaine 2.5% Cream

For Topical Use Only. Not for Ophthalmic Use.

DESCRIPTION

Lidocaine 2.5% and Prilocaine 2.5%, a topical anesthetic agent, 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 15 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 lidocaine 2.5% and prilocaine 2.5% cream contains lidocaine 25 mg, prilocaine 25 mg,

carboxypolymethylene (as a thickening agent), polyoxyethylene fatty acid esters (as emulsifiers),

purified water to 1 gram, and sodium hydroxide to adjust pH (pH range 9.0-9.4). Lidocaine 2.5% and

prilocaine 2.5% cream contains no preservative, however it passes the USP antimicrobial effectiveness

test due to the pH. The specific gravity of lidocaine 2.5% and prilocaine 2.5% cream is 1.00.

CLINICAL PHARMACOLOGY

Mechanism of Action:

Lidocaine 2.5% and prilocaine 2.5% cream, 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 lidocaine 2.5% and

prilocaine 2.5% cream depend primarily on the duration of application. To provide sufficient analgesia

for clinical procedures such as intravenous catheter placement and venipuncture, lidocaine 2.5% and

prilocaine 2.5% 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, lidocaine 2.5% and

prilocaine 2.5% 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 lidocaine 2.5%

and prilocaine 2.5% 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 lidocaine 2.5% and prilocaine 2.5% cream may cause a transient, local blanching

followed by a transient, local redness or erythema.

Pharmacokinetics :

Lidocaine 2.5% and prilocaine 2.5% 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 lidocaine 2.5% and

prilocaine 2.5% 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 lidocaine 2.5% and prilocaine 2.5% cream (1.5 g

lidocaine and 1.5 g prilocaine) was applied to 400 cm

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 Lidocaine 2.5% and Prilocaine 2.5% cream:

Normal Volunteers (N=16)

Lidocaine 2.5% and Prilocaine

2.5% Cream (g)

Area

(cm

)

Time

on

(hrs )

Drug Content

(mg)

Abs orbed

(mg)

C

(µg/mL)

T

(hr)

lidocaine

1500

0.12

prilocaine

1500

0.07

lidocaine

1500

0.28

prilocaine

1500

0.14

When 60 g of lidocaine 2.5% and prilocaine 2.5% cream was applied over 400 cm

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, lidocaine 2.5% and prilocaine

2.5% cream was applied to penile skin in 20 adult male patients in doses ranging from 0.5 g to 3.3 g for

2

max

max

Maximum recommended duration of exposure is 4 hours.

15 minutes. Plasma concentrations of lidocaine and prilocaine following lidocaine 2.5% and prilocaine

2.5% 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 lidocaine 2.5% and prilocaine 2.5% cream to broken or inflamed

skin, or to 2,000 cm

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 lidocaine 2.5% and prilocaine 2.5% cream applied to genital mucous membranes was

studied in two open-label clinical trials. Twenty-nine patients received 10 g of lidocaine 2.5% and

prilocaine 2.5% cream applied for 10 to 60 minutes in the vaginal fornices. Plasma concentrations of

lidocaine and prilocaine following lidocaine 2.5% and prilocaine 2.5% 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 (t

) 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 lidocaine 2.5% and prilocaine 2.5% 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.

Clinical Studies

Lidocaine 2.5% and prilocaine 2.5% 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. Lidocaine 2.5% and

prilocaine 2.5% cream was comparable to subcutaneous lidocaine, but was less efficacious than

intradermal lidocaine. Most patients found lidocaine 2.5% and prilocaine 2.5% cream treatment

preferable to lidocaine infiltration or ethyl chloride spray.

Lidocaine 2.5% and prilocaine 2.5% 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 lidocaine 2.5%

and prilocaine 2.5% cream for 2 to 5 hours provided dermal analgesia comparable to lidocaine

infiltration.

Lidocaine 2.5% and prilocaine 2.5% cream application in children was studied in seven non-US studies

(320 patients) and one US study (100 patients). In controlled studies, application of lidocaine 2.5% and

prilocaine 2.5% 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, lidocaine 2.5% and prilocaine 2.5% cream was less effective than in older children or adults.

