Browse the corpus

1 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 )

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for recommended dosages and administration information for adult and pediatric patients ( 2 ) 2.1 Important Dosage and Administration Information • Lidocaine Hydrochloride and Epinephrine Injection is not recommended for intrathecal use. • Avoid use of Lidocaine Hydrochloride and Epinephrine solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [see Warnings and Precautions (5.3) ] . • Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use. • Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit. Lidocaine Hydrochloride and Epinephrine Injections are clear, colorless to slightly yellow solutions. Do not administer solutions which are discolored or contain particulate matter. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions which are discolored (e.g., pinkish or darker than slightly yellow) or which contain particulate matter or precipitate should not be administered. • Mixing or the prior or intercurrent use of any other local anesthetic with Lidocaine Hydrochloride and Epinephrine Injection is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions • Lidocaine Hydrochloride and Epinephrine Injection is to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed. • Use Lidocaine Hydrochloride and Epinephrine Injection only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Warnings and Precautions (5.1) , Adverse Reactions (6) , Overdosage (10) ] . • The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with Lidocaine Hydrochloride and Epinephrine Injection [see Warnings and Precautions (5.1) , Drug Interactions (7.1) , Overdosage (10) ] . • Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting Lidocaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection [see Warnings and Precautions (5.7) ] . • Avoid rapid injection of a large volume of Lidocaine Hydrochloride and Epinephrine Injection and use fractional (incremental) doses when feasible. • 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. The lowest dosage of Lidocaine Hydrochloride and Epinephrine Injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions.

the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access. The lowest dosage of Lidocaine Hydrochloride and Epinephrine Injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions. • Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient’s level of consciousness after each local anesthetic injection. • Use Lidocaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis [see Warnings and Precautions (5.10) ] . 2.2 Recommended Concentrations and Dosages of Lidocaine Hydrochloride and Epinephrine Injection/Lidocaine Hydrochloride Injection (without Epinephrine) in Adults The dosage of Lidocaine Hydrochloride and Epinephrine Injection administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. Administer the smallest dosage and concentration required to produce the desired result. The types of block and recommended Lidocaine Hydrochloride Injection (without epinephrine) concentrations are shown in Table 1. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. Consider administration of solutions containing epinephrine when large volumes are required. Table 1: Recommended Dosages in Adults Procedure Lidocaine Hydrochloride Injection (without epinephrine) Conc (%) Vol (mL) Total Dose (mg) Infiltration Percutaneous 0.5 or 1 1 to 60 5 to 300 Intravenous regional 0.5 10 to 60 50 to 300 Dose should not exceed 4 mg/kg. Peripheral Nerve Blocks, e.g., Brachial 1.5 15 to 20 225 to 300 Dental 2 1 to 5 20 to 100 Intercostal 1 3 30 Paravertebral 1 3 to 5 30 to 50 Pudendal (each side) 1 10 100 Paracervical Obstetrical analgesia (each side) 1 10 100 Sympathetic Nerve Blocks, e.g., Cervical (stellate ganglion) 1 5 50 Lumbar 1 5 to 10 50 to 100 Central Neural Blocks Epidural Dose determined by number of dermatomes to be anesthetized (2 to 3 mL/dermatome). Thoracic 1 20 to 30 200 to 300 Lumbar Analgesia 1 25 to 30 250 to 300 Anesthesia 1.5 15 to 20 225 to 300 2 10 to 15 200 to 300 Caudal Obstetrical analgesia 1 20 to 30 200 to 300 Surgical anesthesia 1.5 15 to 20 225 to 300 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 [see Dosage and Administration (2.6) ] . These recommended doses serve only as a guide to the amount of local anesthetic required for most indicated 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. The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site.

and smallest dose that will produce the desired result should be given. The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site. 2.3 Use in Epidural Anesthesia During the administration of epidural anesthesia, it is recommended that a test dose of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the initial and all supplemental doses, because a catheter in the epidural space can migrate into a blood vessel or through the dura [see Dosage and Administration (2.4) ] . During epidural administration, administer Lidocaine Hydrochloride and Epinephrine Injection, 1.5% (15 mg/mL) and 2% (20 mg/mL) solutions in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Administer injections slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Perform syringe aspirations before and during each supplemental injection in continuous (intermittent) catheter techniques. Repeat doses of lidocaine should be preceded by a test dose containing epinephrine if not clinically contraindicated. Use only the single-dose vials for caudal or epidural anesthesia; avoid use of the multiple-dose vials for these procedures, which contain a preservative [see Dosage and Administration (2.1 , 2.4) , Warnings and Precautions (5.7) ] . 2.4 Test Dose for Epidural Blocks 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. Three mL of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit. This test dose may serve as a warning of unintended intravascular or intrathecal injection. Closely monitor for early clinical signs of toxicity following each test dose [see Warnings and Precautions (5.7) ] . Allot adequate time for onset of spinal block to detect possible intrathecal injection. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal, or cardiovascular effects from the epinephrine [see Warnings and Precautions (5.1) , Overdosage (10) ] . 2.6 Maximum Recommended Dosage Adults For normal healthy adults, the individual maximum recommended dose of Lidocaine Hydrochloride and Epinephrine Injection should not exceed 7 mg/kg 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 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, a higher total dose may be administered if required to produce adequate anesthesia.

. 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, a higher total dose 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 Use in Specific Populations (8.1) ] . Pediatric Patients A maximum dose of Lidocaine Hydrochloride and Epinephrine Injection for children varies based on age and weight. For children over 3 years of age with 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 approximately 23 kg, the dose of lidocaine hydrochloride should not exceed approximately 75 mg to 100 mg (3.3 mg/kg to 4.4 mg/kg). The use of dilute solutions (i.e., 0.25% to 0.5%) and total dosages not to exceed 3 mg/kg are recommended for induction of intravenous regional anesthesia in children. The lowest effective concentration and lowest effective dose should be used. Dilution of available concentrations with 0.9% sodium chloride injection may be required to obtain the required final concentration.

