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  • CLASSES

    Topical Local Anesthetics

    DEA CLASS

    Rx

    DESCRIPTION

    Local anesthetics for topical administration; available as a patch that becomes warm once the outer packaging is removed and as a cream that forms a pliable peel on the skin when exposed to air.

    COMMON BRAND NAMES

    Pliaglis, Synera

    HOW SUPPLIED

    Lidocaine, Tetracaine/Pliaglis Topical Cream: 7-7%
    Synera Topical Film: 70-70mg

    DOSAGE & INDICATIONS

    For use as local anesthesia to provide topical anesthesia to normal intact skin.
    For superficial dermatological procedures such as excision, electrodesiccation, and shave biopsy of skin lesions.
    Topical dosage (dermal patch only, e.g., Synera)
    Adults

    1 patch applied for 30 minutes before the procedure to skin lesion area. Remove the patch before the procedure. Do not leave a patch on the skin for longer than 30 minutes.

    Children and Adolescents 3 to 17 years

    1 patch applied for 30 minutes before the procedure to skin lesion area. Remove the patch before the procedure. Do not leave a patch on the skin for longer than 30 minutes.

    For superficial venous access.
    Topical dosage (dermal patch only, e.g., Synera)
    Adults

    1 patch applied for 20 to 30 minutes before the procedure to the desired venipuncture or IV cannulation site. Remove the patch before attempting venipuncture. Do not leave a patch on the skin for longer than 30 minutes. Application of 1 additional patch to a new site to facilitate venous access after a failed attempt is acceptable.

    Children and Adolescents 3 to 17 years

    1 patch applied for 20 to 30 minutes before the procedure to the desired venipuncture or IV cannulation site. Remove the patch before attempting venipuncture. Do not leave a patch on the skin for longer than 30 minutes. Application of 1 additional patch to a new site to facilitate venous access after a failed attempt is acceptable.

    For superficial dermatological procedures such as dermal filler injection, pulsed dye laser therapy, and facial laser resurfacing.
    Topical dosage (cream only)
    Adults

    Apply an amount required to achieve proper coverage for the treatment site surface area topically to intact skin 20 to 30 minutes before the procedure. The dose of cream that provides effective local dermal analgesia depends on the duration of the application.

    For laser-assisted tattoo removal.
    Topical dosage (cream only)
    Adults

    Apply an amount required to achieve proper coverage for the treatment site surface area topically to intact skin 60 minutes before the procedure. The dose of cream that provides effective local dermal analgesia depends on the duration of the application.

    MAXIMUM DOSAGE

    Adults

    1 patch on the body at any given time; maximal application area of the cream should not exceed 62 inch2.

    Geriatric

    1 patch on the body at any given time; maximal application area of the cream should not exceed 62 inch2.

    Adolescents

    1 patch on the body at any given time; safety and efficacy of the cream have not been established.

    Children

    3 years and older: 1 patch on the body at any given time; safety and efficacy of the cream have not been established.
    Younger than 3 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific dosing guidelines are not available. The half-life of lidocaine may be increased in patients with hepatic impairment.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Topical Administration
    Cream/Ointment/Lotion Formulations

    Topical Cream:
    Do not apply to a procedure site after a procedure has been performed.
    Wash hands before and after application.
    Apply only to intact skin. Avoid application to broken or inflamed skin, the lips, or in the mouth, ears, eyes, or other areas.
    Squeeze out and measure the amount of cream that approximates the amount required to achieve proper coverage using the ruler on the applicator included in the carton.
    Apply the cream evenly and thinly (approximately 1 mm or the thickness of a dime) across the treatment area using a flat-surfaced tool such as a spatula or tongue depressor.
    After the required application time has elapsed, remove the peel by pulling on a free edge with the fingers. Do not leave the peel on the skin for longer than recommended durations.
    Dispose of used peels in such a way as to prevent accidental exposure to children or pets. Large amounts of active ingredients are contained in used peels.

    Transdermal Patch Formulations

    Dermal patch (Synera):
    Wash hands before and after application.
    Remove the outer packaging immediately before the patch is applied to the skin.
    Do not cut the patch, remove the top cover, or cover the holes on the top side of the patch. If the patch is cut, excess drug could be released. If the top cover is removed, the patch may generate too much heat. If the holes on the top side of the patch are covered, heat may not be generated.
    Apply only to intact skin. Do not apply to broken or inflamed skin or in the mouth, ears, eyes, or to other areas.
    Do not leave a patch on the skin for longer than 30 minutes. Systemic exposure of lidocaine and tetracaine is thought to be directly related to the application duration.
    The patch must be removed before magnetic resonance imaging (MRI), as the integrated heating component of the patch contains iron powder.
    Used patches should be folded together at the adhesive sides and disposed of in such a way as to prevent accidental exposure to children or pets.