Lidocaine 2.5% and prilocaine 2.5% cream was compared with placebo in the laser treatment of facial

port-wine stains in 72 pediatric patients (ages 5−16). Lidocaine 2.5% and prilocaine 2.5% cream was

effective in providing pain relief during laser treatment.

Lidocaine 2.5% and prilocaine 2.5% cream alone was compared with lidocaine 2.5% and prilocaine

2.5% 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 lidocaine 2.5% and

prilocaine 2.5% cream was not effective as a sole anesthetic agent in managing the pain from the

surgical procedure. The administration of lidocaine 2.5% and prilocaine 2.5% 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.

Lidocaine 2.5% and prilocaine 2.5% cream was studied in 105 full term neonates (gestational age: 37

weeks) for blood drawing and circumcision procedures. When considering the use of lidocaine 2.5%

and prilocaine 2.5% 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 lidocaine 2.5% and prilocaine 2.5% cream application in these

studies on intact skin included paleness, redness and edema and were transient in nature (see ADVERSE

REACTIONS).

The application of lidocaine 2.5% and prilocaine 2.5% 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 lidocaine 2.5% and prilocaine 2.5% cream and 20

patients received placebo). Lidocaine 2.5% and prilocaine 2.5% 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 lidocaine 2.5% and prilocaine 2.5%

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 lidocaine 2.5% and

prilocaine 2.5% cream and 23 patients received placebo) scheduled for infiltration prior to a surgical

procedure of the external vulva or genital mucosa. Lidocaine 2.5% and prilocaine 2.5% 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 lidocaine 2.5% and prilocaine 2.5% 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 lidocaine 2.5% and prilocaine 2.5%

cream (1−2 g/10 cm

). 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 LIDOCAINE 2.5% AND PRILOCAINE 2.5% 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 lidocaine 2.5%

and prilocaine 2.5% cream

Maximum

Application Area

Maximum

Application

Time

0 up to 3 months or < 5

10 cm

1 hour

3 up to 12 months and >

5 kg

20 cm

4 hours

1 to 6 years and > 10

10 g

100 cm

4 hours

7 to 12 years and > 20

20 g

200 cm

4 hours

Please note: If a patient greater than 3 months old does not meet the minimum weight requirement, the

maximum total dose of lidocaine 2.5% and prilocaine 2.5% cream should be restricted to that which

corresponds to the patient’s weight

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.

INDICATIONS AND USAGE

*

These are broad guidelines for avoiding systemic toxicity in applying lidocaine 2.5% and prilocaine 2.5% 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 0.04 5 (±0.016) mg/cm 2/hr. The estimated mean (±SD) absorption of prilocaine is

0.077 (±0.036) mg/cm 2/hr.

Lidocaine 2.5% and prilocaine 2.5% cream (a eutectic mixture of lidocaine 2.5% and prilocaine 2.5%)

is indicated as a topical anesthetic for use on:

normal intact skin for local analgesia.

genital mucous membranes for superficial minor surgery and as pretreatment for infiltration

anesthesia.

Lidocaine 2.5% and prilocaine 2.5% cream is not recommended in any clinical situation when

penetration or migration beyond the tympanic membrane into the middle ear is possible because of the

ototoxic effects observed in animal studies (see WARNINGS).

CONTRAINDICATIONS

lidocaine 2.5% and prilocaine 2.5% cream (lidocaine 2.5% and prilocaine 2.5%) is contraindicated in

patients with a known history of sensitivity to local anesthetics of the amide type or to any other

component of the product.

WARNINGS

Application of lidocaine 2.5% and prilocaine 2.5% cream to larger areas or for longer times than those

recommended could result in sufficient absorption of lidocaine and prilocaine resulting in serious

adverse effects (see Individualization of Dose).

Patients treated with class III anti-arrhythmic drugs (eg, amiodarone, bretylium, sotalol, dofetilide)

should be under close surveillance and ECG monitoring considered, because cardiac effects may be

additive.

Studies in laboratory animals (guinea pigs) have shown that lidocaine 2.5% and prilocaine 2.5% cream

has an ototoxic effect when instilled into the middle ear. In these same studies, animals exposed to

lidocaine 2.5% and prilocaine 2.5% cream only in the external auditory canal, showed no abnormality.

lidocaine 2.5% and prilocaine 2.5% cream should not be used in any clinical situation when its

penetration or migration beyond the tympanic membrane into the middle ear is possible.

