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ZTLIDO™
(lidocaine) Topical System
ZTLIDO (lidocaine topical system) 1.8% is a single-layer, drug-in-adhesive topical delivery system comprised of an adhesive material containing 36 mg lidocaine, which is applied to a pliable nonwoven cloth backing and covered with a polyethylene terephthalate film release liner. The release liner is removed prior to application to the skin. The size of ZTLIDO is 10 cm × 14 cm × 0.08 cm.
Lidocaine, an amide local anesthetic, is chemically designated as acetamide, 2-(diethylamino)-N-(2,6dimethylphenyl), has an octanol: water partition ratio of 43 at pH 7.4, and has the following structure:
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Each ZTLIDO contains 36 mg of lidocaine (18 mg per gram adhesive) in a non-aqueous base and also contains the following inactive ingredients: butylated hydroxytoluene, dipropylene glycol, isostearic acid, mineral oil, polyisobutylene, silicone dioxide, styrene/isoprene/styrene block copolymer, and terpene resin.
ZTLIDO (lidocaine topical system) 1.8% is indicated for relief of pain associated with post-herpetic neuralgia (PHN).
Because of the difference in bioavailability of ZTLIDO compared to Lidoderm® (lidocaine patch 5%), a different dosage strength is required to be administered to the patient. One ZTLIDO (lidocaine topical system) 1.8% provides equivalent lidocaine exposure to one Lidoderm® (lidocaine patch 5%) [see CLINICAL PHARMACOLOGY].
When ZTLIDO is used concomitantly with other products containing local anesthetic agents, the total amount of drug absorbed from all formulations must be considered.
ZTLIDO may not stick if it gets wet. Advise patients to avoid contact with water, such as bathing, swimming, or showering.
Instruct patients to wash hands immediately after handling ZTLIDO and to avoid contact with eyes [see WARNINGS AND PRECAUTIONS, PATIENT INFORMATION].
Instruct patients to store ZTLIDO inside the sealed envelope and to apply immediately after removal from the envelope. Advise them to store ZTLIDO out of the reach of children, pets, and others. Instruct patients to, after use, fold used ZTLIDO so that the adhesive side sticks to itself and safely discard used ZTLIDO or pieces of cut ZTLIDO where children and pets cannot get to them [see WARNINGS AND PRECAUTIONS, PATIENT INFORMATION].
Advise patients not to apply external heat sources, such as heating pads or electric blankets, directly to ZTLIDO because plasma lidocaine levels are increased. ZTLIDO can be applied, however, to the administration site after moderate heat exposure, such as 15 minutes of heating pad exposure on a medium setting [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY, PATIENT INFORMATION].
ZTLIDO may be used during moderate exercise, such as biking for 30 minutes.
ZTLIDO topical systems that have lifted at the edges may be reattached by pressing firmly on the edges. If a ZTLIDO topical system comes off completely and will not stick to patient's skin, it should be thrown away and a new ZTLIDO topical system should be applied for a total duration of 12 hours of used and new topical system together.
Apply ZTLIDO to intact skin to cover the most painful area. Apply the prescribed number of topical systems (maximum of 3), only once for up to 12 hours within a 24-hour period (12 hours on and 12 hours off). ZTLIDO may be cut into smaller sizes with scissors prior to removal of the release liner. Clothing may be worn over the area of application. Smaller areas of treatment are recommended in a debilitated patient, or a patient with impaired elimination.
If irritation or a burning sensation occurs during application, advise patients to remove ZTLIDO and do not reapply until the irritation subsides.
ZTLIDO 1.8% is available as a single-use topical system packaged in an individual envelope.
ZTLIDO (lidocaine topical system) 1.8% is available as the following:
Carton of 30 topical systems, packaged into individual child-resistant envelopes.
NDC 69557-111-30
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].
Manufactured for: Scilex Pharmaceuticals Inc. San Diego, CA 92121 USA. Revised: Feb 2018
The following serious adverse reactions are described elsewhere in the labeling:
The following adverse reactions from voluntary reports or clinical studies have been reported with lidocaine. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin And Subcutaneous Tissues: blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erosions, erythema, exfoliation, flushing, irritation, papules, petechia, pruritus, vesicles, and abnormal sensation.
Immune system: angioedema, bronchospasm, dermatitis, dyspnea, hypersensitivity, laryngospasm, pruritus, shock, and urticaria.
