LIDOCAINE AND PRILOCAINE

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 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: 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: 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 emulsifiers), carbomer homopolymer type B, 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 USP, 2.5%/2.5% is 1.00. Lidocaine Structure with formal and Mole wt Prilocaine with formula and mole weight

Lidocaine and Prilocaine Cream USP, 2.5%/2.5% (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, 2.5%/2.5% 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 effect observed in animal studies (see WARNINGS ).

Adult Patients-Intact Skin A thick layer of Lidocaine and Prilocaine Cream USP, 2.5%/2.5% 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 USP, 2.5%/2.5% (1/2 the 5 g tube) over 20 to 25 cm 2 of skin surface for at least 1 hour. In controlled clinical trials using Lidocaine and Prilocaine Cream USP, 2.5%/2.5%, 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 USP, 2.5%/2.5% per 10 cm 2 of 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 USP, 2.5%/2.5% (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 USP, 2.5%/2.5%. 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 acuminate, as well as for use as pretreatment for anesthetic infiltration, apply a thick layer (5 to 10 grams) of Lidocaine and Prilocaine Cream USP, 2.5%/2.5% 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 USP, 2.5%/2.5% 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 USP, 2.5%/2.5%. Pediatric Patients-Intact Skin The following are the maximum recommended doses, application areas and application times for Lidocaine and Prilocaine Cream USP, 2.5%/2.5% based on a child's age and weight: Age and Body Weight Requirements Maximum Total Dose of Lidocaine and Prilocaine Cream USP, 2.5%/2.5% Maximum Application Area Maximum Application Time 0 up to 3 months or < 5 kg 1 g 10 cm 2 1 hour 3 up to 12 months and >5 kg 2 g 20 cm 2 4 hours 1 to 6 years and > 10 kg 10 g 100 cm 2 4 hours 7 to 12 years and > 20 kg 20 g 200 cm 2 4 hours 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 USP, 2.5%/2.5% 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 USP, 2.5%/2.5% (see PRECAUTIONS ). When applying Lidocaine and Prilocaine Cream USP, 2.5%/2.5% 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 USP, 2.5%/2.5% or the occlusive dressing. A secondary protective covering to prevent inadvertent disruption of the application site may be useful. Lidocaine and Prilocaine cream, 2.5%/2.5% 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 USP, 2.5%/2.5% 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 USP, 2.5%/2.5% 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 USP, 2.5%/2.5% 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 ).

Lidocaine and prilocaine cream, 2.5%/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.

Localized Reactions During or immediately after treatment with lidocaine and prilocaine cream, 2.5%/2.5% 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, 2.5%/2.5% have been reported. The relationship to lidocaine and prilocaine cream, 2.5%/2.5% or the underlying procedure has not been established. In clinical studies on intact skin involving over 1,300 lidocaine and prilocaine cream, 2.5%/2.5%-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, 2.5%/2.5%. 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, 2.5%/2.5%. In patients treated with lidocaine and prilocaine cream, 2.5%/2.5% 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, 2.5%/2.5%-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, 2.5%/2.5%, 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 report SUSPECTED ADVERSE REACTIONS , contact PAI Pharma at 1-800-845-8210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Lidocaine and prilocaine cream, 2.5%/2.5% 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. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 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 and prilocaine cream, 2.5%/2.5% be used concomitantly with other products containing lidocaine and/or prilocaine, cumulative doses from all formulations must be considered.

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) [see USP Controlled Room Temperature]. Do Not Freeze. DISTRIBUTED BY PAI Pharma Greenville, SC 29605 www.paipharma.com Rev. 03/25 I10020325