Ralydan

Ralydan is indicated for use on intact skin in adults to provide topical local analgesia for superficial dermatological procedures such as dermal filler injection, pulsed dye laser therapy, facial laser resurfacing, and laser-assisted tattoo removal.

Important Dosage And Administration Instructions

• For use in adults only.
• Ralydan should only be applied to intact skin.
• Remove Ralydan if skin irritation or a burning sensation occurs during application.
• In order to minimize the risk of systemic toxicity, do not exceed the recommended amount of drug to apply or the duration of the application.
• Avoid eye contact with Ralydan.
• Wash hands after handling Ralydan.
• Upon removal from the treatment site, discard the used Ralydan in a location that is out of the reach of children and pets. Access to Ralydan by children or pets should be prevented during usage and storage of the product.

Recommended Dosing Duration

• For superficial dermatological procedures, such as dermal filler injection, non-ablative laser facial resurfacing, or pulsed-dye laser therapy, apply Ralydan to intact skin for 20 to30 minutes prior to the procedure. See Table 1 for instructions on the amount to apply.
• For superficial dermatological procedures, such as laser-assisted tattoo removal, apply Ralydan to intact skin for 60 minutes prior to the procedure. See Table 1 for instructions on the amount to apply.

Recommended Dosage

The dose of Ralydan that provides effective local dermal analgesia depends on the duration of the application. Although not specifically studied, a shorter duration of application may result in a less complete dermal analgesia or a shorter duration of adequate dermal analgesia.

Determine The Amount Of Drug To Apply

The amount (length) of Ralydan that should be dispensed is determined by the size of the area to be treated (see Table 1).

1. Using the ruler supplied on the carton, squeeze out and measure the amount of Ralydan that approximates the amount required to achieve proper coverage.
2. Spread Ralydan evenly and thinly (approximately 1 mm or the thickness of a dime) across the treatment area using a flat-surfaced tool such as a metal spatula or tongue depressor.
3. After waiting the required application time, remove the Ralydan by grasping a free-edge with your fingers and pulling it away from the skin.

Table 1. Amount of Ralydan According to Treatment Site Surface Area

• Ralydan is contraindicated in patients with a known history of sensitivity to lidocaine or tetracaine, local anesthetics of the amide or ester type, or to any other component of the product.
• Ralydan is contraindicated in patients with para-aminobenzoic acid (PABA) hypersensitivity.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Overexposure

• Application of Ralydan for longer times than those recommended or application of Ralydan over larger surface areas than those recommended could result in absorption of lidocaine and tetracaine at doses that could lead to serious adverse effects.
• When Ralydan is used concomitantly with other products containing local anesthetic agents, consider the amount absorbed from all formulations since the systemic toxic effects are thought to be additive and potentially synergistic with lidocaine and tetracaine.
• Ralydan is not recommended for use on mucous membranes or on areas with a compromised skin barrier because these uses have not been adequately studied. Application to broken or inflamed skin may result in toxic blood concentrations of lidocaine and tetracaine from increased absorption.
• Use Ralydan with caution in patients who may be more sensitive to the systemic effects of lidocaine and tetracaine, including the acutely ill or debilitated.
• Patients with severe hepatic disease or pseudocholinesterase deficiency, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations of lidocaine and tetracaine.

Risks Of Secondary Exposure To Children And Pets

Used Ralydan contains a large amount of lidocaine and tetracaine. The potential exists for a small child or pet to suffer serious adverse effects from ingesting Ralydan, although this risk with Ralydan has not been evaluated. After use, replace the cap securely on the tube. It is important to store and dispose of Ralydan out of the reach of children and pets.

Methemoglobinemia

Several local anesthetics, including lidocaine and tetracaine, have been associated with methemoglobinemia (metHB), particularly in conjunction with methemoglobin-inducing agents. Based on the literature, patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methemoglobinemia are more susceptible to drug-induced methemoglobinemia. Use of Ralydan in patients with a history of congenital or idiopathic methemoglobinemia is not advised.

Patients taking concomitant drugs associated with drug-induced methemoglobinemia, such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, p–aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine, may be at greater risk for developing methemoglobinemia.

