Emla (Lidocaine – Prilocaine)

EMLA® Cream/Patch

Astra

Lidocaine – Prilocaine

Topical Anesthetic for Dermal Analgesia

Action And Clinical Pharmacology: EMLA (Eutectic Mixture of Local Anesthetics) is a 1:1 oil/water emulsion of a eutectic mixture of lidocaine and prilocaine bases. Dermal analgesia is a result of the migration of lidocaine and prilocaine into the epidermal and dermal layers of the skin followed by the accumulation of these agents in the vicinity of dermal pain receptors and nerve endings. Lidocaine and prilocaine are both amide-type local anesthetic agents. They stabilize the neuronal membrane preventing the initiation and conduction of nerve impulses, thereby effecting local anesthetic action. EMLA provides dermal analgesia; the depth of which depends upon the application time and the applied dose. Analgesia may be less for deeper structures.

EMLA may produce a transient biphasic vascular response involving initial vasoconstriction followed by vasodilation at the application site (see Adverse Effects). In patients with atopic dermatitis, a shorter biphasic response involving initial vasoconstriction followed by vasodilation may be seen. Erythema may be observed after 30 to 60 minutes.

Systemic absorption of lidocaine and prilocaine from EMLA is dependent upon the applied dose, application time, the thickness of the skin which varies between different areas of the body, and other conditions of the skin.

It is well known that patients with atopic dermatitis show abnormal vascular reactions to pharmacological stimuli. In patients with atopic dermatitis, percutaneous absorption of EMLA is more rapid and greater than in normal skin. In 2 patients, within 1 hour after application of 4 to 6 g EMLA to a 25 cmarea of the forearm, lidocaine and prilocaine plasma levels were higher than those observed in normal skin. However, in these patients, the systemic plasma levels were 100 times lower than those associated with toxicity. There have been 2 reports of purpura at the application site after 60 minutes. After a repeated application of 30 minutes in 1 of these patients, no reaction was seen. In patients with atopic dermatitis, a shorter application time should be used (see Precautions). It should be noted, however, that dermatological procedures were not performed in the above patients. Clinical data are not available at present to permit dosage recommendations.

Prilocaine has a larger distribution volume than lidocaine which results in lower plasma concentrations of prilocaine when equal amounts of prilocaine and lidocaine are administered. At concentrations produced by application of EMLA, lidocaine is approximately 60 to 80% bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 µg/mL of free base), the plasma protein binding of lidocaine is concentration dependent. Prilocaine is 55% bound to plasma proteins.

It is not known if lidocaine or prilocaine are metabolized in the skin. Lidocaine is metabolized rapidly by the liver to a number of metabolites including monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which have pharmacologic activity similar to, but less potent than that of lidocaine. Prilocaine is metabolized in both the liver and kidneys by amidases to various metabolites including ortho-toluidine and N-n-propylalanine.

Intact Skin: Local analgesia of intact skin is achieved after 60 minutes’ application under an occlusive dressing. The analgesic efficacy and the depth of skin analgesia have been shown to increase with application times up to 120 minutes. The duration of analgesia after a 1- to 2-hour application is at least 2 hours. After a longer application time than 5 hours, the analgesia will decrease.

The depth of analgesia, as measured by the insertion of a needle through the skin, is about 3 mm after a 60-minute application, about 4 mm after a 90-minute application and about 5 mm after a 120-minute application.

Both the analgesic efficacy and depth continue to increase after the removal of the cream from the skin surface, i.e., after a 60-minute application time to the dorsum of the hand, the analgesic efficacy continued to increase for 15 minutes, and persisted for a total of 75 minutes after removal of the cream.

After application to the thigh in adults (60 g cream/400 cmfor 3 hours), the extent of absorption was approximately 5% of lidocaine and prilocaine. Maximum plasma concentrations (mean 0.12 and 0.07 µg/mL respectively), were reached approximately 2 to 6 hours after the application.

