PRIKAAN lidocaine and prilocaine

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

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Active ingredient:
LIDOCAINE (UNII: 98PI200987) (LIDOCAINE - UNII:98PI200987)
Available from:
Shoreline Pharmaceuticals, Inc.
INN (International Name):
LIDOCAINE
Composition:
LIDOCAINE 25 mg in 1 g
Prescription type:
PRESCRIPTION DRUG
Authorization status:
New Drug Application Authorized Generic

PRIKAAN- lidocaine and prilocaine

Shoreline Pharmaceuticals, Inc.

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Prikaan™

(Lidocaine 2.5% and Prilocaine 2.5% Cream, USP and Frame Style Transparent Dressing)

DESCRIPTION

Lidocaine 2.5% and Prilocaine 2.5% Cream, USP is an emulsion in which the oil phase is a eutectic

mixture of lidocaine and prilocaine cream 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 5 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 and prilocaine cream contains lidocaine 25 mg, prilocaine 25 mg,

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

sodium hydroxide to adjust to a pH approximating 9, and purified water to 1 gram. Lidocaine and

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

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

CLINICAL PHARMACOLOGY

Mechanism of Action: Lidocaine and prilocaine 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 and prilocaine

cream depend primarily on the duration of application. To provide sufficient analgesia for clinical

procedures such as intravenous catheter placement and venipuncture, 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 graft harvesting, 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 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 lidocaine and prilocaine cream may cause a transient, local blanching followed by

a transient, local redness or erythema.

Pharmacokinetics: Lidocaine and prilocaine 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 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 lidocaine and prilocaine 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

and Prilocaine Cream: Normal Volunteers (N=16)

*Maximum recommended duration of exposure is 4 hours.

Lidocaine and

Prilocaine

Cream (g)

Area

(cm )

Time on

(hrs)

Drug Content

(mg)

Absorbed

(mg)

(μg/mL)

(hr)

lidocaine 1500

0.12

prilocaine 1500

0.07

lidocaine 1500

0.28

prilocaine 1500

0.14

When 60 g of lidocaine and prilocaine 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 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 lidocaine and prilocaine 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 lidocaine and prilocaine 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 and prilocaine cream applied to genital mucous membranes was studied in

two open-label clinical trials. Twenty-nine patients received 10 g of lidocaine and prilocaine cream

applied for 10 to 60 minutes in the vaginal fornices. Plasma concentrations of lidocaine and prilocaine

following 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 (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 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 dehydro- genase

deficiencies and patients taking oxidizing drugs such as antimalarials and sulfonamides are more

susceptible to methemoglobinemia (see Methemoglobinemia subsection of WARNINGS).

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 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. Lidocaine and prilocaine cream was

comparable to subcutaneous lidocaine, but was less efficacious than intradermal lidocaine. Most

patients found lidocaine and prilocaine cream treatment preferable to lidocaine infiltration or ethyl

chloride spray.

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 lidocaine and

prilocaine cream for 2 to 5 hours provided dermal analgesia comparable to lidocaine infiltration.

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 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, lidocaine and

prilocaine cream was less effective than in older children or adults.

Lidocaine and prilocaine cream was compared with placebo in the laser treatment of facial port-wine

stains in 72 pediatric patients (ages 5 to 16). Lidocaine and prilocaine cream was effective in providing

pain relief during laser treatment.

Lidocaine and prilocaine cream alone was compared with 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 lidocaine and prilocaine cream was not effective as

a sole anesthetic agent in managing the pain from the surgical procedure. The administration of

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.

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 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 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 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 lidocaine and prilocaine cream and 20 patients received

placebo). 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 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 lidocaine and prilocaine cream and 23 patients received

placebo) scheduled for infiltration prior to a surgical procedure of the external vulva or genital

mucosa. 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 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 lidocaine and prilocaine cream (1 to

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 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

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

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

the patient's weight.

* These are broad guidelines for avoiding systemic toxicity in applying 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/cm /hr.

The estimated mean (±SD) absorption of prilocaine is 0.077 (±0.036) mg/cm /hr.

Age and Body Weight

Requirements

Maximum Total

Dose of Lidocaine and

Prilocaine cream

Maximum

Application Area**

Maximum

Application Time

0 up to 3 months or < 5 kg

10 cm

1 hour

3 up to 12 months and > 5 kg

20 cm

4 hours

1 to 6 years and > 10 kg

10 g

100 cm

4 hours

7 to 12 years and > 20 kg

20 g

200 cm

4 hours

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

Lidocaine and prilocaine 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 and prilocaine 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 and prilocaine 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 and prilocaine 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 (e.g., 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 and prilocaine cream has an

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

and prilocaine cream only in the external auditory canal, showed no abnormality. Lidocaine and

prilocaine 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 and prilocaine 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, para-aminosalicylic acid, phenacetin,

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

methemoglobinemia.