Methemoglobinemia

Lidocaine 2.5% and prilocaine 2.5% cream should not be used in those rare patients with congenital or

idiopathic methemoglobinemia and in infants under the age of twelve months who are receiving

treatment with methemoglobin-inducing agents.

Very young patients or patients with glucose-6-phosphate dehydrogenase deficiencies are more

susceptible to methemoglobinemia.

Patients taking drugs associated with drug-induced methemoglobinemia such as sulfonamides,

acetaminophen, acetanilid, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and

nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, paraaminosalicylic acid, phenacetin,

phenobarbital, phenytoin, primaquine, quinine, are also at greater risk for developing

methemoglobinemia.

There have been reports of significant methemoglobinemia (20-30%) in infants and children following

excessive applications of lidocaine 2.5% and prilocaine 2.5% cream. These cases involved the use of

large doses, larger than recommended areas of application, or infants under the age of 3 months who did

not have fully mature enzyme systems. In addition, a few of these cases involved the concomitant

administration of methemoglobin-inducing agents. Most patients recovered spontaneously after removal

of the cream. Treatment with IV methylene blue may be effective if required.

Physicians are cautioned to make sure that parents or other caregivers understand the need for careful

application of lidocaine 2.5% and prilocaine 2.5% cream, to ensure that the doses and areas of

application recommended in Table 2 are not exceeded (especially in children under the age of 3 months)

and to limit the period of application to the minimum required to achieve the desired anesthesia.

Neonates and infants up to 3 months of age should be monitored for Met-Hb levels before, during, and

after the application of lidocaine 2.5% and prilocaine 2.5% cream, provided the test results can be

obtained quickly.

PRECAUTIONS

General:

Repeated doses of lidocaine 2.5% and prilocaine 2.5% cream may increase blood levels of lidocaine

and prilocaine. lidocaine 2.5% and prilocaine 2.5% cream should be used with caution in patients who

may be more sensitive to the systemic effects of lidocaine and prilocaine including acutely ill,

debilitated, or elderly patients.

Lidocaine 2.5% and prilocaine 2.5% cream should not be applied to open wounds.

Care should be taken not to allow lidocaine 2.5% and prilocaine 2.5% cream to come in contact with the

eye because animal studies have demonstrated severe eye irritation. Also the loss of protective

reflexes can permit corneal irritation and potential abrasion. Absorption of lidocaine 2.5% and

prilocaine 2.5% 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

shown cross sensitivity to lidocaine and/or prilocaine; however, lidocaine 2.5% and prilocaine 2.5%

cream should be used with caution in patients with 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 at greater 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 lidocaine

2.5% and prilocaine 2.5% cream on intradermal injections of live vaccines has not been determined.

Information for Patients:

When lidocaine 2.5% and prilocaine 2.5% cream is used, the patient should be aware that the production

of dermal analgesia may be accompanied by the block of all sensations in the treated skin. For this

reason, the patient should avoid inadvertent trauma to the treated area by scratching, rubbing, or

exposure to extreme hot or cold temperatures until complete sensation has returned.

Lidocaine 2.5% and prilocaine 2.5% cream should not be applied near the eyes or on open wounds.

Drug Interactions:

Lidocaine 2.5% and prilocaine 2.5% cream should be used with caution in patients receiving Class I

antiarrhythmic drugs (such as tocainide and mexiletine) since the toxic effects are additive and

potentially synergistic.

Prilocaine may contribute to the formation of methemoglobin in patients treated with other drugs

known to cause this condition (see Methemoglobinemia subsection of WARNINGS).

Specific interaction studies with lidocaine/prilocaine and class III anti-arrhythmic drugs (eg,

amiodarone, bretylium, sotalol, dofetilide) have not been performed, but caution is advised (see

WARNINGS).

Should lidocaine 2.5% and prilocaine 2.5% cream be used concomitantly with other products containing

lidocaine and/or prilocaine, cumulative doses from all formulations must be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Long-term studies in animals designed to evaluate the carcinogenic potential of

lidocaine and prilocaine have not been conducted.