The extent of systemic absorption was approximately 10% following application to the face (10 g/100 cmfor 2 hours). Maximum plasma levels (mean 0.16 µg/mL lidocaine and 0.06 µg/mL prilocaine) were reached after approximately 1.5 to 3 hours.

In adults, a thick layer of EMLA cream (corresponding to approximately 150 g) has been applied to intact skin areas of up to 1 300 cmfor application times of up to 3 hours. The highest individual plasma levels observed were 1.1 µg/mL lidocaine and 0.2 µg/mL prilocaine. These levels were below those at which symptoms of toxicity would be expected to occur (5 to 10 µg/mL either agent; see also Adverse Effects).

In clinical studies with children, EMLA patch has been shown to be as efficacious and safe as EMLA cream in anesthetizing the skin when applied for 60 to 180 minutes prior to venipuncture. There have been no observed differences in local skin reactions which were of clinical significance.

Genital Mucosa: Absorption from the genital mucosa is more rapid, i.e., maximum plasma concentrations are reached 20 to 45 minutes after application as opposed to 1.5 to 6 hours after application to intact skin. As a result, onset time and duration of action are shorter than after application to intact skin.

After the application of 10 g EMLA cream for 10 minutes to vaginal mucosa, maximum plasma concentrations of lidocaine and prilocaine (mean 0.18 µg/mL and 0.15 µg/mL, respectively) were reached after 20 to 45 minutes.

Leg Ulcers: After application of 5 to 10 g of EMLA to leg ulcers 15 to 64 cmin size, for 30 minutes, maximum plasma concentrations of lidocaine ranged from 0.05 to 0.25 µg/mL. In one individual, 0.84 µg/mL was reached. Maximum plasma concentrations of prilocaine ranged from 0.02 to 0.08 µg/mL. These maximum concentrations were reached within 1 to 2.5 hours. After prolonged application (24 hours) of 1 g EMLA/10 cmto leg ulcers 50 to 100 cm maximum plasma concentrations of lidocaine and prilocaine ranged from 0.18 to 0.7 µg/mL and 0.06 to 0.28 µg/mL, and were observed 2 to 4 hours (in one patient 6 to 8 hours) after administration. With repeated applications, i.e., up to 15 times within a 1-month period, plasma levels of lidocaine and the metabolites, monoglycinexylidide, glycinexylidide and 2,6-xylidine, and prilocaine and the metabolite, o-toluidine, were low with no apparent accumulation.

No negative influence on ulcer healing or bacterial flora has been observed. In studies, EMLA was shown to reduce the number of cleansing sessions required to achieve a clean ulcer compared to placebo cream, and reduced the postcleansing pain up to 4 hours after debridement.

Indications And Clinical Uses: Cream: Topical analgesia of intact skin in connection with needle insertion, e.g., i.v. catheters or prior to blood sampling; superficial surgical procedures, e.g., removal of molluscum contagiosum, split-skin grafting, electrolysis; laser treatment.

Topical analgesia of genital mucosa in connection with: local infiltration anesthesia; surgical procedures lasting not longer than 10 minutes on small superficial localized lesions, e.g., removal of condylomata by laser or cautery, and biopsies.

Topical analgesia of leg ulcers in connection with: mechanical cleansing/debridement, e.g., the removal of necrotic tissue and debris by curettes, scissors, tweezers, etc.

Patch: Topical analgesia of intact skin in connection with: needle insertion, e.g., i.v. catheters or prior to blood sampling.

Contra-Indications: Patients who are hypersensitive to local anesthetics of the amide type or to any other component of the product (see Supplied); with congenital or idiopathic methemoglobinemia; who are less than 6 months of age, until further clinical data are available; children between 6 to 12 months requiring treatment with methemoglobin-inducing agents e.g., sulfonamides.

Manufacturers’ Warnings In Clinical States: EMLA is not recommended in any clinical situation where it can penetrate or migrate into the middle ear. Tests on laboratory animals (guinea pigs) have shown that EMLA has an ototoxic effect when instilled into the middle ear. When the same animals were exposed to EMLA in the external auditory canal, no abnormalities were seen. EMLA causes minor structural damage to the tympanic membrane in rats when applied directly to the membrane. The relevance of this finding to the clinical situation is not known.

