LidoSite

Lidosite is part of the drug classes:

• Adrenergic and dopaminergic agents

• Inhaled alpha and beta adrenoreceptor agonists

• Local hemostatics

• Other agents for local oral treatment

• Sympathomimetics in glaucoma therapy

• Sympathomimetics, plain

• Amides

• Analgesics and anesthetics

• Anesthetics for topical use

• Anesthetics, local

• Antiarrhythmics, class Ib

Mechanism of Action: Lidocaine belongs to the amide class of local anesthetics. Lidocaine blocks sodium ion channels required for the initiation and conduction of nerve impulses resulting in local anesthesia. Epinephrine contributes to the analgesic effect of the LidoSite™ System, presumably because of its vasoconstrictor activity, which is thought to decrease the rate of removal of lidocaine from the site of administration.

Hemodynamics: Epinephrine or excessive blood levels of lidocaine may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. However, doses delivered directly to the skin by iontophoresis when LidoSite™ System is used as directed are not expected to result in blood levels high enough to cause these hemodynamic effects. (See PHARMACOKINETICS).

Pharmacodynamics: In a single-center, prospective, placebo-controlled double-blind study, 20 adult subjects were evaluated to quantify the depth of the anesthetic effect over time from both pain and sensory perspectives following treatment with the LidoSite™ System. The placebo was a LidoSite™ System utilizing a patch containing epinephrine only, but with application of current. An 18-gauge needle with constant 200-grams pressure was used to penetrate the skin at a rate of 0.2 mm/sec. Subjects indicated the points at which they felt pressure and pain, identified as the sensory penetration depth (SD) and the pain threshold depth (PD), respectively. Immediately following completion of a 10-minute iontophoretic treatment with LidoSite™ System, the average SD and the PD were 3.9 mm and 6.4 mm, respectively, compared to 1.4 mm and 3.0 mm, respectively, after placebo treatment. Sixty minutes after removal of the LidoSite™ System, the average SD and PD increased to 5.6 mm and 10.7 mm, respectively, compared to 1.4 mm and 3.4 mm, respectively, with placebo treatment.

Pharmacokinetics:

Absorption: Plasma levels of lidocaine were below the minimum level of quantitation, 5 ng/ml, in healthy adult or pediatric subjects after three sequential LidoSite™ System applications at different sites over a 3.5 hour period. Epinephrine levels did not exceed the normal physiologic range (10 - 50 pg/mL) in healthy adult subjects after a single standard LidoSite™ System application.

CNS toxicity may occur over a range of plasma concentrations of local anesthetics. CNS toxicity may typically be found around 5000 ng/mL of lidocaine. However a small number of patients reportedly may show signs of toxicity at approximately 1000 ng/mL.

Distribution: Lidocaine is 70% protein bound in plasma, mainly to α-1-acid glycoprotein. When administered intravenously, the mean volume of distribution for lidocaine (for a 60-kg person) was 90 L at steady state. Lidocaine crosses the placental and blood-brain barriers, presumably by passive diffusion.

Metabolism: It is not known if lidocaine is metabolized in the skin. Lidocaine is metabolized by the liver, and metabolites and unchanged drug are excreted by the kidneys.

The predominant metabolism of lidocaine is through N-dealkylation to monoethylglycinexylidide (MEGX) and glycinexylidide (GX), and is mainly mediated by CYP3A4. These metabolites are hydrolyzed to 2,6-xylidine, which is converted to 4-hydroxy-2, 6-xylidine (mediated by CYP2A6), the major urinary metabolite in man. 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. MEGX has an antiarrhythmic and convulsant activity similar to that of lidocaine and a somewhat longer half-life. GX has a weak antiarrhythmic effect but lacks convulsant activity and has a half-life of about 10 hours.

Elimination: Lidocaine and its metabolites are excreted by the kidneys. Following an intravenous bolus injection, the elimination half-life of lidocaine is typically 1.5 to 2.0 hours. Approximately 90% of administered lidocaine is excreted in the form of various metabolites, and less than 10% is excreted unchanged. 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. Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites. During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly subjects (2.5 hours) than in younger subjects (1.5 hours).

Pediatrics: Plasma levels of lidocaine in pediatric subjects between 6 and 15 years of age were below the minimum level of quantitation, <5 ng/ml, after three sequential LidoSite™ System applications on different sites over a 3.5-hour period.

Geriatrics: The pharmacokinetics of lidocaine have not been specifically studied in geriatric subjects. However, during intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly subjects (2.5 hours) than in younger subjects (1.5 hours).

Special populations: No pharmacokinetic studies were conducted to specifically address special populations.

Renal Impairment: Lidocaine and its metabolites are known to be excreted by the kidney, and metabolites may accumulate in patients with impaired renal function.