    STORAGE

    Pliaglis:
    - Do not freeze
    - May be stored at room temperature not exceeding 77 degrees F for up to 3 months
    - Refrigerate (between 36 and 46 degrees F)
    Synera:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the contraindications/precautions of the lidocaine; tetracaine combination product. Clinicians may wish to consult the individual monographs for more information about each agent.

    Amide local anesthetic hypersensitivity, ester local anesthetic hypersensitivity, para-aminobenzoic acid, PABA hypersensitivity, paraben hypersensitivity

    Lidocaine; tetracaine is contraindicated for use in patients with amide local anesthetic hypersensitivity, ester local anesthetic hypersensitivity, or para-aminobenzoic acid, PABA hypersensitivity. The patch and the cream also contain methylparaben and propylparaben, which are known to precipitate anaphylaxis and/or severe asthmatic attacks in patients with paraben hypersensitivity.

    Magnetic resonance imaging (MRI)

    The lidocaine; tetracaine patch must be removed from a patient before they undergo magnetic resonance imaging (MRI), as the integrated heating component of the patch contains iron powder. Failure to remove the patch may cause burns during the MRI.

    Accidental exposure, children, infants

    The lidocaine; tetracaine patches are only indicated for use in children at least 3 years of age, and the cream is not indicated for use in patients less than 18 years of age. In a trial of patients aged 5—17 years undergoing blood draw or intravenous line placement, cream applied for 30 minutes failed to show efficacy over placebo in reducing the pain associated with the procedure. To avoid accidental exposure and accidental ingestion, store and dispose of lidocaine patches and cream out of the reach of infants, children, and pets. Used or new lidocaine; tetracaine patches or cream contains a large amount of lidocaine and tetracaine (at least 90% of the initial amount in the patch). The potential exists for small children or pets to suffer serious adverse effects from chewing or ingesting a new or used lidocaine; tetracaine patch or cream.

    Pregnancy

    There are no adequate data on the developmental risk associated with lidocaine; tetracaine use during human pregnancy. Drug-associated risks of major birth defects or miscarriage with parenteral lidocaine use during pregnancy were not observed from an epidemiologic study and case series. Systemic exposure to lidocaine; tetracaine is expected to be low compared to exposure following parenteral dosing, and the exposure is not expected to result in significant fetal exposure. In animal studies, lower fetal body weights were observed in the offspring of pregnant rats given a continuous subcutaneous infusion of lidocaine during organogenesis at doses approximately 1.3 times the maximum human recommended dose (MHRD) of 53 grams of lidocaine; tetracaine cream. Neonatal developmental delays were seen in offspring of pregnant rats who received lidocaine injection containing 1:100,000 epinephrine in the masseter jaw muscle or the gum of the lower jaw. No adverse embryofetal effects were seen following subcutaneous administration of tetracaine to pregnant rats and rabbits during organogenesis at 0.03 times the MHRD of lidocaine; tetracaine cream.

    Breast-feeding

    Lidocaine is excreted in breast milk with a milk:plasma ratio of 0.4 to 1.1 following parenteral administration. It is unknown whether tetracaine is excreted in breast milk. The low concentrations of lidocaine and tetracaine found in the plasma after topical administration are unlikely to cause adverse effects in the nursing infant. If used in the lactating mother, lidocaine; tetracaine should not be applied directly to the nipple and areola to avoid direct infant exposure. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for lidocaine; tetracaine and any potential adverse effects on the breast-fed infant from lidocaine; tetracaine or the underlying maternal condition.[31353] [52329]

