Aprizio Pak II (Page 3 of 5)

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 2 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 2 ; 60 to 960 times SDA) and rats (900 to 4,800 mg/m 2 ; 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 2 in mice, 900 mg/m 2 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 2 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.

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