Lidocaine and Prilocaine

Localized Reactions: During or immediately after treatment with EMLA (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 EMLA (lidocaine and prilocaine) Cream have been reported. The relationship to EMLA (lidocaine and prilocaine) Cream or the underlying procedure has not been established. In clinical studies on intact skin involving over 1,300 EMLA (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 EMLA (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 EMLA (lidocaine and prilocaine) Cream.

In patients treated with EMLA (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 EMLA (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 EMLA (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.

Mechanism of Action: Lidocaine and Prilocaine cream, 2.5%/2.5%, applied to intact skin under occlusive dressing, provides dermal analgesia by the release of Lidocaine and Prilocaine from the cream into the epidermal and dermal layers of the skin and by the accumulation of Lidocaine and Prilocaine in the vicinity of dermal pain receptors and nerve endings. Lidocaine and Prilocaine are amide-type local anesthetic agents. Both Lidocaine and Prilocaine stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action.

The onset, depth and duration of dermal analgesia on intact skin provided by Lidocaine and Prilocaine cream, 2.5%/2.5% depends primarily on the duration of application. To provide sufficient analgesia for clinical procedures such as intravenous catheter placement and venipuncture, Lidocaine and Prilocaine cream, 2.5%/2.5% should be applied under an occlusive dressing for at least 1 hour. To provide dermal analgesia for clinical procedures such as split skin graft harvesting, Lidocaine and Prilocaine cream, 2.5%/2.5% should be applied under occlusive dressing for at least 2 hours. Satisfactory dermal analgesia is achieved 1 hour after application, reaches maximum at 2 to 3 hours, and persists for 1 to 2 hours after removal. Absorption from the genital mucosa is more rapid and onset time is shorter (5 to 10 minutes) than after application to intact skin. After a 5 to 10 minute application of Lidocaine and Prilocaine cream, 2.5%/2.5% to female genital mucosa, the average duration of effective analgesia to an argon laser stimulus (which produced a sharp, pricking pain) was 15 to 20 minutes (individual variations in the range of 5 to 45 minutes).

Dermal application of Lidocaine and Prilocaine cream, 2.5%/2.5% may cause a transient, local blanching followed by a transient, local redness or erythema.

Pharmacokinetics: Lidocaine and Prilocaine cream, 2.5%/2.5% is a eutectic mixture of lidocaine 2.5% and prilocaine 2.5% formulated as an oil in water emulsion. In this eutectic mixture, both anesthetics are liquid at room temperature (see DESCRIPTION) and the penetration and subsequent systemic absorption of both prilocaine and lidocaine are enhanced over that which would be seen if each component in crystalline form was applied separately as a 2.5% topical cream.

Absorption- The amount of Lidocaine and Prilocaine systemically absorbed from Lidocaine and Prilocaine cream, 2.5%/2.5% is directly related to both the duration of application and to the area over which it is applied. In two pharmacokinetic studies, 60 g of Lidocaine and Prilocaine cream, 2.5%/2.5% (1.5 g lidocaine and 1.5 g prilocaine) was applied to 400 cm2 of intact skin on the lateral thigh and then covered by an occlusive dressing. The subjects were then randomized such that one-half of the subjects had the occlusive dressing and residual cream removed after 3 hours, while the remainder left the dressing in place for 24 hours. The results from these studies are summarized below.

* Maximum recommended duration of exposure is 4 hours.

When 60 g of Lidocaine and Prilocaine cream, 2.5%/2.5% was applied over 400 cm2 for 24 hours, peak blood levels of lidocaine are approximately 1/20 the systemic toxic level. Likewise, the maximum prilocaine level is about 1/36 the toxic level. In a pharmacokinetic study, Lidocaine and Prilocaine cream, 2.5%/2.5% was applied to penile skin in 20 adult male patients in doses ranging from 0.5 g to 3.3 g for 15 minutes. Plasma concentrations of Lidocaine and Prilocaine following Lidocaine and Prilocaine cream, 2.5%/2.5% application in this study were consistently low (2.5-16 ng/mL for lidocaine and 2.5-7 ng/mL for prilocaine). The application of Lidocaine and Prilocaine cream, 2.5%/2.5% to broken or inflamed skin, or to 2,000 cm2 or more of skin where more of both anesthetics are absorbed, could result in higher plasma levels that could, in susceptible individuals, produce a systemic pharmacologic response.

