Lidocaine Hydrochloride and Epinephrine

INDICATIONS AND USAGE Lidocaine Hydrochloride and Epinephrine Injection is indicated in adult and pediatric patients for the production of local or regional anesthesia or analgesia for surgery, dental, and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations of Lidocaine Hydrochloride and Epinephrine Injection are recommended for each type of block indicated to produce local or regional anesthesia or analgesia [see Dosage and Administration (2.2) ] . Lidocaine Hydrochloride and Epinephrine Injection is a combination of lidocaine, an amide local anesthetic, and epinephrine, an alpha and beta adrenergic agonist. Lidocaine Hydrochloride and Epinephrine Injection is indicated in adult and pediatric patients for the production of local or regional anesthesia or analgesia for surgery, dental, and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. For each type of block indicated to produce local or regional anesthesia or analgesia, specific concentrations and presentations are recommended. ( 1 , 2.2 )

DOSAGE AND ADMINISTRATION Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of Lidocaine Hydrochloride Injection, USP for various types of anesthetic procedures. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. When larger volumes are required, only solutions containing epinephrine should be used except in those cases where vasopressor drugs may be contraindicated. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Lidocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION ). These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures. The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient. In all cases the lowest concentration and smallest dose that will produce the desired result should be given. Dosages should be reduced for children and for the elderly and debilitated patients and patients with cardiac and/or liver disease. The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (i.e., total dose) of local anesthetic used. Thus, an increase in volume and concentration of Lidocaine Hydrochloride Injection, USP will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia. However, increasing the volume and concentration of Lidocaine Hydrochloride Injection, USP may result in a more profound fall in blood pressure when used in epidural anesthesia. Although the incidence of side effects with lidocaine HCl is quite low, caution should be exercised when employing large volumes and concentrations, since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected. Epidural Anesthesia For an epidural test dose, only the following available specific product of Lidocaine Hydrochloride and Epinephrine Injection, USP by Hospira is recommended: 1.5% with epinephrine 1:200,000.................................................................5 mL single-dose ampuls For epidural anesthesia, only the following available specific products of Lidocaine Hydrochloride and Epinephrine Injection, USP by Hospira are recommended: 1% with epinephrine 1:200,000 . . . . . . . . . . . . . . . . . . . . . . 30 mL single-dose vials 1.5% with epinephrine 1:200,000 . . . . . . . . . . . . . . . . . . . . 30 mL single-dose vials 2% with epinephrine 1:200,000 . . . . . . . . . . . . . . . . . . . . . . 20 mL single-dose vials Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block, provided they are employed as single-dose units. These solutions contain no bacteriostatic agent. In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome). Caudal and Lumbar Epidural Block As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block. The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter. Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient "epinephrine response" within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure. Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of Lidocaine Hydrochloride and Epinephrine Injection, USP through the catheter should be avoided, and, when feasible, fractional doses should be administered. In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter. MAXIMUM RECOMMENDED DOSAGES Adults For normal healthy adults, the individual maximum recommended dose of Lidocaine Hydrochloride and Epinephrine Injection, USP should not exceed 7 mg/kg (3.5 mg/lb) of body weight, and in general it is recommended that the maximum total dose not exceed 500 mg. When used without epinephrine the maximum individual dose should not exceed 4.5 mg/kg (2 mg/lb) of body weight, and in general it is recommended that the maximum total dose does not exceed 300 mg. For continuous epidural or caudal anesthesia, the maximum recommended dosage should not be administered at intervals of less than 90 minutes. When continuous lumbar or