Precautions: Due to insufficient data on absorption, EMLA should not be applied to open wounds as a result of trauma. Note: Leg ulcers often follow a slight trauma but are not classified as traumatic wounds.

Care should be taken when applying EMLA to patients with atopic dermatitis. A more rapid and greater absorption through the skin is observed in these patients. A shorter application time should be used (see Pharmacology). Sufficient data regarding absorption and local reactions are not available at present. Clinical data to permit dosage recommendations are also not available.

EMLA should not be applied to or near to the eyes as it causes corneal irritation. This reaction may be reversible. Damage to the eye may also occur from undetected foreign bodies.

Special care should be employed to reduce the risk of rubbing the eye with EMLA. Special care should also be employed to ensure the occlusive bandage or patch is secure. This will avoid accidental dislocation and exposure of EMLA, especially in young children.

Drug Interactions: Prilocaine, a component of EMLA, accentuates the formation of methemoglobin (MetHb) by a mechanism involving metabolism of prilocaine to o-toluidine and subsequent oxidation of hemoglobin to MetHb. The in vivo reduction of MetHb back to 02Hb is dependent on the presence of MetHb reductase.

In infants below the age of 3 months, the MetHb reductase levels are lower than in older children and in adults. In these infants and in patients treated with other drugs known to induce methemoglobinemia, i.e., sulfonamides, EMLA may induce the formation of methemoglobin and result in overt clinical signs of methemoglobinemia (see Adverse Effects).

With large doses of EMLA, consideration should be given to the risk of systemic toxicity in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics since the toxic effects are additive.

Pregnancy: The safety of EMLA during pregnancy has not been established in humans. Lidocaine and prilocaine cross the placental barrier and may be absorbed by the fetal tissues. It is reasonable to assume that lidocaine and prilocaine have been used in a large number of pregnant women and women of childbearing age. No specific disturbances to the reproductive process have so far been reported, e.g., an increased incidence of malformations. However, care should be given during early pregnancy when maximum organogenesis takes place.

Lactation: Lidocaine and, in all probability, prilocaine, are excreted in human milk, but in such small quantities that there is generally no risk of the infant being affected at therapeutic dose levels due to low systemic absorption.

Children: Until further clinical data are available, EMLA should not be used in children under the age of 6 months, children between 6 and 12 months of age receiving treatment with methemoglobin-inducing agents such as sulfonamides (see Adverse Effects).

Adverse Reactions: Intact Skin/Genital Mucosa: Common Events (>1%): Transient local reactions at the application site such as paleness, erythema (redness) and edema. Uncommon Events (>0.1%)
Leg Ulcer: Common Events (>1%): Transient local reactions at the application site such as paleness, erythema (redness) and edema. Skin sensations, e.g., an initial usually mild burning, itch or warmth at the application site.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Rare cases of methemoglobinemia have been reported. In the unlikely event of toxicity following epidermal application of EMLA, signs of systemic toxicity anticipated would be similar in nature to those observed following other routes of administration of local anesthetics.

Local anesthetic toxicity is manifested by symptoms of nervous system excitation and in severe cases, central nervous and cardiovascular depression.

Severe neurological symptoms (convulsions, CNS depression) must be treated symptomatically by respiratory support and the administration of anticonvulsive drugs. Methemoglobinemia may be treated with methylene blue slowly injected i.v.

Dosage And Administration: Cream: Intact Skin: A thick layer of EMLA cream is applied to the skin and covered with an occlusive dressing for at least 1 hour. The occlusive dressing may remain in place for up to 5 hours. No benefit will be derived from application longer than 5 hours.

Minor procedures, e.g., needle insertion and surgical treatment of localized lesions: 1/2 of a small tube (approximately 2.5 g). Minimum application time: at least 1 hour.