    Burns, eczema, occlusive dressing, skin abrasion

    Applying lidocaine; tetracaine patches or cream to severely traumatized skin (e.g., skin abrasion, eczema, burns), to large surface areas, or to warm skin (e.g., after exercise or applying thermal heat wraps or heating pads) can increase its absorption, possibly increasing the risk of systemic toxicity. Also, applying large amounts of lidocaine; tetracaine or using an occlusive dressing (skin wraps) can increase lidocaine; tetracaine absorption. Excessive dosing by applying multiple patches or by applying the patch or wearing the cream for longer than the recommended wearing time could result in increased absorption of lidocaine and tetracaine. Prolonged use of topical anesthetics is not recommended. At least 2 reports of deaths exist after application of topical anesthetics prior to cosmetic procedures. In both instances, women, aged 22 and 25 years, applied topical anesthetics to their legs and wrapped the treated area, as directed, in plastic wrap to enhance the numbing effect of the cream. Both women died from toxic effects of the topical anesthetic. The preparations used in both cases were compounded in pharmacies and contained high amounts of lidocaine and tetracaine. In order to reduce the risk of toxicity due to increased absorption of topical anesthetic, the FDA recommends patients use a topical anesthetic containing the lowest amount of medication needed to relieve pain, apply the medication sparingly, and only treat known or anticipated areas of pain. Further, do not apply the anesthetic to broken or irritated skin, be aware of potential adverse reactions, and do not cover or apply heat to the treated area.

    Ocular exposure

    Avoid ocular exposure of lidocaine; tetracaine patches and cream based upon the findings of severe eye irritation with the use of similar products in animals. If eye contact occurs, immediately wash the eye with water or saline, and protect the eye until sensation returns.

    Pseudocholinesterase deficiency

    Ester-type local anesthetics, like lidocaine; tetracaine, should be used cautiously, if at all, in patients with low plasma concentrations of pseudocholinesterase (e.g., pseudocholinesterase deficiency). Tetracaine, an ester-type local anesthetic, is metabolized by plasma esterases. Patients with pseudocholinesterase deficiency are at a greater risk of developing toxic tetracaine concentrations.

    Geriatric

    As compared with placebo, the analgesic effect of a lidocaine; tetracaine patch as determined by a visual analog scale was not as pronounced in older versus younger patients. Further, 35% of 54 patients 65 years and older who received a lidocaine; tetracaine patch and 28% of 25 patients who received a placebo patch required a rescue lidocaine injection during a superficial dermatologic procedure. In contrast, no overall differences in safety and effectiveness of the cream were observed between older and younger patients. If the cream or a patch is used in geriatric patients, cautious use is recommended. The elderly may have decreased hepatic function, decreased cardiac function, or be on multiple drugs and, thus, be more sensitive to possible systemic effects of lidocaine; tetracaine. Further, the half-life of lidocaine is longer in patients at least 65 years of age as compared with younger patients (see Pharmacokinetics). Lidocaine accumulation increases the risk of systemic toxicity (see Mechanism of Action). Resuscitative equipment and facilities should be readily available in case of an emergency.

    Heart failure, hepatic disease, hepatic encephalopathy, hepatitis

    Although systemic absorption is low following topical application, lidocaine may have decreased metabolism in debilitated patients, the acutely ill, and patients with conditions that reduce hepatic blood flow such as hepatic disease (e.g., hepatic encephalopathy, hepatitis) and congestive heart failure. Higher plasma concentrations of lidocaine could theoretically occur in the presence of hepatic impairment. Also, repeated doses of lidocaine may cause a significant increase in blood concentrations with each successive dose. Lidocaine accumulation increases the risk of systemic toxicity. Cautious use of lidocaine; tetracaine is recommended for acutely ill, debilitated, or elderly patients, as they may have decreased hepatic function, decreased cardiac function, or be on multiple drugs and thus, be more sensitive to possible systemic effects of lidocaine; tetracaine. Resuscitative equipment and facilities should be readily available in case of an emergency.

    Cardiac disease, G6PD deficiency, methemoglobinemia, neonates, pulmonary disease

    Methemoglobinemia has been reported with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), preexisting (congenital or idiopathic) methemoglobinemia, cardiac or pulmonary compromise (cardiac disease or pulmonary disease), neonates and infants younger than 6 months, and those with concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing methemoglobinemia. Monitor such patients closely for signs and symptoms of methemoglobinemia if a local anesthetic must be used. Signs of methemoglobinemia may occur immediately or may be delayed hours after exposure. Immediately discontinue the local anesthetic to avoid serious central nervous system and cardiovascular adverse events, as methemoglobin concentrations may continue to rise. Patients may require supportive care such as oxygen therapy and hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. [52329]

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    bronchospasm / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    coma / Early / Incidence not known
    methemoglobinemia / Early / Incidence not known