caudal epidural anesthesia is used for non-obstetrical procedures, more drug may be administered if required to produce adequate anesthesia. The maximum recommended dose per 90 minute period of lidocaine hydrochloride for paracervical block in obstetrical patients and non-obstetrical patients is 200 mg total. One half of the total dose is usually administered to each side. Inject slowly, five minutes between sides (see also discussion of paracervical block in PRECAUTIONS ). Children It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child's age and weight. For example, in a child of 5 years weighing 50 lbs the dose of lidocaine HCl should not exceed 75 to 100 mg (1.5 to 2 mg/lb). The use of even more dilute solutions (i.e., 0.25 to 0.5%) and total dosages not to exceed 3 mg/kg (1.4 mg/lb) are recommended for induction of intravenous regional anesthesia in children. In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. In some cases it will be necessary to dilute available concentrations with 0.9% sodium chloride injection in order to obtain the required final concentration. FOR EPIDURAL USE ONLY. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Do not use the injection if its color is pinkish or darker than slightly yellow or if it contains a precipitate. THE ABOVE SUGGESTED CONCENTRATIONS AND VOLUMES SERVE ONLY AS A GUIDE. OTHER VOLUMES AND CONCENTRATIONS MAY BE USED PROVIDED THE TOTAL MAXIMUM RECOMMENDED DOSE IS NOT EXCEEDED. STERILIZATION, STORAGE AND TECHNICAL PROCEDURES Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, zinc, copper, etc) should not be used for skin or mucous membrane disinfection as they have been related to incidents of swelling and edema. When chemical disinfection of multi-dose vials is desired, either iso

WARNINGS AND PRECAUTIONS Dose-Related Toxicity : Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after injection of Lidocaine Hydrochloride and Epinephrine. ( 5.1 ) Methemoglobinemia : Cases of methemoglobinemia have been reported in association with local anesthetics use. See full prescribing information for more details on managing these risks. ( 5.2 ) Chondrolysis with Intra-Articular Infusion : Avoid intra-articular infusions as there have been post-marketing reports of chondrolysis in patients receiving such infusion. ( 5.4 ) Allergic-Type Reactions to Sulfites in Lidocaine Hydrochloride and Epinephrine Injection and Anaphylactic Reactions : Lidocaine Hydrochloride and Epinephrine Injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. ( 5.6 ) Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection : Unintended intravascular or intrathecal injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progression ultimately to respiratory arrest. Aspirate for blood or cerebrospinal fluid (where applicable) prior to each dose and consider using a test dose of Lidocaine Hydrochloride and Epinephrine. ( 5.7 ) 5.1 Dose-Related Toxicity The safety and effectiveness of Lidocaine Hydrochloride and Epinephrine Injection depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after injection of Lidocaine Hydrochloride and Epinephrine Injection solutions. Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death. During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access. Use the lowest dosage of Lidocaine Hydrochloride and Epinephrine Injection that results in effective anesthesia to avoid high plasma levels and serious adverse effects. Avoid rapid injection of a large volume of Lidocaine Hydrochloride and Epinephrine Injection solution and administer fractional (incremental) doses when feasible. Injection of repeated doses of Lidocaine Hydrochloride and Epinephrine Injection may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status. 5.2 Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition [see Drug Interactions (7.5)]. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue Lidocaine Hydrochloride and Epinephrine Injection and any other oxidizing agents. Depending on the severity of the symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. 5.3 Antimicrobial Preservatives in Multiple-Dose Vials Avoid use of Lidocaine Hydrochloride and Epinephrine Injection solutions containing antimicrobial preservatives (i.e., those supplied in multiple-dose vials) for epidural or caudal anesthesia because safety has not been established with such use. 5.4 Chondrolysis with Intra-Articular Infusion Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2 nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. 