3 DOSAGE FORMS AND STRENGTHS For Epidural test dose, Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: • 1.5% (75 mg/5 mL) (15 mg/mL), 5 mL single-dose ampuls Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: • 1.5% (450 mg/30 mL) (15 mg/mL), 30 mL single-dose vials • 2% (400 mg/20 mL) (20 mg/mL), 20 mL single-dose vials Lidocaine Hydrochloride and Epinephrine Injection 1:200,000, USP is a clear, colorless to slightly yellow solution available as: • 0.5% (250 mg/mL) (5 mg/mL), 50 mL multiple-dose vials Lidocaine Hydrochloride and Epinephrine Injection 1:100,000, USP is a clear, colorless to slightly yellow solution available as: • 1% (200 mg/20 mL) (10 mg/mL), 20 mL multiple-dose vials • 1% (300 mg/30 mL) (10 mg/mL), 30 mL multiple-dose vials • 1% (500 mg/50 mL) (10 mg/mL), 50 mL multiple-dose vials • 2% (400 mg/20 mL) (20 mg/mL), 20 mL multiple-dose vials • 2% (600 mg/30 mL) (20 mg/mL), 30 mL multiple-dose vials • 2% (1000 mg/50 mL) (20 mg/mL), 50 mL multiple-dose vials • For epidural test dose, Lidocaine Hydrochloride and Epinephrine 1:200,000 Injection, USP, Single-dose Ampuls: 1.5% • Lidocaine Hydrochloride and Epinephrine 1:200,000 Injection, USP, Single-dose Vials: 1.5%, 2% • Lidocaine Hydrochloride and Epinephrine 1:200,000 Injection, USP, Multiple-dose Vials: 0.5% • Lidocaine Hydrochloride and Epinephrine 1:100,000 Injection, USP, Multiple-dose Vials: 1%, 2%

4 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 )

5 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.

n. 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) ] .

amine 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 that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. Anaphylactic reactions may occur following administration of lidocaine hydrochloride [see Adverse Reactions (6) ] . Lidocaine hydrochloride should be used with caution in persons with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to lidocaine hydrochloride. 5.7 Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection Unintended intravascular or intrathecal injection of Lidocaine Hydrochloride and Epinephrine Injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Unintentional intrathecal injection during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column has resulted in underventilation or apnea ("Total or High Spinal"). A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia [see Adverse Reactions (6) ] . Aspirate for blood or cerebrospinal fluid (where applicable) before injecting Lidocaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection. Use of Test Dose with Epidural Anesthesia To serve as a warning of unintended intravascular or intrathecal injection, 3 mL of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) may be used as a test dose prior to administration of the full dose in caudal and lumbar epidural blocks [see Dosage and Administration (2.4) ] .

travascular or intrathecal injection, 3 mL of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) may be used as a test dose prior to administration of the full dose in caudal and lumbar epidural blocks [see Dosage and Administration (2.4) ] . Three mL of Lidocaine Hydrochloride and Epinephrine Injection (1.5% lidocaine with 1:200,000 epinephrine) without antimicrobial preservative contains 45 mg lidocaine and 15 mcg epinephrine. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. Signs/symptoms of unintended intravascular or intrathecal injection of the test dose of Lidocaine Hydrochloride and Epinephrine Injection and monitoring recommendations are described below. • Unintended intravascular injection: Likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and/or 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. Therefore, following the test dose, the heart rate should be monitored for increases. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure. • Unintended intrathecal injection: Evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects [see Overdosage (10) ] . 5.8 Risk of Toxicity in Patients with Hepatic Impairment Because amide local anesthetics such as lidocaine are metabolized by the liver, consider reduced dosing and increased monitoring for lidocaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with lidocaine hydrochloride, especially with repeat doses [see Use in Specific Populations (8.6) ] . 5.9 Risk of Use in Patients with Impaired Cardiovascular Function Lidocaine should also be given in reduced doses in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Monitor patients closely for blood pressure, heart rate, and ECG changes. 5.10 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood Supply Use Lidocaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply, such as digits, nose, external ear, or penis. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. 5.11 Risk of Cardiac Arrhythmias with Concomitant Use of Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Lidocaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Drug Interactions (7.6) ] . In deciding whether to concurrently use Lidocaine Hydrochloride and Epinephrine Injection with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account.

whether to concurrently use Lidocaine Hydrochloride and Epinephrine Injection with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. 5.12 Risk of Adverse Reactions with Use in the Head and Neck Area Small doses of local anesthetics (e.g., Lidocaine Hydrochloride and Epinephrine Injection) injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Monitor circulation and respiration and constantly observe patients receiving Lidocaine Hydrochloride and Epinephrine Injection blocks. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see Dosage and Administration (2.2) ] . 5.13 Familial Malignant Hyperthermia Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for the management of malignant hyperthermia should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using). 5.14 Risk of Respiratory Arrest with Use in Ophthalmic Surgery Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block (e.g., with Lidocaine Hydrochloride and Epinephrine Injection), as with all other regional procedures, resuscitative equipment and drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be immediately available. As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses. 5.15 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa in Dental Applications Because of the long duration of anesthesia, when Lidocaine Hydrochloride and Epinephrine Injection [0.5% (5 mg/mL) of lidocaine] is used for dental injections, warn patients about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns [see Patient Counseling Information (17) ] . 5.16 Drug/Laboratory Test Interactions The intramuscular injection of lidocaine hydrochloride may result in an increase in creatine phosphokinase levels.

of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns [see Patient Counseling Information (17) ] . 5.16 Drug/Laboratory Test Interactions The intramuscular injection of lidocaine hydrochloride may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination, without isoenzyme separation, as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine hydrochloride.

6 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.

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.

s 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.

7 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) ] .

g 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.