The absorption of Lidocaine and Prilocaine cream, 2.5%/2.5% applied to genital mucous membranes was studied in two open-label clinical trials. Twenty-nine patients received 10 g of Lidocaine and Prilocaine cream, 2.5%/2.5% applied for 10 to 60 minutes in the vaginal fornices. Plasma concentrations of Lidocaine and Prilocaine following Lidocaine and Prilocaine cream, 2.5%/2.5% application in these studies ranged from 148 to 641 ng/mL for lidocaine and 40 to 346 ng/mL for prilocaine and time to reach maximum concentration (tmax) ranged from 21 to 125 minutes for lidocaine and from 21 to 95 minutes for prilocaine. These levels are well below the concentrations anticipated to give rise to systemic toxicity (approximately 5000 ng/mL for Lidocaine and Prilocaine).

Distribution- When each drug is administered intravenously, the steady-state volume of distribution is 1.1 to 2.1 L/kg (mean 1.5, ±0.3 SD, n=13) for lidocaine and is 0.7 to 4.4 L/kg (mean 2.6, ±1.3 SD, n=13) for prilocaine. The larger distribution volume for prilocaine produces the lower plasma concentrations of prilocaine observed when equal amounts of prilocaine and lidocaine are administered. At concentrations produced by application of Lidocaine and Prilocaine cream, 2.5%/2.5%, lidocaine is approximately 70% bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 mcg/mL of free base) the plasma protein binding of lidocaine is concentration dependent. Prilocaine is 55% bound to plasma proteins. Both Lidocaine and Prilocaine cross the placental and blood brain barrier, presumably by passive diffusion.

Metabolism- 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. The metabolite, 2,6-xylidine, has unknown pharmacologic activity. Following intravenous administration, MEGX and GX concentrations in serum range from 11 to 36% and from 5 to 11% of lidocaine concentrations, respectively. Prilocaine is metabolized in both the liver and kidneys by amidases to various metabolites including ortho-toluidine and N-n-propylalanine. It is not metabolized by plasma esterases. The ortho-toluidine metabolite has been shown to be carcinogenic in several animal models (see Carcinogenesis subsection of PRECAUTIONS). In addition, ortho-toluidine can produce methemoglobinemia following systemic doses of prilocaine approximating 8 mg/kg (see ADVERSE REACTIONS). Very young patients, patients with glucose-6-phosphate dehydrogenase deficiencies and patients taking oxidizing drugs such as antimalarials and sulfonamides are more susceptible to methemoglobinemia (see Methemoglobinemia subsection of PRECAUTIONS).

Elimination- The terminal elimination half-life of lidocaine from the plasma following IV administration is approximately 65 to 150 minutes (mean 110, ±24 SD, n=13). More than 98% of an absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. The systemic clearance is 10 to 20 mL/min/kg (mean 13, ±3 SD, n=13). The elimination half-life of prilocaine is approximately 10 to 150 minutes (mean 70, ±48 SD, n=13). The systemic clearance is 18 to 64 mL/min/kg (mean 38, ±15 SD, n=13). During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours). No studies are available on the intravenous pharmacokinetics of prilocaine in elderly patients.

Pediatrics- Some pharmacokinetic (PK) data are available in infants (1 month to <2 years old) and children (2 to <12 years old). One PK study was conducted in 9 full-term neonates (mean age: 7 days and mean gestational age: 38.8 weeks). The study results show that neonates had comparable plasma Lidocaine and Prilocaine concentrations and blood methemoglobin concentrations as those found in previous pediatric PK studies and clinical trials. There was a tendency towards an increase in methemoglobin formation. However, due to assay limitations and very little amount of blood that could be collected from neonates, large variations in the above reported concentrations were found.