Hepatic Impairment: The half-life of lidocaine may be prolonged two-fold or more in patients with liver dysfunction. Because of their inability to metabolize local anesthetics normally, patients with severe hepatic disease are at a greater risk of developing toxic plasma concentrations of lidocaine.

LidoSite™ System is a topical local anesthetic delivery system indicated for use on normal intact skin to provide local analgesia for superficial dermatological procedures such as venipuncture, intravenous cannulation, and laser ablation of superficial skin lesions.

LidoSite™ System is indicated for use on patients 5 years of age and older.

General: Since amide-type local anesthetics are metabolized by the liver, LidoSite™ System should be used with caution in patients with hepatic disease. Patients with severe hepatic disease normally are at a greater risk of developing toxic plasma concentrations.

LidoSite™ System should be used with caution in persons with known drug sensitivities. Patients allergic to para-amino-benzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross sensitivity to lidocaine. Nevertheless, LidoSite™ System should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain.

Lidocaine and epinephrine should be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for changes in cardiac conduction, contractility, and oxygen demand that may be caused by systemic exposure to these drugs.

LidoSite™ System should be applied only by a health care practitioner in a health care setting. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use when LidoSite™ System is administered. (See WARNINGS and ADVERSE REACTIONS).

The intended treatment site should not be covered with excessive hair, as that may affect patch adhesion. The LidoSite™ System has not been tested for safety or effectiveness in the head and neck areas, over-damaged or denuded skin, or on mucous membranes.

The safety of LidoSite™ System has not been tested in patients who have received long-term treatment with corticosteroids. Clinical judgment should be exercised when considering the use of LidoSite™ System in these patients, as they may be more susceptible to skin injury from LidoSite™ System.

The LidoSite™ Patch reservoirs must remain in complete contact with the skin during treatment. Therefore, restricting motion is recommended for those application sites where movement could release the patch from the skin.

Following iontophoresis and patch removal, the treatment site should be cleansed according to standard practice prior to starting the medical procedure.

Non-intact skin: Application to broken or inflamed skin, may result in local tissue injury or higher blood concentrations of lidocaine from increased absorption. LidoSite™ System is only recommended for use on intact skin.

Eye exposure: The contact of LidoSite™ Patch with eyes, should be avoided based on the findings of severe eye irritation with the use of similar products in animals. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns.

Repeated application of LidoSite™ System may increase blood levels of lidocaine. LidoSite™ System should be used with caution in patients who may be more sensitive to the systemic effects of lidocaine, including acutely ill, debilitated, or elderly patients.

Lidocaine has been shown to inhibit viral and bacterial growth. The effect of LidoSite™ Patch on intradermal injections of live vaccines has not been determined.

Information For Patients: When LidoSite™ System is used, the patient should be aware that block of all sensations in the treated skin may occur. For this reason, the patient should avoid inadvertent trauma to the treated area by scratching, rubbing or exposure to extreme hot or cold temperatures until complete sensation has returned. Diminished sensation may persist for an hour or more (See PHARMACODYNAMICS). Patients should be advised to monitor the treated area for the return of sensation.

The appearance of the treated area may appear to be blanched or red which are normal reactions and usually disappear within 24 hours. Patients should be instructed to monitor the site and report persistent pain, redness and other skin abnormalities based upon directions provided by the health care professional.

Clinically Significant Drug Interactions: Monoamine Oxidase Inhibitors: The administration of local anesthetics containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe prolonged hypertension.

Antiarrhythmic Drugs: LidoSite™ System should be used with caution in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine) since the systemic toxic effects are thought to be additive and potentially synergistic.

Local Anesthetics: When LidoSite™ System is used concomitantly with other products containing local anesthetic agents, the systemic exposure from all formulations must be considered.

CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY

Carcinogenesis: Long-term studies to evaluate the carcinogenic potential of lidocaine in animals have not been conducted.

Mutagenesis: The mutagenic potential of lidocaine HCl has been tested in the Ames Salmonella/Mammalian Microsome Test, by analysis of structural chromosome aberrations in human lymphocytes in vitro, and by the mouse micronucleus test in vivo. There was no indication of any mutagenic effects in these tests.

Impairment of Fertility: Studies to evaluate the effects of lidocaine on fertility in animals have not been conducted.

Use in Pregnancy: Teratogenic Effects: Pregnancy Category B.

Reproduction studies have been performed in rats at doses up to 500 mg/kg/day, s.c. (6.6 times the human injected dose) via mini-osmotic pumps and have revealed no significant adverse reproductive or teratogenic effects attributable to lidocaine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: Lidocaine is excreted in human milk. The milk to plasma ratio of systemically administered lidocaine is 0.4. Caution should be exercised when LidoSite™ System is administered to a nursing woman.