5.5 Risk of Adverse Reactions Due to Drug Interactions with Lidocaine Hydrochloride and Epinephrine Injection Risk of Severe, Persistent Hypertension Due to Drug Interactions Between Lidocaine Hydrochloride and Epinephrine Injection and Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Administration of Lidocaine Hydrochloride and Epinephrine Injection in patients receiving monoamine oxidase inhibitors (MAOI), or tricyclic antidepressants may result in severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's hemodynamic status is essential [see Drug Interactions (7.2) ] . Risk of Severe, Persistent Hypertension or Cerebrovascular Accidents Due to Drug Interactions Between Lidocaine Hydrochloride and Epinephrine Injection and Ergot-Type Oxytocic Drugs Concurrent administration of Lidocaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of Lidocaine Hydrochloride and Epinephrine Injection concomitantly with ergot-type oxytocic drugs [see Drug Interactions (7.3) ] . Risk of Hypertension and Bradycardia Due to Drug Interactions Between Lidocaine Hydrochloride and Epinephrine Injection and Nonselective Beta-Adrenergic Antagonists Administration of Lidocaine Hydrochloride and Epinephrine Injection in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's blood pressure and heart rate is essential [see Drug Interactions (7.4) ] . 5.6 Allergic-Type Reactions to Sulfites in Lidocaine Hydrochloride and Epinephrine Injection and Anaphylactic Reactions Lidocaine Hydrochloride and Epinephrine Injection solutions contain sodium metabisulfite, a sulfite

Contraindications Lidocaine Hydrochloride and Epinephrine Injections are contraindicated in patients with a known hypersensitivity to lidocaine or to any local anesthetics of the amide-type or to other components of Lidocaine Hydrochloride and Epinephrine Injections. Known hypersensitivity to any local anesthetic agent of the amide-type or to other components of Lidocaine Hydrochloride and Epinephrine Injection. (4) (4)

DRUG INTERACTIONS • Local Anesthetics : The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. ( 7.1 ) • Monoamine Oxidase Inhibitors and Tricyclic Antidepressants : Administration of Lidocaine Hydrochloride and Epinephrine Injection to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension Concurrent use of these agents should generally be avoided. ( 5.5 , 7.2 ) • Ergot-type Oxytocic drugs : Concurrent administration of Lidocaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. ( 5.5 , 7.3 ) • Nonselective Beta-Adrenergic Antagonists : Administration of Lidocaine Hydrochloride and Epinephrine Injection in patients receiving nonselective beta-adrenergic antagonist may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. ( 5.5 , 7.4 ) • Drugs Associated with Methemoglobinemia : Patients are at increased risk of developing methemoglobinemia when concurrently exposed to nitrates, nitrites, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants and other drugs. ( 7.5 ) • Potent Inhalation Anesthetics : Serious dose-related cardiac arrhythmias may occur if preparations containing epinephrine are used in patients during or following the administration of potent inhalation anesthetics. ( 5.11 , 7.6 ) 7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with Lidocaine Hydrochloride and Epinephrine Injection cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Warnings and Precautions (5.1) ] . 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants The administration of Lidocaine Hydrochloride and Epinephrine Injection to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient’s hemodynamic status is essential [see Warnings and Precautions (5.5) ] . 7.3 Ergot-Type Oxytocic Drugs Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of Lidocaine Hydrochloride and Epinephrine Injection concomitantly with ergot-type oxytocic drugs [see Warnings and Precautions (5.5) ] . 7.4 Nonselective Beta-Adrenergic Antagonists Administration of Lidocaine Hydrochloride and Epinephrine Injection in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's blood pressure and heart rate is essential [see Warnings and Precautions (5.5) ] . 7.5 Drugs Associated with Methemoglobinemia Patients that are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following oxidizing agents: Class Examples Nitrates/Nitrites nitroglycerin, nitroprusside, nitric oxide, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, rasburicase, ifosfamide, hydroxyurea Antibiotics dapsone, sulfonamides, nitrofurantoin, para- aminosalicylic acid Antimalarials chloroquine, primaquine Anticonvulsants phenytoin, sodium valproate, phenobarbital Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing epinephrine (e.g., Lidocaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.11) ] . 7.7 Phenothiazines and Butyrophenones Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of Lidocaine Hydrochloride with Epinephrine and these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.