Dermal procedures on larger areas, e.g., split-skin grafting, electrolysis: A thick layer should be applied to the skin (approximately 1.5 to 2 g/10 cm. Minimum application time: at least 2 hours.

Laser treatment, e.g., removal of warts, tattoos, port-wine stains, dermatofibromata, nevi: A fairly thick layer should be applied to the skin (approximately 1 to 2 g/10 cm.

Infants between 6 and 12 months of age: At least 1 hour prior to the start of the procedure, a thick layer should be applied to the skin and covered with an occlusive dressing (see also Precautions). The total dose should not exceed 2 g with the total treated skin area not being larger than 16 cm The application time should not be longer than 4 hours. Pharmacokinetic data for parameters which exceed these recommendations are not available at present.

Infants under the age of 6 months: Not recommended (see Contraindications).

Genital Mucosa: For all procedures, the cream should be left in contact with the mucosa for 5 to 10 minutes. Occlusion is not necessary. The surgical treatment should commence immediately after removal of the cream.

Local infiltration anesthesia, 1/2 of a small tube (approximately 2.5 g) applied to the site selected for infiltration.

Surgical procedures lasting not longer than 10 minutes on localized lesions, e.g., removal of condylomata by laser or cautery, and biopsies: 1/2 of a small tube (approximately 2.5 g) per lesion.

Infants under the age of 6 months: Not recommended (see Contraindications).

Leg Ulcers: A thick layer of cream is applied to the leg ulcers and covered with an occlusive dressing for at least 30 minutes. An application time of 60 minutes may improve analgesia further, i.e., a longer application time may be required for removal of necrotic tissue compared to fibrinous plaques due to a thicker and more resistant penetration barrier.

Leg ulcers with clinical signs of infection should not be debrided.

The cleansing procedure should start within 10 minutes of removal of the cream. Clinical data from a longer waiting period are not available.

EMLA cream has been used prior to the cleansing of leg ulcers up to 15 times at intervals of 1 to 4 days within a 1- to 2-month period with no apparent loss of effect or increase in local reactions.

Cleansing/Debridement of Leg Ulcers: A thick layer of cream is applied to the leg ulcers (approximately 1 to 2 g/10 cm. Single-dose Use: a maximum of 10 g/100 cm Repeated Doses After 24 to 48 hours: a maximum of 10 g/50 cm Minimum Application Time: at least 30 minutes.

Pharmacokinetic data for doses larger than 10 g are not available.

Infants under the age of 6 months: Not recommended (see Contraindications).

Patch: Minor procedures, e.g., needle insertion. The patch is applied to the skin area selected. Minimum application time: at least 1 hour.

Care should be taken that the patch does not become detached (especially in young children) during the 60-minute wait.

Infants between 6 and 12 months of age: EMLA patch should be applied at least 1 hour prior to the start of the procedure. No more than 2 EMLA patches should be applied at the same time. No increase in methemoglobin levels has been observed following application of 2 g EMLA cream for 4 hours.

Infants under the age of 6 months: Not recommended (see Contraindications).

Availability And Storage: Cream: Each g of cream (5%) contains: lidocaine 25 mg and prilocaine 25 mg as a 1:1 liquid eutectic mixture in a soft, white oil in water cream. Nonmedicinal ingredients: carboxypolymethylene, polyoxyethylene hydrogenated castor oil, sodium hydroxide to adjust pH to 8.7 to 9.7 and purified water. Tubes of 5 g with 2 occlusive dressings and tubes of 30 g without dressings. Store at room temperature (15 to 30°C). Protect from freezing.

Patch: Each single dose unit patch in the form of an occlusive dressing contains: a laminate backing, an absorbent cellulose disc, and an adhesive tape ring. The disc contains 1 g of the EMLA emulsion, the active contact surface area being approximately 10 cm The surface area of the entire patch is approximately 40 cm Boxes of 2 and 10 single use patches. Store at room temperature 15 to 30°C. Protect from freezing. Single use. Do not reuse.

EMLA® Cream/Patch Astra Lidocaine – Prilocaine Topical Anesthetic for Dermal Analgesia

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