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

following excessive applications of lidocaine and prilocaine 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 orother caregivers understand the need for careful

application of lidocaine and prilocaine 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 and prilocaine cream, provided the test results can be obtained quickly.

PRECAUTIONS

General: Repeated doses of lidocaine and prilocaine cream may increase blood levels of lidocaine and

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

Care should be taken not to allow lidocaine and prilocaine 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 and prilocaine 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 and prilocaine 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

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

Information for Patients: When lidocaine and prilocaine 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 and prilocaine cream should not be applied near the eyes or on open wounds.

Drug Interactions: Lidocaine and prilocaine 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 (e.g.,

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

WARNINGS).

Should lidocaine and prilocaine 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 and prilocaine cream to 400 cm for 3 hours to a small person (50 kg). The

typical application of lidocaine and prilocaine 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 7200 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 in 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 in Salmonella, an in vitro chromosomal aberration assay using human lymphocytes 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 μg/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 and prilocaine 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 and prilocaine 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 and prilocaine 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 and prilocaine 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 and prilocaine cream should be used with care in patients with conditions or therapy

associated with methemoglobinemia (see Methemoglobinemia subsection of WARNINGS).

When using lidocaine and prilocaine 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 and prilocaine cream for heel lancing in

neonates.

Geriatric Use: Of the total number of patients in clinical studies of lidocaine and prilocaine 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 and prilocaine 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

and prilocaine 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

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

have been reported. The relationship to lidocaine and prilocaine cream or the underlying procedure has

not been established. In clinical studies on intact skin involving over 1,300 lidocaine and prilocaine

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 and prilocaine cream.

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

neonates received 1.0 g of lidocaine and prilocaine cream.

In patients treated with lidocaine and prilocaine 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 and prilocaine 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 and prilocaine 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 and prilocaine 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 and prilocaine 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 and prilocaine 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 area

such as split thickness skin graft harvesting, apply 2 grams of lidocaine and prilocaine cream per 10 cm

of skin and allow to remain in contact with the skin for at least 2 hours.

Adult Male Genital Skin: As an adjunct prior to local anesthetic infiltration, apply a thick layer of

lidocaine and prilocaine cream (1 g/10 cm ) to the skin surface for 15 minutes. Local anesthetic

infiltration should be performed immediately after removal of lidocaine and prilocaine cream.

Dermal analgesia can be expected to increase for up to 3 hours under occlusive dressing and persist for

1 to 2 hours after removal of the cream. The amount of lidocaine and prilocaine absorbed during the

period of application can be estimated from the information in Table 2, ** footnote, in Individualization

of Dose.

Adult Female Patients-Genital Mucous Membranes

For minor procedures on the female external genitalia, such as removal of condylomata acuminata, as

well as for use as pretreatment for anesthetic infiltration, apply a thick layer (5 to 10 grams) of lidocaine

and prilocaine cream for 5 to 10 minutes.

Occlusion is not necessary for absorption, but may be helpful to keep the cream in place. Patients

should be lying down during the lidocaine and prilocaine cream application, especially if no occlusion

is used. The procedure or the local anesthetic infiltration should be performed immediately after the

removal of lidocaine and prilocaine cream.

Pediatric Patients-Intact Skin

The following are the maximum recommended doses, application areas and application times for

lidocaine and prilocaine cream based on a child's age and weight:

Age and Body Weight

Requirements

Maximum Total

Dose of Lidocaine and

Prilocaine Cream

Maximum

Application Area

Maximum

Application Time

0 up to 3 months or < 5 kg

10 cm

1 hour

3 up to 12 months and > 5 kg

20 cm

4 hours

1 to 6 years and > 10 kg

10 g

100 cm

4 hours

7 to 12 years and > 20 kg

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 and prilocaine cream should be restricted to that which corresponds to

the patient's weight (see INSTRUCTIONS FOR APPLICATION).

Practitioners should carefully instruct caregivers to avoid application of excessive amounts of

lidocaine and prilocaine cream (see PRECAUTIONS).

When applying lidocaine and prilocaine cream to the skin of young children, care must be taken to

maintain careful observation of the child to prevent accidental ingestion of lidocaine and prilocaine

cream or the occlusive dressing. A secondary protective covering to prevent inadvertent disruption of

the application site may be useful.

Lidocaine and prilocaine cream should not be used in neonates with a gestational age less than 37

weeks nor in infants under the age of 12 months who are receiving treatment with

methemoglobin-inducing agents (see Methemoglobinemia subsection of WARNINGS).

When lidocaine and prilocaine cream (lidocaine 2.5% and prilocaine 2.5%) is used concomitantly with

other products containing local anesthetic agents, the amount absorbed from all formulations must be

considered (see Individualization of Dose). The amount absorbed in the case of lidocaine and prilocaine

cream is determined by the area over which it is applied and the duration of application under occlusion

(see Table 2, ** footnote, in Individualization of Dose).