<table styleCode="Noautorules" width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Class</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Examples</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nitrates/Nitrites </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>nitroglycerin, nitroprusside, nitric oxide, nitrous oxide</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Local anesthetics</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Antineoplastic agents</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>cyclophosphamide, flutamide, rasburicase, ifosfamide, hydroxyurea</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Antibiotics</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>dapsone, sulfonamides, nitrofurantoin, para- aminosalicylic acid</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Antimalarials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>chloroquine, primaquine</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anticonvulsants</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>phenytoin, sodium valproate, phenobarbital</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Other drugs</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>acetaminophen, metoclopramide, quinine, sulfasalazine</paragraph></td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS • Geriatric Use : Elderly patients should be given reduced doses commensurate with their age and physical condition. ( 8.5 ) • Hepatic Impairment : Consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with hepatic impairment. ( 8.6 ) 8.1 Pregnancy Risk Summary Available published data and decades of clinical use with lidocaine hydrochloride in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone and cardiac function (see Clinical Considerations ) . In a published animal reproduction study, pregnant rats administered lidocaine by continuous subcutaneous infusion at a dose approximately 9.6 times the maximum recommended human dose (MRHD) of 500 mg in lidocaine hydrochloride during the period of organogenesis resulted in lower fetal body weights [ see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal adverse reactions Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient’s legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Labor or delivery Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity [see Clinical Pharmacology (12.3) ] . The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. However, dosage recommendations for spinal anesthesia are much lower than dosage recommendations for other major blocks. Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life.

e parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. Data Animal Data Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine hydrochloride. In a published study, lidocaine administered to pregnant rats by continuous subcutaneous infusion during the period of organogenesis at 100, 250, and 500 mg/kg/day, did not produce any structural abnormalities, but did result in lower fetal weights at 500 mg/kg/day dose (approximately 9.6 times the maximum recommended human dose [MRHD] of 500 mg lidocaine on a mg/m 2 basis) in the absence of maternal toxicity. 8.2 Lactation Risk Summary Published data report the presence of lidocaine and its metabolites in human milk in low amounts, along with poor oral bioavailability. There are no data on the effect of lidocaine on the breastfed infant or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lidocaine Hydrochloride and Epinephrine Injection and any potential adverse effects on the breastfed child from Lidocaine Hydrochloride and Epinephrine Injection or from the underlying maternal condition. 8.4 Pediatric Use Dosages in children should be reduced, commensurate with age, body weight and physical condition [see Dosage and Administration (2.6) ] . 8.5 Geriatric Use Elderly patients should be given reduced doses commensurate with their age and physical condition [see Dosage and Administration (2.6) ] . 8.6 Hepatic Impairment Amide-type local anesthetics such as lidocaine are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with hepatic impairment treated with Lidocaine Hydrochloride and Epinephrine Injection, especially with repeat doses [see Warnings and Precautions (5.8) ] .

8.1 Pregnancy Risk Summary Available published data and decades of clinical use with lidocaine hydrochloride in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone and cardiac function (see Clinical Considerations ) . In a published animal reproduction study, pregnant rats administered lidocaine by continuous subcutaneous infusion at a dose approximately 9.6 times the maximum recommended human dose (MRHD) of 500 mg in lidocaine hydrochloride during the period of organogenesis resulted in lower fetal body weights [ see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal adverse reactions Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient’s legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Labor or delivery Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity [see Clinical Pharmacology (12.3) ] . The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. However, dosage recommendations for spinal anesthesia are much lower than dosage recommendations for other major blocks. Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. Data Animal Data Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine hydrochloride.

drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. Data Animal Data Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine hydrochloride. In a published study, lidocaine administered to pregnant rats by continuous subcutaneous infusion during the period of organogenesis at 100, 250, and 500 mg/kg/day, did not produce any structural abnormalities, but did result in lower fetal weights at 500 mg/kg/day dose (approximately 9.6 times the maximum recommended human dose [MRHD] of 500 mg lidocaine on a mg/m 2 basis) in the absence of maternal toxicity.

10 OVERDOSAGE Clinical Presentation Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution [see Warnings and Precautions (5.1) , Adverse Reactions (6) ]. Management The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea due to unintended subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (e.g., ephedrine). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine hydrochloride.

11 DESCRIPTION Lidocaine Hydrochloride and Epinephrine Injection, USP is a sterile, nonpyrogenic solution of lidocaine hydrochloride and epinephrine in water for injection for parenteral administration in various concentrations with characteristics as follows: Concentration Lidocaine hydrochloride Epinephrine Lidocaine hydrochloride (anhyd.) mg/mL Epinephrine mcg/mL Sodium Chloride mg/mL 0.5% 1:200,000 5 5 8 1% 1:200,000 10 5 7 1.5% 1:200,000 15 5 6.5 2% 1:200,000 20 5 6 1% 1:100,000 10 10 7 2% 1:100,000 20 10 6 Sodium metabisulfite 0.5 mg/mL and citric acid, anhydrous 0.2 mg/mL added as stabilizers. The headspace of Lists 1209, 3177, 3178, 3181, 3182 and 3183 are nitrogen gassed. May contain sodium hydroxide and/or hydrochloric acid to adjust pH; pH is 4.5 (3.3 to 5.5). See HOW SUPPLIED section for various sizes and strengths. Multiple-dose vials contain methylparaben 1 mg/mL added as preservative. Single-dose ampuls and vials contain no bacteriostat or antimicrobial agent. Discard unused portion. Lidocaine is a local anesthetic of the amide-type. Lidocaine Hydrochloride, USP is chemically designated 2-(diethyl-amino)-2',6'-acetoxylidide monohydrochloride monohydrate, a white powder freely soluble in water. It has the following structural formula: Epinephrine is a vasoconstrictor. Epinephrine, USP is a sympathomimetic (adrenergic) agent designated chemically as 4-[1-hydroxy-2 (methylamino) ethyl]-1,2 benzenediol, a white, microcrystalline powder. It has the following structural formula: lidocaine-01.jpg lidocaine-02.jpg

<table styleCode="Noautorules" width="100%"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Concentration</content></paragraph><paragraph><content styleCode="bold">Lidocaine hydrochloride</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Epinephrine</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Lidocaine hydrochloride</content></paragraph><paragraph><content styleCode="bold">(anhyd.) mg/mL</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Epinephrine</content></paragraph><paragraph><content styleCode="bold">mcg/mL</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Sodium Chloride</content></paragraph><paragraph><content styleCode="bold">mg/mL</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:200,000</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:200,000</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:200,000</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:200,000</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:100,000</paragraph></td><td align="center" styleCode="Rrul

yleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:100,000</paragraph></td><td align="center" styleCode="Rrul e Lrule Toprule Botrule " valign="middle"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1:100,000</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>6</paragraph></td></tr></tbody></table>

