ZTlido

Ztlido (lidocaine topical system) 1.8% is indicated for relief of pain associated with post-herpetic neuralgia (PHN).

Ztlido 1.8% is available as a single-use topical system packaged in an individual envelope.

Pregnancy

Risk Summary

The limited human data with lidocaine in pregnant woman are not sufficient to inform drug-associated risk for major birth defects and miscarriage.

The use of lidocaine for labor neuraxial analgesia has not been associated with an increased incidence of adverse fetal effects either during delivery or during the neonatal period [see Data]. Should Ztlido be used concomitantly with other products containing lidocaine, consider total drug doses contributed by all formulations.

In a published animal reproduction study, pregnant rats administered lidocaine by continuous subcutaneous infusion at a dose approximately 45 times the maximum recommended daily dose (MRDD) of 108 mg in Ztlido during the period of organogenesis resulted in lower fetal body weights. In a published animal reproduction study, pregnant rats administered lidocaine, containing 1:100,000 epinephrine, injected into the masseter muscle of the jaw or into the gum of the lower jaw at 0.5 times the MRDD on Gestation Day 11 resulted in developmental delays in neonates [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

In 22 parturient women given 1.5% lidocaine epidural anesthesia, there were no effects on neonatal behavior, using the early neonatal neurobehavioral scale (ENNS). Neuraxial analgesia also did not affect fetal heart rate, beat-to-beat variability, or uterine activity.

Animal Data

Reproductive studies with lidocaine have been performed in rats at doses up to 30 mg/kg (2.7 times the maximum recommended daily dose [MRDD] of 108 mg from Ztlido on a mg/m 2 basis) subcutaneously and have revealed no evidence of harm to the fetus due to lidocaine.

In a published study, lidocaine administered to pregnant rats by continuous subcutaneous infusion during the period of organogenesis at 100, 250, and 500 mg/kg/day, did not produce any structural abnormalities, but did result in lower fetal weights at 500 mg/kg/day dose (approximately 45 times the MRDD on a mg/m 2 basis) in the absence of maternal toxicity.

In a published study, lidocaine containing 1:100,000 epinephrine at a dose of 6 mg/kg (approximately 0.5 times the MRDD on a mg/m 2 basis) injected into the masseter muscle of the jaw or into the gum of the lower jaw of pregnant Long-Evans hooded rats on Gestation Day 11 resulted in developmental delays in the neonates. Developmental delays were observed for negative geotaxis, static righting reflex, visual discrimination response, sensitivity and response to thermal and electrical shock stimuli, and water maze acquisition. The developmental delays of the neonatal animals were transient, with responses becoming comparable to untreated animals later in life. The clinical relevance of these animal data is uncertain.

Lactation

Risk Summary

Lidocaine is excreted into human milk. When lidocaine was used as an epidural anesthetic for cesarean section in 27 women, a milk:plasma ratio of 1.07 was observed using AUC values. Lactating women undergoing a dental procedure had an 0.4 milk:plasma ratio. In another dental procedure study, a single patient was administered 20 mg of lidocaine and the milk:plasma ratio was reported as 1.1 at five to six hours after injection. These data and the low concentrations of lidocaine in the plasma after topical administration of Ztlido in recommended doses, suggest that a small amount of lidocaine would be ingested orally by a suckling infant. However, caution should be exercised when Ztlido is administered to a nursing mother, especially when administered with other local anesthetics.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Ztlido did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be done with caution, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Mechanism of Action

Lidocaine is an amide local anesthetic. Lidocaine blocks sodium ion channels required for the initiation and conduction of neuronal impulses.

Pharmacodynamics

The penetration of lidocaine into intact skin after application of Ztlido is sufficient to produce an analgesic effect, but less than the amount necessary to produce a complete sensory block.

Pharmacokinetics

Ztlido has different bioavailability compared to Lidoderm®. In a single-dose, crossover study conducted in 53 healthy volunteers, Ztlido (lidocaine topical system) 1.8% demonstrated equivalent exposure (AUC) and peak concentration (Cmax) of lidocaine to Lidoderm® (lidocaine patch 5%).

Absorption

The amount of lidocaine systemically absorbed from Ztlido is directly related to both the duration of application and the surface area over which it is applied. In a pharmacokinetic study, three Ztlido topical systems were applied over an area of 420 cm 2 of intact skin on the backs of normal healthy volunteers for 12 hours. Blood samples were drawn for determination of lidocaine concentration during the topical system application and for 12 hours after removal of topical systems. The results are summarized in Table 1.