Initial signs and symptoms of methemoglobinemia (which may be delayed for up to several hours following exposure) are characterized by a slate grey cyanosis seen in, e.g., buccal mucous membranes, lips and nail beds. In severe cases, symptoms may include central cyanosis, headache, lethargy, dizziness, fatigue, syncope, dyspnea, CNS depression, seizures, dysrythmia and shock. Methemoglobinemia should be considered if central cyanosis unresponsive to oxygen therapy occurs, especially if metHb-inducing agents have been used. Calculated oxygen saturation and pulse oximetry are inaccurate in the identification of methemoglobinemia. Confirm diagnosis by measuring methemoglobin level with co-oximetry. Normally, metHb levels are <1%, and cyanosis may not be evident until a level of at least 10% is present.

Treat clinically significant symptoms of methemoglobinemia with a standard clinical regimen such as intravenous infusion of methylene blue at a dosage of 1 mg/kg given over a 5 to 30-minute period. Refer to methylene blue dosing information for more detailed instructions on how to manage methemoglobinemia using that product.

There were no reports of methemoglobinemia in the trials of Ralydan Cream; however, providers are cautioned to carefully apply Ralydan Cream to ensure that the doses, areas of application, and duration of application are consistent with those recommended for the intended population.

Anaphylactic Reactions

Allergic or anaphylactic reactions have been associated with lidocaine and tetracaine and may occur with other components of Ralydan. They are characterized by urticaria, angioedema, bronchospasm, and shock. If an allergic reaction occurs, seek emergency help immediately.

Eye Irritation

Avoid contact of Ralydan with the eyes based on the findings of severe eye irritation with the use of similar products in animals. Also, the loss of protective reflexes may predispose to corneal irritation and potential abrasion. If eye contact occurs, immediately wash out the eye with water or saline and protect the eye until sensation returns.

Vaccinations

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either lidocaine or tetracaine.

Mutagenesis

The mutagenic potential of lidocaine base and tetracaine base has been determined in the in vitro Ames bacterial reverse mutation assay, the in vitro chromosome aberration assay using Chinese hamster ovary cells, and the in vivo mouse micronucleus assay. Lidocaine was negative in all three assays. Tetracaine was negative in the in vitro Ames assay and the in vivo mouse micronucleus assay. In the in vitro chromosome aberration assay, tetracaine was negative in the absence of metabolic activation, and equivocal in the presence of metabolic activation.

Impairment Of Fertility

Lidocaine did not affect fertility in female rats when given via continuous subcutaneous infusion via osmotic minipumps up to doses of 250 mg/kg/day (35-fold higher than the level of lidocaine contained in the lowest approved dose of Ralydan based on a mg/m² body surface area comparison). Lidocaine treatment did not affect overall fertility in male rats when given as subcutaneous doses up to 60 mg/kg (8-fold higher than the level of lidocaine contained in the lowest approved dose of Ralydan based on a mg/m² basis), although the treatment caused an increased copulatory interval and led to a dose-related decrease in homogenization resistant sperm head count, daily sperm production, and spermatogenic efficiency. Tetracaine did not affect fertility in male or female rats when given as subcutaneous doses up to 7.5 mg/kg (equivalent to the level of tetracaine in the lowest approved dose of Ralydan on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category B

No adequate and well-controlled studies have been conducted in pregnant women. Ralydan should be used during pregnancy only if the potential benefit justifies risk to the fetus. Lidocaine was not teratogenic in rats at doses up to 60 mg/kg (8-fold higher than the level of lidocaine contained in the lowest approved dose of Ralydan based on a mg/m² body surface area comparison). Lidocaine was not teratogenic in rabbits at doses up to 15 mg/kg (4-fold higher than the level of lidocaine in the lowest approved dose of Ralydan on a mg/m² basis).

Tetracaine was not teratogenic in rats given subcutaneous doses up to 10 mg/kg or in rabbits up to 5 mg/kg (equivalent to the level of tetracaine in the lowest approved dose of Ralydan on a mg/m² basis). Lidocaine and tetracaine given as a 1:1 eutectic mixture of 10 mg/kg each was not teratogenic in rats (equivalent to the level of the active components in the lowest approved dose of Ralydan on a mg/m² basis. Lidocaine and tetracaine given as a 1:1 eutectic mixture of 5 mg/kg each was not teratogenic in rabbits (equivalent to the level of the active components in the lowest approved dose of Ralydan on a mg/m² basis).