Central Nervous System: lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, somnolence, respiratory depression and arrest.
Cardiovascular: bradycardia, hypotension, and cardiovascular collapse leading to arrest.
Other: asthenia, disorientation, headache, hyperesthesia, hypoesthesia, metallic taste, nausea, pain exacerbated, paresthesia, taste alteration, and vomiting.
When ZTLIDO is used in patients receiving Class I antiarrhythmic drugs (such as tocainide and mexiletine), the toxic effects are additive and potentially synergistic. Consider risk/benefit during concomitant use.
When ZTLIDO is used concomitantly with other products containing local anesthetic agents, the effects are additive. Consider the amount of drug absorbed from all formulations when local anesthetic agents are administered concomitantly.
Included as part of the PRECAUTIONS section.
Even a used ZTLIDO topical system contains residual lidocaine after use. The potential exists for a small child or a pet to suffer serious adverse effects from chewing or ingesting a new or used ZTLIDO. It is important for patients to store and dispose of ZTLIDO properly, and keep out of the reach of children, pets, and others [see DOSAGE AND ADMINISTRATION].
Lidocaine toxicity can be expected at lidocaine blood concentrations above 5 mcg/mL. The blood concentration of lidocaine is determined by the rate and extent of lidocaine absorption and elimination. Longer duration of application, application of more than the recommended number of ZTLIDO, smaller patients, or impaired elimination may all contribute to increasing the blood concentration of lidocaine.
If lidocaine overdose is suspected, check drug blood concentration. Management of overdose includes close monitoring, supportive care, and symptomatic treatment [see OVERDOSAGE].
Application of more than the recommended number of ZTLIDO or applying ZTLIDO for longer than the recommended wearing time (12 hours of every 24 hours) could result in increased absorption and high blood concentrations of lidocaine, leading to adverse effects. Advise patients on proper application and duration [see PATIENT INFORMATION].
Impaired elimination may contribute to increasing blood concentrations of lidocaine. Patients with severe hepatic disease are at greater risk of developing toxic blood concentrations of lidocaine because of their inability to metabolize lidocaine normally.
Application to broken or inflamed skin, although not tested, may result in higher blood concentrations of lidocaine from increased absorption. ZTLIDO is only recommended for use on intact skin. Advise patients not to apply ZTLIDO to non-intact skin [see PATIENT INFORMATION].
External Heat Sources
External heat sources may increase drug exposure, leading to overexposure to lidocaine. Advise patients not to apply external heat sources to ZTLIDO during administration [see CLINICAL PHARMACOLOGY, PATIENT INFORMATION].
During or immediately after treatment with ZTLIDO, the skin at the site of application may develop blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours. Inform patients of these potential reactions and that severe skin irritation may occur with ZTLIDO if applied for a longer period than instructed.
Patients allergic to para-aminobenzoic acid (PABA) derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to lidocaine. However, be aware of the potential for cross-sensitivity in patients allergic to PABA derivatives, especially if the etiologic agent is uncertain. Manage hypersensitivity reactions by conventional means. The detection of sensitivity by skin testing is of doubtful value.
The contact of ZTLIDO with eyes, although not studied, should be avoided based on findings of severe eye irritation with the application of similar products in animals. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye (such as, eye glasses/eye wear) until sensation returns.
Advise the patient to read the FDA-approved Patient Labeling and Instructions for Use.
Advise patients to store ZTLIDO out of the reach of children, pets, and others. Advise patients to dispose of used ZTLIDO by folding used ZTLIDO so that the adhesive side sticks to itself and safely discarding used ZTLIDO or pieces of cut ZTLIDO where children, pets, and others cannot come in contact with them.
Advise Patients
Advise patients to wash hands immediately after handling ZTLIDO and to avoid contact with eyes. Instruct patients to, if eye contact should occur, immediately wash out the eye with water or saline and protect the eye until sensation returns [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Long-term studies in animals specifically designed to evaluate the carcinogenic potential of lidocaine or ZTLIDO have not been conducted.
A metabolite, 2,6-xylidine, has been found to be carcinogenic in rats. The clinical significance is not known.
Lidocaine HCl was not mutagenic in the in vitro bacterial reverse mutagenicity assay (Ames test). Lidocaine HCl was not clastogenic in the in vitro chromosome aberration assay with human lymphocytes or in the in vivo mouse micronucleus test.