ADVERSE REACTIONS The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling: • Dose-Related Toxicity [see Warnings and Precautions (5.1) ] • Methemoglobinemia [see Warnings and Precautions (5.2) ] • Chondrolysis with Intra-Articular Infusion [see Warnings and Precautions (5.4) ] • Severe, Persistent Hypertension, Cerebrovascular Accidents, and Bradycardia Due to Drug Interactions [see Warnings and Precautions (5.5) ] • Allergic-Type Reactions [see Warnings and Precautions (5.6) ] • Systemic Toxicities with Unintended Intravascular or Intrathecal Injection [see Warnings and Precautions (5.7) ] • Respiratory Arrest Following Retrobulbar Block [see Warnings and Precautions (5.14) ] The following adverse reactions from voluntary reports or clinical studies have been reported with lidocaine or lidocaine and epinephrine. Because many of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions to Lidocaine Hydrochloride are characteristic of those associated with other amide-type local anesthetic. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation. The most commonly encountered acute adverse reactions that demand immediate counter measures were related to the CNS and the cardiovascular system. These adverse reactions were generally dose-related and due to high plasma levels which may have resulted from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional intrathecal injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) has resulted in underventilation or apnea (“Total or High Spinal”). Also, hypertension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia have occurred. This has led to secondary cardiac arrest when untreated. When used for dental injections, paresthesia of the lips, tongue, and oral tissues have been reported. Persistent paresthesia lasting weeks to months and, in some instances, lasting greater than one year, have also been reported. Nervous System Disorders Adverse reactions were characterized by excitation and/or depression of the central nervous system and included lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. In a prospective review of 10,440 patients who received lidocaine hydrochloride for spinal anesthesia, the incidences of adverse reactions were reported to be about 3 percent each for positional headaches, hypotension and backache; 2 percent for shivering; and less than 1 percent each for peripheral nerve symptoms, nausea, respiratory inadequacy and double vision. Persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances when caudal or lumbar epidural block has been attempted. Backache and headache have also been noted following use of these anesthetic procedures. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration. In the practice of caudal or lumbar epidural block, unintentional penetration of the subarachnoid space by the catheter or needle has occurred. Subsequent adverse effects may have depended partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia have included spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control, all of which had slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Neurologic effects following other procedures or routes of administration have included persistent anesthesia, paresthesia, weakness, paralysis, all with slow, incomplete, or no recovery. Convulsions : Incidence varied with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Cardiac Disorders High doses or unintentional intravascular injection have led to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest [see Warnings and Precautions (5.9) ]. Immune System Disorders Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to the methylparaben used as a preservative in the multiple-dose vials [see Warnings and Precautions (5.6) ] . There have been no reports of cross sensitivity between lidocaine hydrochloride and procainamide or between lidocaine hydrochloride and quinidine. Hematologic Methemoglobinemia [see Warnings and Precautions (5.2) ] . Most common adverse reactions are as follows: • Central Nervous System: Lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. ( 6 ) • Cardiovascular System: Bradycardia, hypotension, and cardiovascular collapse. ( 6 ) • Allergic: Cutaneous lesions, urticaria, edema or anaphylactoid reactions. ( 6 ) • Neurologic: Positional headaches, hypotension and backache. ( 6 ) • Hematologic: Methemoglobinemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc, at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lidocaine stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of nerve impulses, thereby effecting local anesthetic action. Epinephrine is a vasoconstrictor added to lidocaine to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration 12.2 Pharmacodynamics Onset and duration of anesthesia When used for infiltration anesthesia in dental patients, the time of onset averages less than two minutes for FLAVALTA. FLAVALTA (lidocaine HCl 2% solution with a 1:100,000 epinephrine concentration) provides an average pulp anesthesia of at least 60 minutes with an average duration of soft tissue anesthesia of approximately 2½ hours. When used for nerve blocks in dental patients, the time of onset for FLAVALTA averages 2 - 4 minutes. FLAVALTA (lidocaine HCl 2% solution with a 1:100,000 epinephrine concentration) provides pulp anesthesia averaging at least 90 minutes with an average duration of soft tissue anesthesia of 3 to 3½ hours. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6.0 μg free base per mL. Hemodynamics Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. These changes may be attributable to a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system and/or the beta-adrenergic receptor stimulating action of epinephrine when present. 12.3 Pharmacokinetics Absorption Information derived from diverse formulations, concentrations and usages reveals that lidocaine is completely absorbed following parenteral administration, its rate of absorption depending, for example, upon various factors such as the site of administration and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration. Distribution The plasma binding of lidocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentration of 1 to 4 μg of free base per mL, 60 to 80 percent of lidocaine is protein bound. Binding is also dependent on the plasma concentration of the alpha-l-acid glycoprotein. Lidocaine crosses the blood-brain and placental barriers, presumably by passive diffusion. Elimination The elimination half-life of lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2 hours. Metabolism Lidocaine is metabolized rapidly by the liver. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine. Excretion Lidocaine metabolites and the unchanged drug are excreted by the kidneys. Approximately 90% of lidocaine administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2, 6-dimethylaniline. Specific Populations Patients with Hepatic Impairment Because of the rapid rate at which lidocaine is metabolized, any condition that affects liver function may alter lidocaine kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. Patients with Renal Impairment Renal dysfunction does not affect lidocaine kinetics but may increase the accumulation of metabolites.