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lidocaine hydrochloride stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of 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 Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to block of autonomic fibers, 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. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine hydrochloride required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6 mcg free base per mL. 12.3 Pharmacokinetics Systemic plasma levels of lidocaine following Lidocaine Hydrochloride and Epinephrine Injection do not correlate with local efficacy. Absorption Information derived from diverse formulations, concentrations and usages reveals that lidocaine hydrochloride 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 hydrochloride is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg of free base per mL 60 to 80 percent of lidocaine hydrochloride is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine hydrochloride 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 hydrochloride is metabolized rapidly by the liver, and 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 hydrochloride. Excretion Approximately 90% of lidocaine hydrochloride administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged by the kidneys. 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 hydrochloride is metabolized, any condition that affects liver function may alter lidocaine hydrochloride kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction.

-2,6-dimethylaniline. Specific Populations Patients with Hepatic Impairment Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine hydrochloride 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 hydrochloride kinetics but may increase the accumulation of metabolites.

12.1 Mechanism of Action Lidocaine hydrochloride stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of 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 Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to block of autonomic fibers, 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. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine hydrochloride required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6 mcg free base per mL.

12.3 Pharmacokinetics Systemic plasma levels of lidocaine following Lidocaine Hydrochloride and Epinephrine Injection do not correlate with local efficacy. Absorption Information derived from diverse formulations, concentrations and usages reveals that lidocaine hydrochloride 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 hydrochloride is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg of free base per mL 60 to 80 percent of lidocaine hydrochloride is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine hydrochloride 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 hydrochloride is metabolized rapidly by the liver, and 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 hydrochloride. Excretion Approximately 90% of lidocaine hydrochloride administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged by the kidneys. 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 hydrochloride is metabolized, any condition that affects liver function may alter lidocaine hydrochloride 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 hydrochloride kinetics but may increase the accumulation of metabolites.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Studies of lidocaine hydrochloride in animals to evaluate the carcinogenic potential have not been conducted. Mutagenesis Studies of lidocaine hydrochloride in animals to evaluate the mutagenic potential have not been conducted. Impairment of Fertility In a published study, female Sprague-Dawley rats were treated subcutaneously with lidocaine via osmotic pumps starting two weeks prior to mating, and reproductive effects were assessed. Rats dosed up to the high dose of 500 mg/kg/day (approximately 45 times the MRDD on a mg/m 2 basis) showed no effects on copulatory rate, pregnancy rate, numbers of corpora lutea, or implantations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Studies of lidocaine hydrochloride in animals to evaluate the carcinogenic potential have not been conducted. Mutagenesis Studies of lidocaine hydrochloride in animals to evaluate the mutagenic potential have not been conducted. Impairment of Fertility In a published study, female Sprague-Dawley rats were treated subcutaneously with lidocaine via osmotic pumps starting two weeks prior to mating, and reproductive effects were assessed. Rats dosed up to the high dose of 500 mg/kg/day (approximately 45 times the MRDD on a mg/m 2 basis) showed no effects on copulatory rate, pregnancy rate, numbers of corpora lutea, or implantations.

16 HOW SUPPLIED/STORAGE AND HANDLING Do not autoclave. Storage : All solutions should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light . For single-dose vials and ampules: Discard unused portion. For Epidural test dose, Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: Unit of Sale Concentration 1.5% Contains 15 mg lidocaine hydrochloride per mL NDC 0409-1209-01 Tray of 10 single-dose ampuls 75 mg/5 mL (15 mg/mL) NDC 0409-1209-05 Case of 400 single-dose ampuls 75 mg/5 mL (15 mg/mL) NDC 0409-1209-65 Case of 800 single-dose ampuls (Kit Packer) 75 mg/5 mL (15 mg/mL) Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: Unit of Sale Concentration 1.5% Contains 15 mg lidocaine hydrochloride per mL NDC 0409-3181-01 Carton of 5 single-dose fliptop vials 450 mg/30 mL (15 mg/mL) 2% Contains 20 mg lidocaine hydrochloride per mL NDC 0409-3183-01 Carton of 5 single-dose fliptop vials 400 mg/20 mL (20 mg/mL) Lidocaine Hydrochloride and Epinephrine Injection 1:200,000, USP is a clear, colorless to slightly yellow solution available as: Unit of Sale Concentration 0.5% Contains 5 mg lidocaine hydrochloride per mL NDC 0409-3177-01 Tray of 25 multiple-dose fliptop vials 250 mg/50 mL (5 mg/mL) Lidocaine Hydrochloride and Epinephrine Injection 1:100,000, USP is a clear, colorless to slightly yellow solution available as: Unit of Sale Concentration 1% Contains 10 mg lidocaine hydrochloride per mL NDC 0409-0007-10 Carton of 10 multiple-dose fliptop vials 200 mg/20 mL (10 mg/mL) NDC 0409-3178-01 Tray of 25 multiple-dose fliptop vials 200 mg/20 mL (10 mg/mL) NDC 0409-3178-02 Tray of 25 multiple-dose fliptop vials 300 mg/30 mL (10 mg/mL) NDC 0409-3178-03 Tray of 25 multiple-dose fliptop vials 500 mg/50 mL (10 mg/mL) 2% Contains 20 mg lidocaine hydrochloride per mL NDC 0409-0147-10 Carton of 10 multiple-dose fliptop vials 400 mg/20 mL (20 mg/mL) NDC 0409-3182-01 Tray of 25 multiple-dose fliptop vials 400 mg/20 mL (20 mg/mL) NDC 0409-3182-02 Tray of 25 multiple-dose fliptop vials 600 mg/30 mL (20 mg/mL) NDC 0409-3182-03 Tray of 25 multiple-dose fliptop vials 1000 mg/50 mL (20 mg/mL)