Metabolites of prilocaine have been shown to be carcinogenic in laboratory animals. In the animal

studies reported below, doses or blood levels are compared with the Single Dermal Administration

(SDA) of 60 g of lidocaine 2.5% and prilocaine 2.5% cream to 400 cm

for 3 hours to a small person

(50 kg). The typical application of lidocaine 2.5% and prilocaine 2.5% cream for one 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 about the same mg/kg

dose in an infant.

Chronic oral toxicity studies of ortho-toluidine, a metabolite of prilocaine, in mice (450 to 7,200 mg/m

; 60 to 960 times SDA) and rats (900 to 4,800 mg/m

; 60 to 320 times SDA) have shown that ortho-

toluidine is a carcinogen in both species. The tumors included hepatocarcinomas/adenomas in female

mice, multiple occurrences of hemangiosarcomas/hemangiomas in both sexes of mice, sarcomas of

multiple organs, transitional-cell carcinomas/papillomas of urinary bladder in both sexes of rats,

subcutaneous fibromas/fibrosarcomas and mesotheliomas in male rats, and mammary gland

fibroadenomas/adenomas in female rats. The lowest dose tested (450 mg/m

in mice, 900 mg/m

rats, 60 times SDA) was carcinogenic in both species. Thus the no-effect dose must be less than 60

times SDA. The animal studies were conducted at 150 to 2,400 mg/kg in mice and at 150 to 800 mg/kg

in rats. The dosages have been converted to mg/m

for the SDA calculations above.

Mutagenesis: The mutagenic potential of lidocaine HCl has been tested in a bacterial reverse (Ames)

assay test in Salmonella, an in vitro chromosomal aberration assay using human lymphocytes and in an in

vivo micronucleus test 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 mcg/mL was genotoxic in

Escherichia coli DNA repair and phage-induction assays. Urine concentrates from rats treated with

ortho-toluidine (300 mg/kg orally; 300 times SDA) were mutagenic when examined in Salmonella

typhimurium in the presence of metabolic activation. Several other tests on ortho-toluidine, including

reverse mutations in five different Salmonella typhimurium strains in the presence or absence of

metabolic activation and a study to detect single strand 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 the fetus (30 mg/kg subcutaneously; 22 times SDA). Reproduction studies with prilocaine have been

performed in rats and have revealed no evidence of impaired fertility or harm to the fetus (300 mg/kg

intramuscularly; 188 times SDA). There are, however, no adequate and well-controlled studies in

pregnant women. Because animal reproduction studies are not always predictive of human response,

lidocaine 2.5% and prilocaine 2.5% cream should be used during pregnancy only if clearly needed.

Reproduction studies have been performed in rats receiving subcutaneous administration of an aqueous

mixture containing lidocaine HCl and prilocaine HCl at 1:1 (w/w). At 40 mg/kg each, a dose equivalent

to 29 times SDA 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 lidocaine 2.5% and

prilocaine 2.5% cream be used concomitantly with other products containing lidocaine and/or

prilocaine, cumulative doses from all formulations must be considered.

Nursing Mothers:

Lidocaine, and probably prilocaine, are excreted in human milk. Therefore, caution should be exercised

when lidocaine 2.5% and prilocaine 2.5% cream is administered to a nursing mother since the milk:

plasma ratio of lidocaine is 0.4 and is not determined for prilocaine.

Pediatric Use:

Controlled studies of lidocaine 2.5% and prilocaine 2.5% cream in children under the age of seven

years have shown less overall benefit than in older children or adults. These results illustrate the

importance of emotional and psychological support of younger children undergoing medical or

surgical procedures.

Lidocaine 2.5% and prilocaine 2.5% cream should be used with care in patients with conditions or

therapy associated with methemoglobinemia (see Methemoglobinemia subsection of WARNINGS).

When using lidocaine 2.5% and prilocaine 2.5% cream in young children, especially infants under the

age of 3 months, care must be taken to insure that the caregiver understands the need to limit the dose

and area of application, and to prevent accidental ingestion (see DOSAGE AND ADMINISTRATION

and Methemoglobinemia).

In neonates (minimum gestation age: 37 weeks) and children weighing less than 20 kg, the area

and duration of application should be limited (see TABLE 2 in Individualization of Dose).

Studies have not demonstrated the efficacy of lidocaine 2.5% and prilocaine 2.5% cream for heel

lancing in neonates.

