Lidocaine, an amide-type local anesthetic, and tetracaine, an ester-type local anesthetic, are used together in a topical preparation for local anesthesia. Multiple dosage forms are available for clinical use. A patch (Synera(TM)) contains 70 mg of each anesthetic; the cream (Pliaglis(TM)) contains 70 mg of each anesthetic per gram. Synera(TM) patch is an emulsion that becomes warm once the outer packaging is removed. The warming occurs from a chemical reaction that is initiated with oxygen exposure and is intended to enhance local anesthetic delivery. The skin temperature under the patch may increase by up to approximately 5 degrees C, but maximum skin temperature will not exceed 40 degrees C. The lidocaine; tetracaine patch is applied for 20-30 minutes before a procedure. Lidocaine; tetracaine cream is applied for 20-30 minutes before superficial procedures such as dermal filler injections or facial laser resurfacing, and for 60 minutes before procedures such as laser-assisted tattoo removal. The cream is designed to form a pliable peel on the skin when exposed to air. The FDA approved the Synera(TM) patch in June 2005 and Pliaglis(TM) cream in June 2006.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific 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.
This monograph discusses the adverse reactions of the lidocaine; tetracaine combination product. Clinicians may wish to consult the individual monographs for more information about each agent.
During or immediately following application of the patch, transient blanching (lightening), edema, or erythema (redness) of the skin may occur. Of 1449 patients who used the lidocaine; tetracaine patch during clinical studies, 71% experienced erythema. Blanching and edema were observed in 12% of patients. Other application site reactions (combined) occurred in < 4%, including contact dermatitis, rash (unspecified), or skin discoloration. In clinical studies of lidocaine; tetracaine cream in 2159 patients, erythema occurred in 47%; skin discoloration such as blanching, ecchymosis, and purpura occurred in 16%; and edema occurred in 14%. Ecchymosis, petechial rash, vesicular rash, bullous rash, perifollicular erythema, perifollicular edema, pruritus, rash (unspecified), maculopapular rash, dry skin, contact dermatitis, and acne vulgaris were noted in < 1% of patients. These reactions were generally mild, transient, and temporary. One patient withdrew due to burning pain at the treatment site. Monitor patients for a local reaction. If skin irritation or a burning sensation occurs, remove the patch or the cream. The development of angioedema (e.g., anaphylactoid reactions), urticaria, bronchospasm, or anaphylactic shock warrants immediate medical attention. Hypersensitivity may occur in susceptible individuals.
Systemic adverse reactions following appropriate application of lidocaine; tetracaine patches or cream are unlikely due to the small amount of lidocaine and tetracaine absorbed. However, 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. Systemic exposure to lidocaine was proportional to the application area and increased with application time up to 60 minutes. Signs of CNS toxicity may start at plasma concentrations of lidocaine as low as 1000 ng/ml, although CNS toxicity is typically observed around 5000 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 as compared with lidocaine. The toxicity of coadministered local anesthetics is thought to be at least additive. Tetracaine and lidocaine, like all local anesthetics, can produce significant CNS and cardiovascular toxicity, particularly when high serum concentrations are achieved. Tetracaine or lidocaine induced CNS toxicity usually presents with symptoms of a CNS stimulation such as anxiety, apprehension, restlessness, disorientation, confusion, dizziness, light-headedness, euphoria, tinnitus, blurred vision, tremor, hot, cold, or numb sensations, and/or seizures. Subsequently, depressive symptoms may occur including drowsiness, respiratory depression, respiratory arrest, or coma. In some patients the symptoms of CNS toxicity may be minor and transient. Symptoms of local anesthetic CNS toxicity appear to occur before cardiotoxic effects. Depression of cardiac excitability and contractility may cause bradycardia, hypotension, arrhythmia exacerbation, and cardiovascular collapse leading to cardiac arrest. Examples of other possible adverse cardiovascular effects associated with high plasma concentrations of local anesthetics include angina, AV block, ventricular arrhythmias, QT prolongation, PR prolongation, atrial fibrillation, and palpitations. CNS-mediated cardiac effects in addition to blockade of sodium, potassium, and calcium channels within the heart may be responsible for some adverse cardiac effects. Of 2159 patients in clinical trials with the cream, 15 cream recipients experienced a systemic adverse event as compared with 4 placebo recipients. The most common systemic adverse events were headache, vomiting, dizziness, and fever, all which occurred at a frequency of < 1%. Other rare systemic reactions were syncope, nausea, confusion, dehydration, hyperventilation, hypotension, nervousness, paresthesias, pharyngitis, stupor, pallor, and diaphoresis. Cardiovascular and CNS side effects resulting from lidocaine; tetracaine administration should be treated with general supportive physiologic measures such as oxygen therapy, assisted ventilation, and IV fluids.
Methemoglobinemia has been reported with local anesthetic use. Signs and symptoms of methemoglobinemia may occur immediately or may be delayed some hours after local anesthetic exposure and are characterized by cyanotic skin discoloration and abnormal coloration of the blood. Other symptoms may include headache, rapid heart rate, shortness of breath, dizziness, and drowsiness. Since methemoglobin concentrations may continue to rise, immediately discontinue lidocaine; tetracaine to avoid serious central nervous system and cardiovascular adverse events including seizures, coma, arrhythmias, and death. Depending on the severity of symptoms, 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Cream dose based on treatment site surface area:
-Area of 2 inch2: 1 inch (equivalent to 1 gram)
-Area of 3 inch2: 2 inches (equivalent to 3 grams)
-Area of 6 inch2: 5 inches (equivalent to 5 grams)
-Area of 12 inch2: 9 inches (equivalent to 11 grams)
-Area of 16 inch2: 12 inches (equivalent to 13 grams)
-Area of 23 inch2: 18 inches (equivalent to 20 grams)
-Area of 31 inch2: 24 inches (equivalent to 26 grams)
-Area of 39 inch2: 30 inches (equivalent to 33 grams)
-Area of 47 inch2: 36 inches (equivalent to 40 grams)
-Area of 54 inch2: 42 inches (equivalent to 46 grams)
-Area of 62 inch2: 48 inches (equivalent to 53 grams)
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 Limits:
-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.
Patients with Hepatic Impairment Dosing
Specific dosing guidelines are not available. The half-life of lidocaine may be increased in patients with hepatic impairment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
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.
Clindamycin; 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.
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.
Menthol; 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.
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.
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.
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
Conditions such as congestive heart failure, liver disease, or myocardial infarction can decrease hepatic blood flow and decrease lidocaine clearance. No data are available on the pharmacokinetic parameters of topically administered lidocaine; tetracaine in patients with hepatic impairment.
Renal Impairment
No data are available on the pharmacokinetic parameters of topically administered lidocaine; tetracaine in patients with renal impairment.
Pediatrics
The peak plasma concentration of lidocaine was 63 ng/ml and of tetracaine was 65 ng/ml after application of one patch for 30 minutes to infants and children 4 months to 12 years of age.
Elderly
Plasma concentrations of lidocaine and tetracaine were undetectable after application of 1 patch for 20 minutes to patients at least 65 years of age. Simultaneous application of 2 patches for a duration of 60 minutes led to a maximum peak lidocaine concentration of 6 ng/ml; tetracaine was undetectable. After application of 31g of the cream over 400 cm2 for 60 minutes, mean peak plasma lidocaine concentrations were 48 ng/ml for 6 patients older than 65 years of age. These concentrations are similar to or lower than those for younger patients receiving similar amounts of the cream. Following intravenous administration, the elimination half-life of lidocaine was 2.5 hours in older patients as compared with 1.5 hours in patients less than 65 years of age.