Pliaglis

CLINICAL PHARMACOLOGY

Mechanism Of Action

Lidocaine is an amide-type local anesthetic agent and tetracaine is an ester-type local anesthetic agent. Both lidocaine and tetracaine block sodium ion channels required for the initiation and conduction of neuronal impulses which, in certain instances, results in local anesthesia. When applied to intact skin, PLIAGLIS Cream provides local dermal analgesia by the release of lidocaine and tetracaine from the peel into the skin.

Pharmacodynamics

Duration of analgesia was evaluated using a pinprick test in 40 adult volunteers. The median duration of analgesia was 11 hours. There was no difference between the 30-minute and 60-minute PLIAGLIS Cream application periods with respect to the mean for time to return of sensation. However, 55% of PLIAGLIS Cream treated subjects still reported diminished sensation at the end of the 13-hour study period.

Pharmacokinetics

Absorption

The amount of lidocaine and tetracaine systemically absorbed from PLIAGLIS Cream is directly related to both the duration of application and the surface area over which it is applied, Table 2. Application of 59 g of PLIAGLIS Cream over 400 cm² for up to 120 minutes to adults produces peak plasma concentrations of lidocaine of 220 ng/mL. Tetracaine plasma levels were not measurable ( < 0.9 ng/mL). Systemic exposure to lidocaine, as measured by Cmax and AUC0-24, was proportional to the application area, and increased with application time up to 60 minutes.

Table 2: Absorption of lidocaine and tetracaine following application of PLIAGLIS Cream

PLIAGLIS Cream (g) Area (cm²) Age Range (yr) n Application Time (min) Drug Content (g) Mean Cmax (ng/mL) Mean Tmax (hr)
21 400 18-64 4 30 Lidocaine, 1.5 49 4
Tetracaine, 1.5 < 0.9 na
33 400 18-64 4 60 Lidocaine, 2.3 96 2.8
Tetracaine, 2.3 < 0.9 na
31 400 ≥ 65 6 60 Lidocaine, 2.2 48 3.8
Tetracaine, 2.2 < 0.9 na
na = not applicable

Distribution

When lidocaine is administered intravenously to healthy volunteers, the steady-state volume of distribution is approximately 0.8 to 1.3 L/kg. At lidocaine concentrations observed following the recommended product application, approximately 75% of lidocaine is bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 mg/mL of free base) the plasma protein binding of lidocaine is concentration dependent. Lidocaine crosses the placental and blood brain barriers, presumably by passive diffusion. CNS toxicity may typically be observed around 5000 ng/mL of lidocaine; however, a small number of patients reportedly may show signs of toxicity at approximately 1000 ng/mL [see OVERDOSAGE]. Volume of distribution and protein binding have not been determined for tetracaine due to rapid hydrolysis in plasma.

Metabolism

It is not known if lidocaine or tetracaine is 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 major metabolic pathway of lidocaine, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4. The metabolite, 2,6-xylidine, has unknown pharmacologic activity. Following intravenous administration of lidocaine, MEGX and GX concentrations in serum range from 11% to 36% and from 5% to 11% of lidocaine concentrations, respectively. Serum concentrations of MEGX were about one-third the serum lidocaine concentrations.

Tetracaine undergoes rapid hydrolysis by plasma esterases. Primary metabolites of tetracaine include para-aminobenzoic acid and diethylaminoethanol, both of which have an unspecified activity.

Elimination

The half-life of lidocaine elimination from the plasma following intravenous administration is approximately 1.8 hr. Lidocaine and its metabolites are excreted by the kidneys. More than 98% of an absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. Less than 10% of lidocaine is excreted unchanged in adults, and approximately 20% is excreted unchanged in neonates. The systemic clearance is approximately 8–10 mL/min/kg. 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). The half-life and clearance for tetracaine has not been established for humans, but hydrolysis in the plasma is rapid.

Special Populations

Elderly: After application of 31g of PLIAGLIS Cream over 400 cm² for 60 minutes, mean peak plasma levels of lidocaine were 48 ng/mL for elderly patients ( > 65 years of age, mean 68.0 ± 3.2 years, n = 6). These levels are similar to or lower than those for younger patients receiving similar amounts of PLIAGLIS Cream.

Cardiac, Renal and Hepatic Impairment: No specific pharmacokinetic studies were conducted. The half-life of lidocaine may be increased in patients with cardiac or hepatic dysfunction. There is no established half-life for tetracaine due to rapid hydrolysis in the plasma.

Clinical Studies

In four clinical trials, adult patients were treated with PLIAGLIS Cream or placebo prior to undergoing a superficial dermatologic procedure. Drug was applied for 20 or 30 minutes for dermatologic procedures such as dermal filler injection, pulsed dye laser therapy, and facial laser resurfacing. Drug was applied for 60 minutes for laser-assisted tattoo removal. Treatment with PLIAGLIS Cream resulted in statistically significantly less pain compared to placebo treatment, as measured by a 100 mm visual analog scale (VAS). Patient efficacy ratings are shown in Table 3.

Table 3: Summary of patient evaluations following application of PLIAGLIS Cream and placebo

Dermatologic Procedure Mean VAS score
PLIAGLIS Cream Placebo
20 Min Application
  Pulsed Dye Laser Therapy (N=80) 16 31
30 Min Application
  Non-Ablative Laser Facial Resurfacing (N=54) 21 38
  Dermal Filler Injections (N=70) 24 37
60 Min Application
  Laser-Assisted Tattoo Removal (N=62) 39 59

Last reviewed on RxList: 12/12/2013
This monograph has been modified to include the generic and brand name in many instances.

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