Lidocaine and Prilocaine: Package Insert and Label Information (Page 2 of 3)

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 cm2 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/m2 ; 60 to 960 times SDA) and rats (900 to 4,800 mg/m2 ; 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/m2 in mice, 900 mg/m2 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/m2 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 cm2 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

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