2.1 Important Dosage and Administration Instructions

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 (12.3)].

When ZTLIDO is used concomitantly with other products containing local anesthetic agents, the total amount of drug absorbed from all formulations must be considered.

Clearly instruct and advise patients:

• to wash hands immediately after handling ZTLIDO and to avoid contact with eyes [see Warnings and Precautions (5.6)] .
• to store ZTLIDO inside the sealed envelope out of the reach of children, pets, and others and to apply immediately after removal from the envelope.
• to fold used ZTLIDO so that the adhesive side sticks to itself and to safely discard used ZTLIDO or pieces of cut ZTLIDO where children and pets cannot get to them [see Warnings and Precautions (5.1)] .
• to never 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 (5.2), Clinical Pharmacology (12.3)] .
• that clothing may be worn over the area of application.
• that ZTLIDO may be used during moderate exercise, such as biking for 30 minutes.
• that ZTLIDO may be exposed to water, such as showering for 10 minutes or immersion for 15 minutes.
• to dry the topical system, after water exposure, by gently patting the skin, not by rubbing the skin or topical system.
• that ZTLIDO topical systems that have lifted at the edges may be reattached by pressing firmly on the edges and that fully detached topical systems may be reapplied as originally directed.
• that if a ZTLIDO topical system comes off completely and will not stick to patient's skin, to remove and properly dispose of the used ZTLIDO and to apply a new ZTLIDO topical system for a total duration of 12 hours of used and new topical system together.
• that if irritation or a burning sensation occurs during application, to remove ZTLIDO and to not reapply until the irritation subsides [see Warnings and Precautions (5.4)] .

2.2 Treatment of Post-Herpetic Neuralgia

Advise patients to apply ZTLIDO to intact skin to cover the most painful area and to 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) [see Warnings and Precautions (5.2)] .

In patients who are debilitated or have impaired elimination, smaller areas of treatment are recommended. Achieve this by cutting ZTLIDO with scissors into a smaller size prior to removing the release liner.

5.1 Accidental Exposure

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 (2.1)].

5.2 Excessive Dosing/Overexposure to Lidocaine

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 (10)] .

5.3 Methemoglobinemia

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue ZTLIDO and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.

5.4 Application Site Reactions

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. If application site reactions occur while the topical system is being worn, advise the patient to remove ZTLIDO and not to reapply until skin reactions subside.

5.5 Hypersensitivity Reactions

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.

5.6 Eye Exposure

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.

7.1 Drugs That May Cause Methemoglobinemia When Used with ZTLIDO

Patients who are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:

Examples of Drugs Associated with Methemoglobinemia:

7.2 Antiarrhythmic Drugs

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.

7.3 Local Anesthetics

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 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 (e.g., a single topical system), reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

12.1 Mechanism of Action

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

12.2 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.

12.3 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 (C max) 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 2of 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 Healthy Volunteers (n = 54, 12-hour application time)

Topical System	Application Site	Area (cm 2)	C max(ng/mL)	T max(hr) *
* median (min, max)
3 Topical systems of ZTLIDO (108 mg)	Back	420	75.1 ± 28.0	13.9 (4.0, 18.0)

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 concentration 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).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Wash hands thoroughly immediately after handling the topical system. Upon removal, fold the topical system in half so that the adhesive side sticks to itself. Discard used ZTLIDO and pieces of cut ZTLIDO in a manner that prevents accidental contact or ingestion by children, pets or others [see Dosage and Administration (2.2), Warnings and Precautions (5.1)] .

Accidental Exposure and Disposal

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 [see Warnings and Precautions (5.1)] .

Proper Application

Advise patients:

• not to apply more than the prescribed number (up to 3 ZTLIDO) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
• not to wear ZTLIDO longer than the recommended wearing time (12 hours of every 24 hours) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
• to apply ZTLIDO to intact skin [see Warnings and Precautions (5.2)].
• to reattach by pressing firmly on the edges of ZTLIDO that are lifting. If a ZTLIDO topical system comes off completely and will not stick to patient's skin, it should be removed and properly disposed of and a new ZTLIDO topical system should be applied for a total duration of 12 hours of used and new topical system together [see Dosage and Administration (2.1, 2.2)] .

Methemoglobinemia

Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to stop use and seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.3)].

Application Site Reactions

Inform patients that skin irritation and other skin reactions may occur at the site of ZTLido application. If skin reactions occur during wear, instruct patients to remove ZTLido and not to reapply until the skin reaction subsides [see Warnings and Precautions (5.4)]

Eye Exposure

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 (2.1), Warnings and Precautions (5.6)] .