<table styleCode="Noautorules" width="70%"><col width="41%"/><col width="40%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Concentration</content></paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5% Contains 15 mg lidocaine hydrochloride per mL</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-1209-01</paragraph><paragraph>Tray of 10 single-dose ampuls</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>75 mg/5 mL</paragraph><paragraph>(15 mg/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-1209-05</paragraph><paragraph>Case of 400 single-dose ampuls</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>75 mg/5 mL</paragraph><paragraph>(15 mg/mL)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 0409-1209-65</paragraph><paragraph>Case of 800 single-dose ampuls (Kit Packer)</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>75 mg/5 mL</paragraph><paragraph>(15 mg/mL)</paragraph></td></tr></tbody></table>

r><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 0409-1209-65</paragraph><paragraph>Case of 800 single-dose ampuls (Kit Packer)</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>75 mg/5 mL</paragraph><paragraph>(15 mg/mL)</paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="70%"><col width="41%"/><col width="40%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Concentration</content></paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5% Contains 15 mg lidocaine hydrochloride per mL</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-3181-01</paragraph><paragraph>Carton of 5 single-dose fliptop vials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>450 mg/30 mL</paragraph><paragraph>(15 mg/mL)</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2% Contains 20 mg lidocaine hydrochloride per mL</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 0409-3183-01</paragraph><paragraph>Carton of 5 single-dose fliptop vials</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>400 mg/20 mL</paragraph><paragraph>(20 mg/mL)</paragraph></td></tr></tbody></table>

r><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 0409-3183-01</paragraph><paragraph>Carton of 5 single-dose fliptop vials</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>400 mg/20 mL</paragraph><paragraph>(20 mg/mL)</paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="70%"><col width="41%"/><col width="40%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Concentration</content></paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5% Contains 5 mg lidocaine hydrochloride per mL</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 0409-3177-01</paragraph><paragraph>Tray of 25 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>250 mg/50 mL</paragraph><paragraph>(5 mg/mL)</paragraph></td></tr></tbody></table>

r><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 0409-3177-01</paragraph><paragraph>Tray of 25 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>250 mg/50 mL</paragraph><paragraph>(5 mg/mL)</paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="70%"><col width="41%"/><col width="40%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Concentration</content></paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1% Contains 10 mg lidocaine hydrochloride per mL</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-0007-10</paragraph><paragraph>Carton of 10 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>200 mg/20 mL</paragraph><paragraph>(10 mg/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-3178-01</paragraph><paragraph>Tray of 25 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>200 mg/20 mL</paragraph><paragraph>(10 mg/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-3178-02</paragraph><paragraph>Tray of 25 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>300 mg/30 mL</paragraph><paragraph>(10 mg/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-3178-03</paragraph><paragraph>Tray of 25 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg/50 mL </paragraph><paragraph>(10 mg/mL)</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2% Contains 20 mg lidocaine hydrochloride per mL</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-0147-10</paragraph><paragraph>Carton of 10 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>400 mg/20 mL </paragraph><paragraph>(20 mg/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-3182-01</paragraph><paragraph>Tray of 25 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>400 mg/20 mL</paragraph><paragraph>(20 mg/mL)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 0409-3182-02</paragraph><paragraph>Tray of 25 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>600 mg/30 mL </paragraph><paragraph>(20 mg/mL)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>NDC 0409-3182-03</paragraph><paragraph>Tray of 25 multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1000 mg/50 mL</paragraph><paragraph>(20 mg/mL)</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION 17.1 Allergic-Type Reactions Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions [see Contraindications (4) , Warnings and Precautions (5.6) , Adverse Reactions (6) ] . 17.2 Temporary Loss of Sensation and Motor Activity After Caudal or Epidural Anesthesia When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Instructions After Dental Injection of Lidocaine Hydrochloride Advise patients receiving dental injections of Lidocaine Hydrochloride not to chew solid foods or to test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours) [see Warnings and Precautions (5.15) ] . 17.3 Methemoglobinemia Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to stop use and seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.2) ] . This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . For medical information about Lidocaine Hydrochloride and Epinephrine Injection, please visit www.pfizermedinfo.com or call 1-800-438-1985. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1298-9.0 lidocaine-03.jpg

1 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)

2 Dosage and Administration 2.1 Important Dosage and Administration Information •Lidocaine Hydrochloride and Epinephrine Injection is not recommended for intrathecal use. •Avoid use of Lidocaine Hydrochloride and Epinephrine solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [see Warnings and Precautions (5.3)]. •Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use. •Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit. Lidocaine Hydrochloride and Epinephrine Injections are clear, colorless to slightly yellow solutions. Do not administer solutions which are discolored or contain particulate matter. •Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions which are discolored (e.g., pinkish or darker than slightly yellow) or which contain particulate matter or precipitate should not be administered. •Mixing or the prior or intercurrent use of any other local anesthetic with Lidocaine Hydrochloride and Epinephrine Injection is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions •Lidocaine Hydrochloride and Epinephrine Injection is to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed. •Use Lidocaine Hydrochloride and Epinephrine Injection only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Warnings and Precautions (5.1), Adverse Reactions (6), Overdosage (10)]. •The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with Lidocaine Hydrochloride and Epinephrine Injection [see Warnings and Precautions (5.1), Drug Interactions (7.1), Overdosage (10)]. •Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting Lidocaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection [see Warnings and Precautions (5.7)]. •Avoid rapid injection of a large volume of Lidocaine Hydrochloride and Epinephrine Injection and use fractional (incremental) doses when feasible. •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. The lowest dosage of Lidocaine Hydrochloride and Epinephrine Injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions. •Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient’s level of consciousness after each local anesthetic injection.