    Moderate

    erythema / Early / 47.0-71.0
    edema / Delayed / 0-14.0
    bullous rash / Early / 0-1.0
    contact dermatitis / Delayed / 0-1.0
    hypotension / Rapid / 0-1.0
    dehydration / Delayed / 0-1.0
    confusion / Early / 0-1.0
    blurred vision / Early / Incidence not known
    respiratory depression / Rapid / Incidence not known
    euphoria / Early / Incidence not known

    Mild

    skin discoloration / Delayed / 0-16.0
    acne vulgaris / Delayed / 0-1.0
    vesicular rash / Delayed / 0-1.0
    maculopapular rash / Early / 0-1.0
    ecchymosis / Delayed / 0-1.0
    rash / Early / 0-1.0
    pruritus / Rapid / 0-1.0
    pharyngitis / Delayed / 0-1.0
    syncope / Early / 0-1.0
    fever / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    dizziness / Early / 0-1.0
    diaphoresis / Early / 0-1.0
    hyperventilation / Early / 0-1.0
    headache / Early / 0-1.0
    pallor / Early / 0-1.0
    vomiting / Early / 0-1.0
    nausea / Early / 0-1.0
    urticaria / Rapid / Incidence not known
    anxiety / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    tremor / Early / Incidence not known
    restlessness / Early / Incidence not known
    tinnitus / Delayed / Incidence not known

    DRUG INTERACTIONS

    Adapalene; Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Benzalkonium Chloride; Benzocaine: (Moderate) Use tetracaine and benzocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Benzocaine: (Moderate) Use tetracaine and benzocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Benzocaine; Butamben; Tetracaine: (Moderate) Use tetracaine and benzocaine together with caution. Monitor cardiovascular and respiratory vital signs, as well as the patient's state of consciousness if used concurrently due to potential for additive CNS and/or cardiovascular toxic effects. Manifestations of toxicity may include CNS excitation and/or depression, cardiac conduction depression, or peripheral vasodilation. Additionally, coadministration may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue local anesthetic use. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Benzoyl Peroxide; Clindamycin: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Benzoyl Peroxide; Erythromycin: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Benzoyl Peroxide; Sulfur: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
    Calamine; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Chloroxylenol; Hydrocortisone; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Dibucaine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Ethyl Chloride: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Hydrocortisone; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Pramoxine; Zinc Acetate: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
    Tretinoin; Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate data on the developmental risk associated with lidocaine; tetracaine use during human pregnancy. Drug-associated risks of major birth defects or miscarriage with parenteral lidocaine use during pregnancy were not observed from an epidemiologic study and case series. Systemic exposure to lidocaine; tetracaine is expected to be low compared to exposure following parenteral dosing, and the exposure is not expected to result in significant fetal exposure. In animal studies, lower fetal body weights were observed in the offspring of pregnant rats given a continuous subcutaneous infusion of lidocaine during organogenesis at doses approximately 1.3 times the maximum human recommended dose (MHRD) of 53 grams of lidocaine; tetracaine cream. Neonatal developmental delays were seen in offspring of pregnant rats who received lidocaine injection containing 1:100,000 epinephrine in the masseter jaw muscle or the gum of the lower jaw. No adverse embryofetal effects were seen following subcutaneous administration of tetracaine to pregnant rats and rabbits during organogenesis at 0.03 times the MHRD of lidocaine; tetracaine cream.

    Lidocaine is excreted in breast milk with a milk:plasma ratio of 0.4 to 1.1 following parenteral administration. It is unknown whether tetracaine is excreted in breast milk. The low concentrations of lidocaine and tetracaine found in the plasma after topical administration are unlikely to cause adverse effects in the nursing infant. If used in the lactating mother, lidocaine; tetracaine should not be applied directly to the nipple and areola to avoid direct infant exposure. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for lidocaine; tetracaine and any potential adverse effects on the breast-fed infant from lidocaine; tetracaine or the underlying maternal condition.[31353] [52329]