*median (min, max)

Repeated application of three Lidoderm® patches simultaneously for 12 hours (recommended maximum daily dose), once per day for three days, indicated that the lidocaine concentration does not increase with daily use. The mean plasma pharmacokinetic profile for the 15 healthy volunteers is shown in Figure 1.

Figure 1

Mean lidocaine blood concentrations after three consecutive daily applications of three Lidoderm patches simultaneously for 12 hours per day in healthy volunteers (n = 15).

The pharmacokinetics of Ztlido (n=3 topical systems) was assessed in 12 healthy volunteers with exposure to external heat source (heating pad at medium setting applied for 20 minutes at Time 0 and 8.5 hours) or undergoing moderate exercise (cycling for 30 minutes at a heart rate of 108 bpm at Time 0, 2.5, 5.5 and 8.5 hours) and compared to pharmacokinetics of Ztlido at rest. Exposure to external heat at 0 and 8.5 hours results in increased peak plasma levels of lidocaine with a mean (SD) of 160.3 ± 100.1 ng/mL versus the peak plasma levels observed at rest with a mean (SD) of 97.6 ± 36.9 ng/mL. For this reason, instruct patients not to apply heating pads directly to Ztlido. Concentrations returned to normal within 4 hours after the heat was removed. No clinically relevant differences in systemic absorption were observed under exercise conditions with a mean (SD) peak plasma concentrations of 90.5 ± 25.4 ng/mL.

A separate study in 12 healthy volunteers showed that there was no effect on Ztlido pharmacokinetics when the topical system is applied to the administration site after external heat exposure (heating pad at medium setting applied for 15 minutes prior to the topical system application) or after engagement in exercise (walking at a moderate pace on a treadmill for approximately 20 minutes beginning approximately 30 minutes prior to the topical system application).

Distribution

When lidocaine is administered intravenously to healthy volunteers, the volume of distribution is 0.7 to 2.7 L/kg (mean 1.5 ± 0.6 SD, n = 15). At concentrations produced by application of Ztlido, lidocaine is approximately 70% bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 μg/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.

Elimination

Metabolism:

It is not known if lidocaine 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. A minor metabolite, 2,6-xylidine, has unknown pharmacologic activity. The blood concentration of this metabolite is negligible following application of Ztlido. Following intravenous administration, MEGX and GX concentrations in serum range from 11 to 36% and from 5 to 11% of lidocaine concentrations, respectively.

Excretion:

Lidocaine and its metabolites are excreted by the kidneys. Less than 10% of lidocaine is excreted unchanged. The half-life of lidocaine elimination from the plasma following IV administration is 81 to 149 minutes (mean 107 ± 22 SD, n = 15). The systemic clearance is 0.33 to 0.90 L/minute (mean 0.64 ± 0.18 SD, n = 15).

Single-dose treatment with lidocaine patch (currently preferred dosage form term for a patch is topical system) was compared to treatment with vehicle patch (without lidocaine), and to no treatment (observation only) in a double-blind, crossover clinical trial with 35 post-herpetic neuralgia patients. Pain intensity and pain relief scores were evaluated periodically for 12 hours. Lidocaine patch performed statistically better than vehicle patch in terms of pain intensity from 4 to 12 hours.

Multiple-dose, two-week treatment with lidocaine patch was compared to vehicle patch (without lidocaine) in a double-blind, crossover clinical trial of withdrawal-type design conducted in 32 patients, who were considered as responders to the open-label use of lidocaine patch prior to the study. The constant type of pain was evaluated but not the pain induced by sensory stimuli (dysesthesia). Statistically significant differences favoring lidocaine patch were observed in terms of time to exit from the trial (14 versus 3.8 days at p-value <0.001), daily average pain relief, and patient's preference of treatment. About half of the patients also took oral medication commonly used in the treatment of post-herpetic neuralgia. The extent of use of concomitant medication was similar in the two treatment groups.

Based on a clinical study in 54 subjects with Ztlido, 47 subjects (87%) had adhesion scores of 0 (≥ 90% adhered) for all evaluations performed every 3 hours during the 12 hours of administration, 7 subjects (13%) had adhesion scores of 1 (≥ 75% to < 90% adhered) for at least one evaluation, and no subjects had scores of 2 or greater (< 75% adhered).