Label: LIDOCAINE AND PRILOCAINE cream

Rx only

Lidocaine and Prilocaine Cream, USP 2.5%/2.5% is an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine 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:

1. C 14H 22N 2OM.W. 234.3

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:

1. C 13H 20N 2OM.W. 220.3

Each gram of Lidocaine and Prilocaine Cream, USP 2.5%/2.5% contains lidocaine 25 mg, prilocaine 25 mg, PEG-60 hydrogenated castor oil (as emulsifier), carbomer homopolymer Type B (as a thickening agent), sodium hydroxide to adjust to a pH approximating 9, and purified water to 1 gram. Lidocaine and Prilocaine Cream, USP 2.5%/2.5% 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.

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 (e.g., 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 2). 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 2/hr.

The estimated mean (±SD) absorption of prilocaine is 0.077 (±0.036) mg/cm 2/hr.

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.

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 skinfor local analgesia.

• genital mucous membranesfor 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).

Lidocaine and Prilocaine Cream 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.

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

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Lidocaine and Prilocaine Cream and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

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.

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.

Peak blood levels following a 60 g application to 400 cm 2of 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.

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 2of 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 2of 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 2) 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:

Table 4: Pediatric Doses:

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 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.

1.5 x 0.2 inches

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 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.

To report SUSPECTED ADVERSE REACTIONS contact Padagis at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 

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

NOT FOR OPHTHALMIC USE.

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

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature].

Rx only

Keep out of the reach of children.

Manufactured by
Groupe Parima Inc., Montreal, Quebec H4S 1X6, Canada

Distributed by
Padagis
Allegan, MI 49010

15R00 RC J2

Rev. 11-22