    MECHANISM OF ACTION

    Mechanism of Action: Both lidocaine and tetracaine block the initiation and conduction of nerve impulses from sensory nerves by decreasing the permeability of the neuronal membrane to sodium ions. Sodium ion channel blockade reversibly stabilizes the membrane and inhibits depolarization, which results in the failure of a propagated action potential and subsequent conduction blockade. Due to interference with the transmission of impulses along sensory nerve fibers, lidocaine; tetracaine relieves pain. The blockade affects all nerve fibers in the following sequence: autonomic, sensory, and motor with effects diminishing in reverse order. Loss of nerve function clinically is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone. Direct nerve membrane penetration is necessary for effective anesthesia, which is achieved by applying the anesthetic topically around the nerve trunks or ganglia supplying the area to be anesthetized.Systemic absorption of local anesthetics can produce effects on the central nervous and cardiovascular systems. Toxic blood concentrations depress cardiac conduction and excitability, which may lead to AV block, ventricular arrhythmia, and cardiac arrest. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Local anesthetics can produce central nervous system stimulation, depression, or both following systemic absorption. Usually, CNS toxicity may be noted with a plasma lidocaine concentration of 5000 ng/ml, although toxicity may occur at concentrations around 1000 ng/ml. Central nervous system stimulation is usually manifested as restlessness, tremors, and shivering progressing to convulsions, depression, coma, and respiratory arrest. However, local anesthetics have a primary depressant effect on the medulla and higher centers. The depressed stage may occur without the prior excitatory stage.

    PHARMACOKINETICS

    Lidocaine; tetracaine is administered topically as a patch or cream. Lidocaine binds mainly to alpha-1-acid glycoprotein. After the recommended application of a Synera patch or of the cream (see Dosage and Administration), approximately 75% of lidocaine is bound to plasma proteins. At much higher plasma concentrations of 1—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. Lidocaine is extensively metabolized by sequential N-deethylation in the liver into two active compounds, monoethylglycinexylidide and glycinexylidide, which possess 100% and 25% of the potency of lidocaine, respectively. The major metabolic pathway of lidocaine to monoethylglycinexylidide and glycinexylidide is primarily mediated by CYP1A2 with a minor role of CYP3A4. The half-life of lidocaine elimination from the plasma following intravenous administration is approximately 1.8 hours. Both lidocaine and its metabolites are renally excreted. It is not known if either lidocaine or tetracaine is metabolized in the skin. Tetracaine is hydrolyzed to para-aminobenzoic acid and diethylaminoethanol by plasma pseudocholinesterases. Tetracaine has the slowest rate of hydrolysis of the ester type local anesthetics and its metabolites are primarily renally excreted. The half-life for tetracaine has not been established due to rapid hydrolysis in the plasma.

    Topical Route

    Following application of a Synera patch to intact, adult skin for 30 minutes, the estimated absorbed dose of lidocaine was 1.7 mg and of tetracaine was 1.6 mg. The peak plasma concentration of lidocaine was 1.7 ng/ml and the tetracaine concentration was below the lower limit of quantification of 0.9 ng/ml. Application of a patch for up to 60 minutes did not significantly increase the plasma concentrations of either lidocaine or tetracaine. In contrast, lidocaine systemic exposure from the cream, as measured by Cmax and systemic exposure over 24 hours, was proportional to the application area and increased with application time up to 60 minutes. The amount of lidocaine and tetracaine systemically absorbed from the cream is directly related to both the duration of application and the surface area over which it is applied. Application of 21 grams of cream over 400 cm2 for 30 minutes results in a mean lidocaine Cmax of 49 ng/ml, obtained at a mean time of 4 hours after application. Application of 33 grams of cream to the same surface area for 60 minutes led to a mean Cmax of 96 ng/ml, which occurred at a mean time of 2.8 hours. Application of 59 g of over the same surface area for up to 120 minutes to adults produces peak plasma concentrations of lidocaine of 220 ng/ml. In each of these cases, tetracaine plasma concentrations were not measurable (< 0.9 ng/ml).
     
    The anesthetic depth and duration achieved with a lidocaine; tetracaine patch was evaluated in a crossover study. As compared with a placebo patch, a lidocaine; tetracaine patch for 30 minutes led to a greater depth and duration of anesthesia. Anesthesia was determined by use of a scale (0 = no sensation, 1 = dull sensation, 2 = sharp, scratching sensation). The mean anesthetic depth was 6.8 mm as compared with 4.7 mm after placebo. Two patients had no pain after lidocaine; tetracaine at 10 mm of penetration, which was the study limit. Of the 12 patients, 10 had anesthesia with the lidocaine; tetracaine patch over the entire 2-hour post-application assessment period, and 11 of the patients had anesthesia at the 10, 20, 30, 40, and 50 minute assessments. In contrast, only 1 patient reported anesthesia with placebo, which occurred at the 10 minute assessment.
     
    As determined by a pinprick test in 40 adults, the median duration of analgesia was 11 hours after 30 or 60 minutes of application of the cream. The mean time for return of sensation was similar between the 30- and 60-minute application periods. Diminished sensation at the end of the 13-hour study period was reported by 55% of patients.