Lidocaine containing 1:100,000 epinephrine at a dose of 6 mg/kg (approximately equivalent to the level of lidocaine in the lowest approved dose Ralydan 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, lead to developmental delays in neonatal behavior among offspring. 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 the animal data is uncertain. Pre-and post-natal maturational, behavioral, or reproductive development was not affected by maternal subcutaneous administration of tetracaine during gestation and lactation up to doses of 7.5 mg/kg (equivalent to the level of tetracaine in the lowest approved dose of Ralydan on a mg/m² basis).

Labor And Delivery

Neither lidocaine nor tetracaine is contraindicated in labor and delivery. In humans, 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. Tetracaine has also been used as a neuraxial anesthetic for cesarean section without apparent adverse effects on offspring. Should Ralydan be used concomitantly with other products containing lidocaine and/or tetracaine, total doses contributed by all formulations must be considered.

Nursing Mothers

Lidocaine is excreted into human milk and it is not known if tetracaine is excreted into human milk. Therefore, caution should be exercised when Ralydan is administered to a nursing mother since the milk:plasma ratio of lidocaine is 0.4 and is not determined for tetracaine. In a prior report, when lidocaine was used as an epidural anesthetic for cesarean section in 27 women, a milk:plasma ratio of 1.07 ±0.82 was found by using AUC values. Following single dose administration of 20 mg of lidocaine for a dental procedure, the point value milk:plasma ratio was similarly reported as 1.1 at five to six hours after injection. Thus, the estimated maximum total daily dose of lidocaine delivered to the infant via breast milk would be approximately 36 mcg/kg. Based on these data and the low concentrations of lidocaine and tetracaine found in the plasma after topical administration of Ralydan in recommended doses, the small amount of these primary compounds and their metabolites that would be ingested orally by a suckling infant is unlikely to cause adverse effects.

Pediatric Use

Safety and effectiveness of Ralydan in pediatric patients have not been established. Unintended exposure in pediatric patients could possibly lead to serious adverse effects. In a trial of Ralydan in pediatric patients aged 5 to17 years undergoing venipuncture (blood draw or intravenous line placement), Ralydan applied for 30 minutes failed to show efficacy over placebo in reducing the pain associated with the procedure.

Geriatric Use

Of the total number of subjects treated with Ralydan in controlled clinical studies, 161 subjects were 65 years and older, while 50 subjects were over 75 years of age. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. However, increased sensitivity in individual patients aged 65 years and older cannot be ruled out.

The following adverse reactions are described elsewhere in the labeling:

• Overexposure
• Risks of Secondary Exposure in Children and Pets
• Methemoglobinemia
• Anaphylactic Reactions
• Eye Irritation

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

However, the adverse reaction information from clinical trials does provide a basis for identifying the adverse events that appear to be related to drug use and for approximating their incidence in clinical practice.

Ralydan has been evaluated for safety in 2159 persons undergoing a superficial dermal procedure. Ralydan was studied in 11 placebo-controlled and 1 active-controlled trials, and in open-label safety trials. All 2159 persons were exposed to only a single application of Ralydan. Adverse reactions were assessed by collecting spontaneously reported adverse reactions, and observations made on formal evaluation of the skin for specific reactions.

Most Common Adverse Reactions In Clinical Trials

Localized Reactions

In clinical studies, the most common local reactions were erythema (47%), skin discoloration (e.g., blanching, ecchymosis, and purpura) (16%), and edema (14%). There were no serious adverse reactions. However, one patient withdrew due to burning pain at the treatment site.

Other Localized Reactions

The following dermal adverse reactions occurred in 1% or less of Ralydan-treated patients: ecchymosis, petechial rash, vesiculobullous rash, perifollicular erythema, perifollicular edema, pruritus, rash, maculopapular rash, dry skin, contact dermatitis, and acne.

Systemic (Dose-Related) Reactions

Across all trials, 19 subjects experienced a systemic adverse reaction, 15 of whom were treated with Ralydan and 4 with placebo. The frequency of systemic adverse reactions was greater for the Ralydan group (1%) than the placebo group (0.3%). The most common systemic adverse events were headache, vomiting, dizziness, and fever, all of which occurred with a frequency of <1%. Other systemic reactions were syncope, nausea, confusion, dehydration, hyperventilation, hypotension, nervousness, paresthesia, pharyngitis, stupor, pallor, and sweating.

