DentiPatch

DENTIPATCH- lidocaine patch
Noven Parmaceuticals, Inc.

DESCRIPTION

The DentiPatch® system contains a local anesthetic agent to be applied topically to the oral cavity. See INDICATIONS for specific uses.

Lidocaine is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-, and has the following structural formula:

Image from Drug Label Content
(click image for full-size original)

The molecular formula of lidocaine is C14 H22 N2 O. The molecular weight is 234.34.

Each 2 cm2 patch contains lidocaine base as the active ingredient in the amount of 46.1 mg. Non-active ingredients include: karaya gum, glycerin, dipropylene glycol, lecithin, propylene glycol, aspartame, spearmint flavor, polyester film laminate and polyester-rayon fabric.

Each unit is sealed in a paper polyethylene-foil pouch.

CLINICAL PHARMACOLOGY

Mechanism of action:

The DentiPatch® system is applied to the buccal mucosa to provide topical anesthesia by releasing lidocaine. Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action.

Onset and duration of action:

The DentiPatch® system acts on intact mucous membranes to produce local anesthesia.

DentiPatch® (Lidocaine Transoral Delivery System)

Anesthesia occurs usually within 2.5 minutes of application, is present for the duration of a 15 minute application period, and persists for approximately 30 minutes following removal.

Hemodynamics:

Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. These changes may be attributable to a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system.

Pharmacokinetics and Metabolism:

Absorption

While systemic availability is not an objective when lidocaine is administered for topical anesthesia, limited absorption occurs following application of the patches to the buccal mucosa. The rate of absorption and percentage of dose absorbed depends upon several variables, including the concentration and total dose administered, the duration of exposure and the vascularity of the tissues at the site of application.

Although the total content of lidocaine base contained in each 2 cm2 system is 46.1 mg, the total amount of drug absorbed during 15 minutes of application is limited as drug delivery is confined to a fixed surface area. Corresponding blood levels of lidocaine following application are less than 0.1 μg/ml. Assuming the toxic range of lidocaine is approximately 5 μg/ml, the maximum plasma concentration achieved from this patch is, therefore, approximately 1/100th of this value.

Image from Drug Label Content
(click image for full-size original)

The figure shows the mean lidocaine plasma concentration following application of the 46.1 mg patch for 15 minutes to a group of normal male volunteers.

In this study, blood levels of lidocaine were compared following application of the patch and 5% Xylocaine® ointment. The maximum plasma concentration following the 46.1 mg patch was approximately 1/7 of those achieved by the ointment.

Another study compared the lidocaine plasma levels following applications of the patch, a 50 mg film of 5% topical ointment and an intravenous control in a cross-over design. The maximum plasma concentration following the 46.1 mg patch was approximately 1/5 of that achieved from the intravenous dose. The relevant mean pharmacokinetic parameters from this study are summarized in the table below. In addition, the table also indicates the range of AUC’s obtained in two independent studies.

MEAN (±SD) PHARMACOKINETIC PARAMETERS OBTAINED FOLLOWING APPLICATION OF THE DENTIPATCH® SYSTEM FOR 15 MINUTES
PHARMACOKINETIC PARAMETERS

Cmax = Maximum observed plasma concentration.

Tmax = Time to maximum plasma concentration.

Apparent dose = Calculated dose (estimated from the AUC0 -α values and the known IV dose).

t1/2 = Apparent terminal elimination half-life.

Lidocaine content (mg) Cmax (ng/mL) Tmax (min) Apparent Dose (mg) t1/2 min AUC0 -α (ng•min/mL)
Study 3005 Study 3006
46.1 16.5 (±7.9) 28.6 (±12.9) 1.55 (±0.77) 102 (±25) 2110 (±930) 3679 (±1432)

The apparent dose of lidocaine averaged 1.55 (± 0.77) mg from the 46.1 mg dosage. This compares to an apparent dose of 3.77 (±2.71) mg from the 5% topical ointment and 4.79 (±0.79) mg from the intravenous drug. In this study, the half-life of elimination of lidocaine following the patch was approximately 2 hours compared to a mean half-life of 112 (±20) minutes following the IV drug.

Metabolism and Excretion

Lidocaine is metabolized rapidly by the liver and metabolites and unchanged drug are excreted by the kidney.

Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation (the hepatic ratio for lidocaine has been reported between 62% and 81% in man). Sequential oxidative N-dealkylation of lidocaine by the cytochrome P-450 system in hepatic microsomes produce two major metabolites, mono-ethylglyciniexylidide (MEGX) and glycine xylidide (GX), both of which have pharma-cologic activity.

Greater than 98% of an administered lidocaine dose can be recovered in the urine as metabolites and parent compound. Approximately 2% of an administered dose is excreted as intact drug in the urine over 24 hours. The primary metabolite found in the urine was 4-hydroxy 2, 6-xylidine, which comprised 73% of the dose in man following an oral dose of 3.0 mg/kg, MEGX and GX are found in small quantities: 4.0% and 2.5%, respectively. Other metabolic products recovered in the urine in amounts of less than 1.0% of an administered dose include 3-hydroxylidocaine, 3-hydroxyMEGX, and 2.6-xylidine. The metabolite 2,6-xylidine has unknown pharmacologic activity but has been demonstrated to be carcinogenic in rats. (See Carcinogenesis subsection of PRECAUTIONS).

Lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 μg free base per mL.

The extent of lidocaine protein binding is variable and is dependent upon the method of sample collection, lidocaine concentration, pH of sample and binding technique utilized. Under controlled conditions and using equilibrium dialysis techniques, the percentage of unbound lidocaine in serum and plasma has been reported to range from 21% to 39% (mean 28-30%). The major binding site of lidocaine in plasma is alpha,-1 acid glycoprotein.

Special Populations

Geriatric

No special studies have been conducted in this age group.

Pediatric

No special studies have been conducted in the pediatric age group.

Gender

No significant differences in absorption, etc. have been found in males and females. In a group of 30 volunteers (16 female, 14 male) receiving the 46.1 mg patch, the observed maximum plasma concentrations were 27.2 (±15.2) ng/mL at 45 (±12.5) minutes following application. Mean maximum concentrations were 31.5 (±17.4) ng/mL in females and 22.2 (±10.6) ng/mL in males.

Race

No specific studies were conducted comparing the pharmacokinetics in different races.

Renal Insufficiency

Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites.

Hepatic Insufficiency

Because of the rapid rate at which lidocaine is metabolized, any condition that affects liver function may alter lidocaine kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction.

Drug-Drug Interactions

Lidocaine is metabolized by cytochrome P450 3A4-7 and 2D6. Inhibitors of these enzymes by H2 antagonists, antibiotics or some antiepileptics may elevate systemic lidocaine levels resulting in a prolonged effect.

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