Geriatric Use:

Of the total number of patients in clinical studies of lidocaine 2.5% and prilocaine 2.5% cream, 180

were age 65 to 74 and 138 were 75 and over. No overall differences in safety or efficacy were

observed between these patients and younger patients. Other reported clinical experience has not

identified differences in responses between the elderly 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 thick layer of lidocaine 2.5% and prilocaine 2.5% cream are very low and well below potentially toxic

levels. However, there are no sufficient data to evaluate quantitative differences in systemic plasma

levels of lidocaine and prilocaine between geriatric and non-geriatric patients following application of

lidocaine 2.5% and prilocaine 2.5% 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

(2.5 hours) than in younger patients (1.5 hours). (See CLINICAL PHARMACOLOGY.)

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal Co., Inc. at 1-800-262-

9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Localized Reactions: During or immediately after treatment with lidocaine 2.5% and prilocaine 2.5%

cream on intact skin, the skin at the site of treatment may develop erythema or edema or may be the locus

of abnormal sensation. Rare cases of discrete purpuric or petechial reactions at the application site have

been reported. Rare cases of hyperpigmentation following the use of lidocaine 2.5% and prilocaine

2.5% cream have been reported. The relationship to lidocaine 2.5% and prilocaine 2.5% cream or the

underlying procedure has not been established. In clinical studies on intact skin involving over 1,300

lidocaine 2.5% and prilocaine 2.5% cream-treated subjects, one or more such local reactions were

noted in 56% of patients, and were generally mild and transient, resolving spontaneously within 1 or 2

hours. There were no serious reactions that were ascribed to lidocaine 2.5% and prilocaine 2.5%

cream.

Two recent reports describe blistering on the foreskin in neonates about to undergo circumcision. Both

neonates received 1.0 g of lidocaine 2.5% and prilocaine 2.5% cream.

In patients treated with lidocaine 2.5% and prilocaine 2.5% 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 lidocaine 2.5% and prilocaine 2.5%

cream-treated patients, one or more application site reactions, usually mild and transient, were noted in

41% of patients. The most common application 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 be managed 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

lidocaine 2.5% and prilocaine 2.5% cream are unlikely due to the small dose absorbed (see

Pharmacokinetics subsection of CLINICAL PHARMACOLOGY). Systemic adverse effects of

lidocaine and/or prilocaine are similar in nature to those observed with other amide local anesthetic

agents including CNS excitation and/or depression (light-headedness, nervousness, apprehension,

euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, 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 the first manifestation

may be drowsiness merging into unconsciousness. Cardiovascular manifestations may include

bradycardia, hypotension and cardiovascular collapse leading to arrest.

OVERDOSAGE

Peak blood levels following a 60 g application to 400 cm

of intact skin for 3 hours are 0.05 to 0.16

µg/mL for lidocaine and 0.02 to 0.10 µg/mL for prilocaine. Toxic levels of lidocaine (> 5 µg/mL)

and/or prilocaine (> 6 µg/mL) cause decreases in cardiac output, total peripheral resistance and mean

arterial pressure. These changes may be attributable to direct depressant effects of these local

anesthetic agents on the cardiovascular system. In the absence of massive topical overdose or oral

ingestion, evaluation should include evaluation of other etiologies for the clinical effects or

overdosage from other sources of lidocaine, prilocaine or other local anesthetics. Consult the package

inserts for parenteral Xylocaine (lidocaine HCl) or Citanest (prilocaine HCl) for further information for

the management of overdose.

DOSAGE AND ADMINISTRATION

Adult Patients − Intact Skin

A thick layer of lidocaine 2.5% and prilocaine 2.5% cream is applied to intact skin and covered with

an occlusive dressing (see INSTRUCTIONS FOR APPLICATION: ).

Minor Dermal Procedures: For minor procedures such as intravenous cannulation and

venipuncture, apply 2.5 grams of lidocaine 2.5% and prilocaine 2.5% cream (1/2 the 5 g tube) over

20 to 25 cm

of skin surface for at least 1 hour. In controlled clinical trials using lidocaine 2.5%

and prilocaine 2.5% cream, two sites were usually prepared in case there was a technical problem

with cannulation or venipuncture at the first site.

Major Dermal Procedures: For more painful dermatological procedures involving a larger skin

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