LiproZonePak

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 cm2 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/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 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.

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 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.)

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.

To measure 1 gram of lidocaine 2.5% and prilocaine 2.5% cream, the cream should be gently squeezed out of the tube as a narrow strip that is 1.45 inches (3.7 cm) long and 0.26 inches (6.6 mm) wide. The strip of lidocaine 2.5% and prilocaine 2.5% 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.

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 2.5% and prilocaine 2.5% cream, which can be harmful, if applied over too much skin at one time in young children.

When applying lidocaine 2.5% and prilocaine 2.5% 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 2.5% and prilocaine 2.5% cream.

Lidocaine 2.5% and prilocaine 2.5% 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 2.5% and prilocaine 2.5% cream, 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 on open wounds.
2. Keep out of reach of children.
3. If your child becomes very dizzy, excessively sleepy, or develops duskiness of the face or lips after applying lidocaine 2.5% and prilocaine 2.5% cream, remove the cream and contact the child's physician at once.

Call your doctor for medical advice about side effects. You may report side effects to Hi-Tech Pharmacal Co., Inc. at 1-800-262-9010 or FDA at 1-800-FDA-1088.

Manufactured by:
Hi-Tech Pharmacal Co., Inc.
Amityville, NY 11701