In a published study, female Sprague-Dawley rats were treated subcutaneously with lidocaine via osmotic pumps starting two weeks prior to mating, and reproductive effects were assessed. Rats dosed up to the high dose of 500 mg/kg/day (approximately 45 times the MRDD on a mg/m² basis) showed no effects on copulatory rate, pregnancy rate, or the numbers of corpora lutea or implantations.
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.
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/m² 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/m² 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/m² 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.
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.
Safety and effectiveness in pediatric patients have not been established.
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.
Lidocaine overdose from cutaneous absorption is rare, but could occur. If there is any suspicion of lidocaine overdose, check drug blood concentration. The management of overdose includes close monitoring, supportive care, and symptomatic treatment. Dialysis is of negligible value in the treatment of acute overdose with lidocaine.
In the absence of massive topical overdose or oral ingestion, evaluation of symptoms of toxicity should include consideration of other etiologies for the clinical effects, or overdosage from other sources of lidocaine or other local anesthetics.
ZTLIDO is contraindicated in patients with a known history of sensitivity to local anesthetics of the amide type, or to any other component of the product.
Lidocaine is an amide local anesthetic. Lidocaine blocks sodium ion channels required for the initiation and conduction of neuronal impulses.
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.
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%).
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 cm² 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.
Table 1 : Mean ± SD Absorption of lidocaine from
ZTLIDO Normal volunteers (n = 54, 12-hour application time)
| Topical System | Application Site | Area (cm²) | Cmax (ng/mL) | Tmax (hr)* |
| 3 Topical systems of ZTLIDO (108 mg) | Back | 420 | 75.1 ± 28.0 | 13.9 (4.0, 18.0) |
| *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).
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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).
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.
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).
ZTLIDO™
(ZEE-TEE-LIE-DOH)
(lidocaine topical system)
What is ZTLIDO?
ZTLIDO is a prescription medicine used for relief of pain from damaged nerves (neuropathic pain) that follows healing of shingles. It is not known if ZTLIDO is safe and effective in children.
Do not use ZTLIDO if you:
Before using ZTLIDO, tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially, tell your healthcare provider if you are using other lidocaine containing products or anesthetic medicines.
How should I use ZTLIDO?
Read the Instructions for Use at the end of this Patient Information leaflet for information about how to apply the ZTLIDO topical system.
What should I avoid while using ZTLIDO?
What are the possible side effects of ZTLIDO?
ZTLIDO may cause serious side effects, including:
These are not all the possible side effects of ZTLIDO.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ZTLIDO?
Keep ZTLIDO and all medicines out of the reach of children, pets, and others.
General information about the safe and effective use of ZTLIDO.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZTLIDO for a condition for which it was not prescribed. Do not give ZTLIDO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ZTLIDO that is written for health professionals.
What are the ingredients in ZTLIDO?
Active ingredient: lidocaine
Inactive ingredients: butylated hydroxytoluene, dipropylene glycol, isostearic acid, mineral oil, polyisobutylene, silicone dioxide, styrene/isoprene/styrene block copolymer, and terpene resin.
Instructions for Use
ZTLIDO™
(ZEE-TEE-LIE-DOH)
 (lidocaine topical system)
Read this Instructions for Use before you start using the ZTLIDO and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical treatment or condition.
Important information:
Figure A: ZTLIDO Topical System
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Applying your ZTLIDO topical system:
Step 1: Select the application site.
Step 2: Using scissors, carefully cut the envelope along the dotted line and open it to remove ZTLIDO.
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Step 3a: Remove the transparent release liner before applying ZTLIDO to the skin. Apply ZTLIDO right away after removing the transparent release liner. Apply ZTLIDO only to intact skin.
Step 3b: Place the adhesive side of ZTLIDO to skin, while not touching the sticky side. Smooth the ZTLIDO using your hands and firmly press to make sure it sticks well to skin.
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Step 4: Wash your hands right away after applying ZTLIDO.
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Removing your ZTLIDO topical system:
Step 5: Remove ZTLIDO from you skin after you have worn it for up to 12 hours.
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Step 6: Throw away the used whole or cut pieces of ZTLIDO where children and pets cannot get to them.
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Application of a replacement ZTLIDO (a new ZTLIDO):
This Patient Information has been approved by the U.S. Food and Drug Administration.