that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions. •Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient’s level of consciousness after each local anesthetic injection. •Use Lidocaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis [see Warnings and Precautions (5.10)]. 2.2 Recommended Concentrations and Dosages of Lidocaine Hydrochloride and Epinephrine Injection/Lidocaine Hydrochloride Injection (without Epinephrine) in Adults The dosage of Lidocaine Hydrochloride and Epinephrine Injection administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. Administer the smallest dosage and concentration required to produce the desired result. The types of block and recommended Lidocaine Hydrochloride Injection (without epinephrine) concentrations are shown in Table 1. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. Consider administration of solutions containing epinephrine when large volumes are required. 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 [see Dosage and Administration (2.5)]. These recommended doses serve only as a guide to the amount of local anesthetic required for most indicated 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. The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site. 2.3 Use in Epidural Anesthesia During the administration of epidural anesthesia, it is recommended that a test dose of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the initial and all supplemental doses, because a catheter in the epidural space can migrate into a blood vessel or through the dura [see Dosage and Administration (2.4)]. During epidural administration, administer Lidocaine Hydrochloride and Epinephrine Injection, 1.5% (15 mg/mL) and 2% (20 mg/mL) solutions in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Administer injections slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Perform syringe aspirations before and during each supplemental injection in continuous (intermittent) catheter techniques. Repeat doses of lidocaine should be preceded by a test dose containing epinephrine if not clinically contraindicated.

aspirations before and during the injection to avoid intravascular injection. Perform syringe aspirations before and during each supplemental injection in continuous (intermittent) catheter techniques. Repeat doses of lidocaine should be preceded by a test dose containing epinephrine if not clinically contraindicated. Use only the single-dose vials for caudal or epidural anesthesia; avoid use of the multiple-dose vials for these procedures, which contain a preservative [see Dosage and Administration (2.1, 2.4), Warnings and Precautions (5.7)]. 2.4 Test Dose for Epidural Blocks 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. Three mL of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit. This test dose may serve as a warning of unintended intravascular or intrathecal injection. Closely monitor for early clinical signs of toxicity following each test dose [see Warnings and Precautions (5.7)]. Allot adequate time for onset of spinal block to detect possible intrathecal injection. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal, or cardiovascular effects from the epinephrine [see Warnings and Precautions (5.1), Overdosage (10)]. 2.5 Maximum Recommended Dosage Adults For normal healthy adults, the individual maximum recommended dose of Lidocaine Hydrochloride and Epinephrine Injection should not exceed 7 mg/kg 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 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, a higher total dose 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 Use in Specific Populations (8.1)]. Pediatric Patients A maximum dose of Lidocaine Hydrochloride and Epinephrine Injection for children varies based on age and weight. For children over 3 years of age with 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 approximately 23 kg, the dose of lidocaine hydrochloride should not exceed approximately 75 mg to 100 mg (3.3 mg/kg to 4.4 mg/kg). The use of dilute solutions (i.e., 0.25% to 0.5%) and total dosages not to exceed 3 mg/kg are recommended for induction of intravenous regional anesthesia in children. The lowest effective concentration and lowest effective dose should be used. Dilution of available concentrations with 0.9% sodium chloride injection may be required to obtain the required final concentration.

al dosages not to exceed 3 mg/kg are recommended for induction of intravenous regional anesthesia in children. The lowest effective concentration and lowest effective dose should be used. Dilution of available concentrations with 0.9% sodium chloride injection may be required to obtain the required final concentration. See Full Prescribing Information for recommended dosages and administration information for adult and pediatric patients (2) Image1.jpg Image2.jpg

See Full Prescribing Information for recommended dosages and administration information for adult and pediatric patients (2) For Epidural test dose, Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: •1.5% (75 mg/5 mL) (15 mg/mL), 5 mL single-dose ampuls Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: •1.5% (450 mg/30 mL) (15 mg/mL), 30 mL single-dose vials •2% (400 mg/20 mL) (20 mg/mL), 20 mL single-dose vials Lidocaine Hydrochloride and Epinephrine Injection 1:200,000, USP is a clear, colorless to slightly yellow solution available as: •0.5% (250 mg/mL) (5 mg/mL), 50 mL multiple-dose vials Lidocaine Hydrochloride and Epinephrine Injection 1:100,000, USP is a clear, colorless to slightly yellow solution available as: •1% (200 mg/20 mL) (10 mg/mL), 20 mL multiple-dose vials •1% (300 mg/30 mL) (10 mg/mL), 30 mL multiple-dose vials •1% (500 mg/50 mL) (10 mg/mL), 50 mL multiple-dose vials •2% (400 mg/20 mL) (20 mg/mL), 20 mL multiple-dose vials •2% (600 mg/30 mL) (20 mg/mL), 30 mL multiple-dose vials •2% (1000 mg/50 mL) (20 mg/mL), 50 mL multiple-dose vials •For epidural test dose, Lidocaine Hydrochloride and Epinephrine 1:200,000 Injection, USP, Single-dose Ampuls: 1.5% •Lidocaine Hydrochloride and Epinephrine 1:200,000 Injection, USP, Single-dose Vials: 1.5%, 2% •Lidocaine Hydrochloride and Epinephrine 1:200,000 Injection, USP, Multiple-dose Vials: 0.5% •Lidocaine Hydrochloride and Epinephrine 1:100,000 Injection, USP, Multiple-dose Vials: 1%, 2%

4 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)

5 Warnings and Precautions 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.

. 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 2nd 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 that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.

rochloride and Epinephrine Injection and Anaphylactic Reactions Lidocaine Hydrochloride and Epinephrine Injection solutions contain 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. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. Anaphylactic reactions may occur following administration of lidocaine hydrochloride [see Adverse Reactions (6)]. Lidocaine hydrochloride should be used with caution in persons with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to lidocaine hydrochloride. 5.7 Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection Unintended intravascular or intrathecal injection of Lidocaine Hydrochloride and Epinephrine Injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Unintentional intrathecal injection during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column has resulted in underventilation or apnea ("Total or High Spinal"). A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia [see Adverse Reactions (6)]. Aspirate for blood or cerebrospinal fluid (where applicable) before injecting Lidocaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection. Use of Test Dose with Epidural Anesthesia To serve as a warning of unintended intravascular or intrathecal injection, 3 mL of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) may be used as a test dose prior to administration of the full dose in caudal and lumbar epidural blocks [see Dosage and Administration (2.4)]. Three mL of Lidocaine Hydrochloride and Epinephrine Injection (1.5% lidocaine with 1:200,000 epinephrine) without antimicrobial preservative contains 45 mg lidocaine and 15 mcg epinephrine. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. Signs/symptoms of unintended intravascular or intrathecal injection of the test dose of Lidocaine Hydrochloride and Epinephrine Injection and monitoring recommendations are described below. •Unintended intravascular injection: Likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and/or 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. Therefore, following the test dose, the heart rate should be monitored for increases. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure. •Unintended intrathecal injection: Evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects [see Overdosage (10)].