Systemic adverse reactions of lidocaine and tetracaine are similar in nature to those observed with other amide and ester local anesthetic agents, including CNS excitation and/or depression (lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensation of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest). Excitatory CNS reactions may be brief or not occur at all, in which case the first manifestation may be drowsiness merging into unconsciousness. Signs of CNS toxicity may start at plasma concentrations of lidocaine at 1000 ng/mL. The plasma concentrations at which tetracaine toxicity may occur are less well characterized; however, systemic toxicity with tetracaine is thought to occur with much lower plasma concentrations compared with lidocaine. The toxicity of co-administered local anesthetics is thought to be at least additive. Cardiovascular manifestations may include bradycardia, hypotension and cardiovascular collapse leading to arrest.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Ralydan.

Because these reactions are 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.

Eye disorders: Eyelid swelling

Skin: Pruritus, Rash, Skin Burning Sensation, Erythema, Urticaria

Other: Drug ineffective

Application of 59 g of Ralydan over 400 cm² for up to 120 minutes to adults produces peak plasma concentrations of lidocaine of 220 ng/mL. Toxic levels of lidocaine (>5000 ng/mL) cause CNS toxicity, including the risk of seizure. Signs of CNS toxicity may start at plasma concentrations of lidocaine as low as 1000 ng/mL, andthe risk of seizures generally increases with increasing plasma levels. Very high levels of lidocaine can cause respiratory arrest, coma, decreases in cardiac output, total peripheral resistance and mean arterial pressure, ventricular arrhythmias and cardiac arrest.

Tetracaine is associated with a profile of systemic CNS and cardiovascular adverse events similar to lidocaine, although toxicity associated with tetracaine is thought to occur at lower doses compared to lidocaine. The toxicity of co-administered local anesthetics is thought to be at least additive. In the absence of massive topical overdose or oral ingestion, other etiologies for the clinical effects or overdosage from other sources of lidocaine, tetracaine or other local anesthetics should be considered.

The management of overdosage includes close monitoring, supportive care and symptomatic treatment. Dialysis is of negligible value in the treatment of acute overdosage of lidocaine or tetracaine.

Duration of analgesia was evaluated using a pinprick test in 40 adult volunteers. The median duration of analgesia was 11 hours. There was no difference between the 30-minute and 60-minute Ralydan application periods with respect to the mean for time to return of sensation. However, 55% of Ralydan treated subjects still reported diminished sensation at the end of the 13-hour study period.

Absorption

The amount of lidocaine and tetracaine systemically absorbed from Ralydan is directly related to both the duration of application and the surface area over which it is applied, Table 2.

Application of 59 g of Ralydan over 400 cm² for up to 120 minutes to adults produces peak plasma concentrations of lidocaine of 220 ng/mL. Tetracaine plasma levels were not measurable (<0.9 ng/mL). Systemic exposure to lidocaine, as measured by Cmax and AUC0-24, was proportional to the application area, and increased with application time up to 60 minutes.

Table 2. Absorption of lidocaine and tetracaine following application of Ralydan

Distribution

When lidocaine is administered intravenously to healthy volunteers, the steady-state volume of distribution is approximately 0.8 to 1.3 L/kg. At lidocaine concentrations observed following the recommended product application, approximately 75% of lidocaine is bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 mg/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. CNS toxicity may typically be observed around 5000 ng/mL of lidocaine; however, a small number of patients reportedly may show signs of toxicity at approximately 1000 ng/mL. Volume of distribution and protein binding have not been determined for tetracaine due to rapid hydrolysis in plasma.

Metabolism

It is not known if lidocaine or tetracaine 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. The major metabolic pathway of lidocaine, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4. The metabolite, 2,6-xylidine, has unknown pharmacologic activity. 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. Serum concentrations of MEGX were about one-third the serum lidocaine concentrations.

Tetracaine undergoes rapid hydrolysis by plasma esterases. Primary metabolites of tetracaine include para-aminobenzoic acid and diethylaminoethanol, both of which have an unspecified activity.

Elimination

The half-life of lidocaine elimination from the plasma following intravenous administration is approximately 1.8 hr. Lidocaine and its metabolites are excreted by the kidneys. More than 98% of an absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. Less than 10% of lidocaine is excreted unchanged in adults, and approximately 20% is excreted unchanged in neonates. The systemic clearance is approximately 8 to 10 mL/min/kg. During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours). The half-life and clearance for tetracaine has not been established for humans, but hydrolysis in the plasma is rapid.