Pediatric Use: The safety and effectiveness of the LidoSite™ System have been established in pediatric patients five years and older based on adequate and well-controlled studies (see CLINICAL STUDIES). The recommended dose for pediatric patients five years and older is the same as for adults.

Safety and effectiveness in pediatric patients below the age of five years have not been established.

Geriatric Use: In the clinical studies, there were sixty patients over 65 years of age and thirty-one patients over 75 years of age. No overall differences in safety or efficacy were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between elderly and younger patients. However, greater sensitivity of individual patients greater than 65 years of age cannot be ruled out. In clinical studies of intravenously administered lidocaine, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours) (See CLINICAL PHARMACOLOGY).

Labor and Delivery: The effects of LidoSite™ System on the mother and fetus, on the duration of labor or delivery, and on neonatal outcome and maturation have not been studied. Should LidoSite™ System be used concomitantly with other products containing lidocaine and/or epinephrine, total doses contributed by all formulations must be considered (See DOSAGE AND ADMINISTRATION).

LidoSite™ Controller can only be used with the LidoSite™ Patch as the complete LidoSite™ System, and LidoSite™ Patches should only be used with a LidoSite™ Controller.

LidoSite™ System should be applied only by a health care practitioner in a health care setting.

One LidoSite™ Patch is to be used with one LidoSite™ Controller. Do not use a damaged or altered patch. To administer, see the “LidoSite™ Topical System Instructions” contained in this package insert. Following iontophoresis and patch removal, the treatment site should be cleansed according to standard practice prior to the medical procedure. Disinfecting agents containing heavy metal ions (mercury, zinc, copper, etc.) should not be used for skin disinfection prior to iontophoresis as they have been associated with swelling and edema.

LidoSite™ Controller should not be subjected to any sterilization procedure.

LidoSite™ Controller should be disposed of in a trash receptacle.

Recommended Dose:	Each iontophoretic treatment delivers lidocaine and epinephrine at the 5-cm2 site below the circular reservoir. Only one LidoSite™ Patch should be used at a time.
Application:	See “LidoSite™ Topical System Instructions” Apply patch immediately after opening pouch. The LidoSite™ Patch reservoirs must remain in complete contact with the skin during treatment to ensure maximal safety and efficacy. A new patch may be applied to a different skin site after 30 minutes. The LidoSite™ Patch is for single use only.
Treatment Duration:	Current delivery lasts for 10 minutes following actuation of the LidoSite™ Controller. In clinical studies the medical procedure was initiated within 10 minutes of patch removal.
Patch Disposal:	LidoSite™ Patch should be disposed of as medical waste.
Storage Conditions:	Store LidoSite™ Patches at controlled room temperature (20°C-25°C; 68°F-77°F).

The LidoSite™ Controller is not designed to be serviced or repaired. The unit is sealed, contains a non-replaceable battery, and requires no calibration.

No Flashing GREEN and YELLOW During Self Check

If the controller does not go through the alternating GREEN and YELLOW flashing indicators when the ON button is first pressed, discard the unit.

Constant YELLOW indicator

The battery is below operational limits and the unit should be discarded.

No Flashing GREEN indicator With Patch Connected

• The patch is improperly connected to the controller, or
• The patch was previously used, or
• The patch was improperly placed on the patient or no skin was detected.

More than 1,000 adults and children (ages 5 to 17 years) participated in clinical studies evaluating the safety and efficacy of the LidoSite system in providing topical anesthesia. Two pivotal LidoSite studies compared the system (administering lidocaine 10% and epinephrine 0.1%) with placebo for use prior to needle injections or intravenous (IV) insertions. Additional studies evaluated the efficacy of the system for use prior to the removal of surface skin lesions (via incision or laser treatment). Patients treated with Vyteris' LidoSite system experienced significantly less pain associated with needlestick procedures compared with subjects treated with the placebo system. Consequently, fewer patients in the active group reported experiencing severe pain and most reported feeling little or no pain in contrast to patients in the placebo group. In these studies, the patients were evaluated using established pain assessment tools including the Facial Affective Scale (FAS) (A = no pain, I = maximal pain) or the Visual Analogue Scale (VAS) (0 = no pain, 10 = maximal pain) methods. Evaluations were taken immediately following LidoSite patch removal and at 24 hours for side effects. Pain score evaluations from both scales resulted in statistically significantly less pain for those who used the LidoSite system, as compared to placebo. In these studies, the most common side effect was mild erythema (skin redness), which disappeared for most patients within 24-hours.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Some side effects of LidoSite may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.