Special Populations- No specific PK studies were conducted. The half-life may be increased in cardiac or hepatic dysfunction. Prilocaine's half-life also may be increased in hepatic or renal dysfunction since both of these organs are involved in prilocaine metabolism.

Peak blood levels following a 60 g application to 400 cm2 of intact skin for 3 hours are 0.05 to 0.16 mcg/mL for lidocaine and 0.02 to 0.10 mcg/mL for prilocaine. Toxic levels of lidocaine (>5 mcg/mL) and/or prilocaine (>6 mcg/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.

(LYE doe kane & PRIL oh kane)

EMLA: 1 to 2 hours after removal; Genital mucosa: 15 to 20 minutes after application (range: 5 to 45 minutes)

Oraqix: ~20 minutes

US labeling:

Cream: Topical anesthetic for use on normal intact skin to provide local analgesia; for use on genital mucous membranes for superficial minor surgery; and as pretreatment for infiltration anesthesia.

Periodontal gel: Topical anesthetic for use in periodontal pockets during scaling and/or root planing procedures

Canadian labeling:

Cream: Topical anesthetic for use on intact skin in connection with: IV cannulation or venipuncture; superficial surgical procedures (eg, split skin grafting, electrolysis, removal of molluscum contagiosum); laser treatment for superficial skin surgery (eg, telangiectasia, port wine stains, warts, moles, skin nodules, scar tissue); surgical procedures of genital mucosa (≤10 minutes) on small superficial localized lesions (eg, removal of condylomata by laser or cautery, biopsies); local infiltration anesthesia in genital mucous membranes; mechanical cleansing/debridement of leg ulcers; vaccination with measles-mumps-rubella (MMR), diphtheria-pertussis-tetanus-poliovirus (DPTP), Haemophilus influenzae b, and hepatitis B.

Patch: Topical anesthetic for use on intact skin in connection with IV cannulation or venipuncture; vaccination with measles-mumps-rubella (MMR), diphtheria-pertussis-tetanus-poliovirus (DPTP), Haemophilus influenzae b, and hepatitis B.

Periodontal gel: Topical anesthetic for use in periodontal pockets during scaling and/or root planing procedures

There are no dosage adjustments provided in the manufacturer labeling. Lidocaine and prilocaine primarily undergo hepatic metabolism and their pharmacokinetics are not expected to be changed significantly in renal impairment.

Smaller areas of treatment are recommended for patients with severe hepatic impairment.

Cream/patch:

>10%:

Dermatologic: Pallor (local: 37%)

Local: Application site erythema (21% to 30%), application site burning (17%)

1% to 10%:

Central nervous system: Local alterations in temperature sensations (7%)

Local: Application site edema (6% to 10%), application site pruritus (2%)

Frequency not defined:

Dermatologic: Hyperpigmentation, stinging of the skin (local), urticaria

Hematologic & oncologic: Local purpuric or petechial reaction

<1% (Limited to important or life-threatening): Anaphylactic shock, angioedema, blistering of foreskin, bronchospasm, central nervous system depression, central nervous system stimulation, central nervous system toxicity (high dose), circulatory shock (high dose), hypotension, methemoglobinemia (high dose)

Periodontal gel:

>10%: Local: Application site reaction (13%, includes abscess, edema, irritation, numbness, pain, ulceration, vesicles)

1% to 10%:

Central nervous system: Bitter taste (2%), fatigue (1%)

Gastrointestinal: Nausea (1%)

Hypersensitivity: Local hypersensitivity reaction

Respiratory: Flu-like symptoms (1%), respiratory tract infection (1%)

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience redness, temperature sensitivity, pale skin, bad taste, or nausea. Have patient report immediately to prescriber signs of methemoglobinemia (blue or gray color of the lips, nails, or skin; abnormal heartbeat; seizures; severe dizziness or passing out; severe headache; fatigue; loss of strength and energy; or shortness of breath), or severe application site irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.