Although the incidence of systemic adverse reactions with lidocaine and prilocaine cream is very low,

caution should be exercised, particularly when applying it over large areas and leaving it on for longer

than 2 hours. The incidence of systemic adverse reactions can be expected to be directly proportional

to the area and time of exposure (see Individualization of Dose).

INSTRUCTIONS FOR APPLICATION:

To measure 1 gram of lidocaine and prilocaine cream, the Cream should be gently squeezed out of the

tube as a narrow strip that is 1.5 inches (3.8 cm) long and 0.2 inches (5 mm) wide. The strip of lidocaine

and prilocaine cream should be contained within the lines of the diagram shown below.

Use the number of strips that equals your dose, like the examples in the table below.

Dosing Information

1 gram = 1 strip

2 grams = 2 strips

2.5 grams = 2.5 strips

For adult and pediatric patients, apply ONLY as prescribed by your physician.

If your child is below the age of 3 months or small for their age, please inform your doctor before

applying lidocaine and prilocaine cream, which can be harmful, if applied over too much skin at one

time in young children.

When applying lidocaine and prilocaine cream to the intact skin of young children, it is important that

they be carefully observed by an adult in order to prevent the accidental ingestion of or eye contact with

lidocaine and prilocaine cream.

Lidocaine and prilocaine cream must be applied to intact skin at least 1 hour before the start of a routine

procedure and for 2 hours before the start of a painful procedure. A protective covering of the cream is

not necessary for absorption but may be helpful to keep the cream in place.

If using a protective covering, your doctor will remove it, wipe off the lidocaine and prilocaine cream,

and clean the entire area with an antiseptic solution before the procedure. The duration of effective skin

anesthesia will be at least 1 hour after removal of the protective covering.

Precautions

1. Do not apply near eyes or open wounds.

2. Keep out of the reach of children.

3. If your child becomes very dizzy, excessively sleepy, or develops duskiness of the face or lips

after applying lidocaine and prilocaine cream, remove the cream and contact the child's physician at

once.

HOW SUPPLIED

Lidocaine 2.5% and Prilocaine 2.5% Cream, USP is available as the following:

NDC 0591-2070-30 30 gram/tube packed individually, in a child-resistant tube.

KEEP CONTAINER TIGHTLY CLOSED AT ALL TIMES WHEN NOT IN USE.NOT FOR

OPHTHALMIC USE.

Storage: Store at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature].

Rx only

Keep out of the reach of children.

For all medical inquiries contact:

ACTAVIS

Medical Communications

Parsippany, NJ 07054

1-800-272-5525

Manufactured By:

IGI Laboratories Inc.

Buena, NJ 08310 USA

Prikaan™

(Lidocaine 2.5% and Prilocaine 2.5% Cream, USP and Frame Style Transparent Dressing)

Packaged in the USA for:

Shoreline Pharmaceuticals, Inc.

Panorama City, CA 91402

For questions or information

call toll-free: 818-643-4237

Rev. 36744-01

PRIKAAN

lidocaine and prilocaine kit

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 9 6 21-8 28

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 9 6 21-8 28 -0 0

1 in 1 PACKAGE

0 9 /0 8 /20 16

Quantity of Parts

Part #

Package Quantity

Total Product Quantity

Pa rt 1

3 TUBE

9 0 g

Part 1 of 1

LIDOCAINE AND PRILOCAINE

lidocaine and prilocaine cream

Shoreline Pharmaceuticals, Inc.

Product Information

Ite m Code (Source )

NDC:0 59 1-20 70

Route of Administration

TOPICAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LIDO CAINE (UNII: 9 8 PI20 0 9 8 7) (LIDOCAINE - UNII:9 8 PI20 0 9 8 7)

LIDOCAINE

25 mg in 1 g

PRILO CAINE (UNII: 0 46 O35D44R) (PRILOCAINE - UNII:0 46 O35D44R)

PRILOCAINE

25 mg in 1 g

Inactive Ingredients

Ingredient Name

Stre ng th

PEG-55 HYDRO GENATED CASTO R O IL (UNII: 0 WZF150 6 N9 )

CARBO MER HO MO PO LYMER TYPE B ( ALLYL SUCRO SE CRO SSLINKED) (UNII: Z135WT9 20 8 )

WATER (UNII: 0 59 QF0 KO0 R)

SO DIUM HYDRO XIDE (UNII: 55X0 4QC32I)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:0 59 1-20 70 -30

1 in 1 CARTON

1

30 g in 1 TUBE; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA autho rized generic

NDA0 19 9 41

11/12/20 12

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA autho rized generic

NDA0 19 9 41

0 9 /0 8 /20 16

Labeler -

Shoreline Pharmaceuticals, Inc. (078542781)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

PureTek Co rpo ratio n

78 59 6 10 46

pa c k(6 9 6 21-8 28 )

Revised: 9/2016

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