injection: Evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects [see Overdosage (10)]. 5.8 Risk of Toxicity in Patients with Hepatic Impairment Because amide local anesthetics such as lidocaine are metabolized by the liver, consider reduced dosing and increased monitoring for lidocaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with lidocaine hydrochloride, especially with repeat doses [see Use in Specific Populations (8.6)]. 5.9 Risk of Use in Patients with Impaired Cardiovascular Function Lidocaine should also be given in reduced doses in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Monitor patients closely for blood pressure, heart rate, and ECG changes. 5.10 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood Supply Use Lidocaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply, such as digits, nose, external ear, or penis. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. 5.11 Risk of Cardiac Arrhythmias with Concomitant Use of Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Lidocaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Drug Interactions (7.6)]. In deciding whether to concurrently use Lidocaine Hydrochloride and Epinephrine Injection with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. 5.12 Risk of Adverse Reactions with Use in the Head and Neck Area Small doses of local anesthetics (e.g., Lidocaine Hydrochloride and Epinephrine Injection) injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Monitor circulation and respiration and constantly observe patients receiving Lidocaine Hydrochloride and Epinephrine Injection blocks. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see Dosage and Administration (2.2)]. 5.13 Familial Malignant Hyperthermia Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia.

onnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see Dosage and Administration (2.2)]. 5.13 Familial Malignant Hyperthermia Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for the management of malignant hyperthermia should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using). 5.14 Risk of Respiratory Arrest with Use in Ophthalmic Surgery Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block (e.g., with Lidocaine Hydrochloride and Epinephrine Injection), as with all other regional procedures, resuscitative equipment and drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be immediately available. As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses. 5.15 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa in Dental Applications Because of the long duration of anesthesia, when Lidocaine Hydrochloride and Epinephrine Injection [0.5% (5 mg/mL) of lidocaine] is used for dental injections, warn patients about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns [see Patient Counseling Information (17)]. 5.16 Drug/Laboratory Test Interactions The intramuscular injection of lidocaine hydrochloride may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination, without isoenzyme separation, as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine hydrochloride. • 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.

s 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)

6 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.

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.

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.

7 Drug Interactions 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: 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. • 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.

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) Image3.jpg

8 Use In Specific Populations Risk Summary Available published data and decades of clinical use with lidocaine hydrochloride in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone and cardiac function (see Clinical Considerations). In a published animal reproduction study, pregnant rats administered lidocaine by continuous subcutaneous infusion at a dose approximately 9.6 times the maximum recommended human dose (MRHD) of 500 mg in lidocaine hydrochloride during the period of organogenesis resulted in lower fetal body weights [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal adverse reactions Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient’s legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Labor or delivery Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity [see Clinical Pharmacology (12.3)]. The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. However, dosage recommendations for spinal anesthesia are much lower than dosage recommendations for other major blocks. Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. Data Animal Data Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine hydrochloride.

drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. Data Animal Data Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine hydrochloride. In a published study, lidocaine administered to pregnant rats by continuous subcutaneous infusion during the period of organogenesis at 100, 250, and 500 mg/kg/day, did not produce any structural abnormalities, but did result in lower fetal weights at 500 mg/kg/day dose (approximately 9.6 times the maximum recommended human dose [MRHD] of 500 mg lidocaine on a mg/m2 basis) in the absence of maternal toxicity. 8.2 Lactation Risk Summary Published data report the presence of lidocaine and its metabolites in human milk in low amounts, along with poor oral bioavailability. There are no data on the effect of lidocaine on the breastfed infant or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lidocaine Hydrochloride and Epinephrine Injection and any potential adverse effects on the breastfed child from Lidocaine Hydrochloride and Epinephrine Injection or from the underlying maternal condition. 8.4 Pediatric Use Dosages in children should be reduced, commensurate with age, body weight and physical condition [see Dosage and Administration (2.5)]. 8.5 Geriatric Use Elderly patients should be given reduced doses commensurate with their age and physical condition [see Dosage and Administration (2.5)]. 8.6 Hepatic Impairment Amide-type local anesthetics such as lidocaine are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with hepatic impairment treated with Lidocaine Hydrochloride and Epinephrine Injection, especially with repeat doses [see Warnings and Precautions (5.8)]. Geriatric Use : Elderly patients should be given reduced doses commensurate with their age and physical condition. (8.5) Hepatic Impairment : Consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with hepatic impairment. (8.6) See 17 for PATIENT COUNSELI INFORMATION. Revised: 5/2025

10 Overdosage Clinical Presentation Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution [see Warnings and Precautions (5.1), Adverse Reactions (6)]. Management The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea due to unintended subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (e.g., ephedrine). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine hydrochloride.

