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 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.
See Use in Pregnancy.
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.
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.
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.
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 ensure 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.
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).
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 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 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 (lightheadedness, 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.
Peak blood levels following a 60 g application to 400 cm2 of intact skin for 3 hours are 0.05 to 0.16 mcg/mL for lidocaine and 0.02 to 0.10 mcg/mL for prilocaine. Toxic levels of lidocaine (>5 mcg/mL) and/or prilocaine (>6 mcg/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.
A thick layer of lidocaine and prilocaine cream is applied to intact skin and covered with an occlusive dressing (see INSTRUCTIONS FOR APPLICATION).
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 cm2 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.
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