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, 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.
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).
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.
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.
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.
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 (eg, 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.
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 cm2). 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.
|Age and Body Weight Requirements||Maximum Total Dose of Lidocaine and Prilocaine Cream||Maximum Application Area †||Maximum Application Time|
|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.|
|0 up to 3 months or < 5 kg||1 g||10 cm2||1 hour|
|3 up to 12 months and > 5 kg||2 g||20 cm2||4 hours|
|1 to 6 years and > 10 kg||10 g||100 cm2||4 hours|
|7 to 12 years and > 20 kg||20 g||200 cm2||4 hours|
An I.V. antiarrhythmic dose of lidocaine is 1 mg/kg (70 mg/70 kg) and gives a blood level of about 1 mcg/mL. Toxicity would be expected at blood levels above 5 mcg/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.
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