11 Description Lidocaine Hydrochloride and Epinephrine Injection, USP is a sterile, nonpyrogenic solution of lidocaine hydrochloride and epinephrine in water for injection for parenteral administration in various concentrations with characteristics as follows: Sodium metabisulfite 0.5 mg/mL and citric acid, anhydrous 0.2 mg/mL added as stabilizers. The headspace of Lists 1209, 3177, 3178, 3181, 3182 and 3183 are nitrogen gassed. May contain sodium hydroxide and/or hydrochloric acid to adjust pH; pH is 4.5 (3.3 to 5.5). See HOW SUPPLIED section for various sizes and strengths. Multiple-dose vials contain methylparaben 1 mg/mL added as preservative. Single-dose ampuls and vials contain no bacteriostat or antimicrobial agent. Discard unused portion. Lidocaine is a local anesthetic of the amide-type. Lidocaine Hydrochloride, USP is chemically designated 2-(diethyl-amino)-2',6'-acetoxylidide monohydrochloride monohydrate, a white powder freely soluble in water. It has the following structural formula: Epinephrine is a vasoconstrictor. Epinephrine, USP is a sympathomimetic (adrenergic) agent designated chemically as 4-[1-hydroxy-2 (methylamino) ethyl]-1,2 benzenediol, a white, microcrystalline powder. It has the following structural formula: Image4.jpg image description image description

12 Clinical Pharmacology 12.1 Mechanism of Action Lidocaine hydrochloride stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of 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 Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to block of autonomic fibers, 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. The net effect is normally a modest hypotension when the recommended dosages are not exceeded. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine hydrochloride required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6 mcg free base per mL. 12.3 Pharmacokinetics Systemic plasma levels of lidocaine following Lidocaine Hydrochloride and Epinephrine Injection do not correlate with local efficacy. Absorption Information derived from diverse formulations, concentrations and usages reveals that lidocaine hydrochloride 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 hydrochloride is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg of free base per mL 60 to 80 percent of lidocaine hydrochloride is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine hydrochloride 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 hydrochloride is metabolized rapidly by the liver, and 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 hydrochloride. Excretion Approximately 90% of lidocaine hydrochloride administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged by the kidneys. 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 hydrochloride is metabolized, any condition that affects liver function may alter lidocaine hydrochloride kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction.

13 Nonclinical Toxicology 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Studies of lidocaine hydrochloride in animals to evaluate the carcinogenic potential have not been conducted. Mutagenesis Studies of lidocaine hydrochloride in animals to evaluate the mutagenic potential have not been conducted. Impairment of Fertility In a published study, female Sprague-Dawley rats were treated subcutaneously with lidocaine via osmotic pumps starting two weeks prior to mating, and reproductive effects were assessed. Rats dosed up to the high dose of 500 mg/kg/day (approximately 45 times the MRDD on a mg/m 2 basis) showed no effects on copulatory rate, pregnancy rate, numbers of corpora lutea, or implantations.

16 How Supplied/Sorage and Handling Do not autoclave. Storage : All solutions should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light . For single-dose vials and ampules: Discard unused portion. For Epidural test dose, Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: Lidocaine Hydrochloride and Epinephrine Injection 1:200,000, USP is a clear, colorless to slightly yellow solution available as: Lidocaine Hydrochloride and Epinephrine Injection 1:100,000, USP is a clear, colorless to slightly yellow solution available as: Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 From Original Manufacturer/Distributor's NDC and Unit of Sale To Henry Schein Repackaged Product NDC and Unit of Sale Total Strength/Total Volume (Concentration) per unit NDC 0409-3177-01 Tray of 25 Fliptop Vials NDC 0404-9886-50 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3177-16) Lidocaine HCl 0.5% (250 mg/50mL) (5 mg/mL) and Epinephrine 1:200,000 NDC 0409-3178-02 Tray of 25 Fliptop Vials NDC 0404-9891-20 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3178-17) Lidocaine HCl 1% (300 mg/30 mL) (10 mg/mL) and Epinephrine 1:100,000 NDC 0409-3178-03 Tray of 25 Fliptop Vials NDC 0404-9891-50 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3178-18) Lidocaine HCl 1% (500 mg/50 mL) (10 mg/mL) and Epinephrine 1:100,000 NDC 0409-3182-02 Tray of 25 Fliptop Vials NDC 0404-9896-30 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3182-21) Lidocaine HCl 2% (600 mg/30mL) (20 mg/mL) and Epinephrine 1:100,000 NDC 0409-3182-03 Tray of 25 Fliptop Vials NDC 0404-9896-50 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3182-31) Lidocaine HCl 2% (1000 mg/50 mL) (20 mg/mL) and Epinephrine 1:100,000 Image5.jpg Image6.jpg Image7.jpg Image8.jpg

<table width="100%"><caption> Product repackaged by: Henry Schein, Inc., Bastian, VA 24314</caption><tbody><tr><td>From Original Manufacturer/Distributor&apos;s NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit </td></tr><tr><td>NDC 0409-3177-01 Tray of 25 Fliptop Vials</td><td>NDC 0404-9886-50 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3177-16)</td><td>Lidocaine HCl 0.5% (250 mg/50mL) (5 mg/mL) and Epinephrine 1:200,000</td></tr><tr><td>NDC 0409-3178-02 Tray of 25 Fliptop Vials</td><td>NDC 0404-9891-20 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3178-17)</td><td>Lidocaine HCl 1% (300 mg/30 mL) (10 mg/mL) and Epinephrine 1:100,000</td></tr><tr><td>NDC 0409-3178-03 Tray of 25 Fliptop Vials</td><td>NDC 0404-9891-50 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3178-18)</td><td>Lidocaine HCl 1% (500 mg/50 mL) (10 mg/mL) and Epinephrine 1:100,000</td></tr><tr><td>NDC 0409-3182-02 Tray of 25 Fliptop Vials</td><td>NDC 0404-9896-30 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3182-21)</td><td>Lidocaine HCl 2% (600 mg/30mL) (20 mg/mL) and Epinephrine 1:100,000</td></tr><tr><td>NDC 0409-3182-03 Tray of 25 Fliptop Vials</td><td>NDC 0404-9896-50 1 Multiple Dose Fliptop Vial in a bag (Vial bears NDC 0409-3182-31)</td><td>Lidocaine HCl 2% (1000 mg/50 mL) (20 mg/mL) and Epinephrine 1:100,000</td></tr></tbody></table>

17 Patient Counseling 17.1 Allergic-Type Reactions Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions [see Contraindications (4), Warnings and Precautions (5.6), Adverse Reactions (6)]. 17.2 Temporary Loss of Sensation and Motor Activity After Caudal or Epidural Anesthesia When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Instructions After Dental Injection of Lidocaine Hydrochloride Advise patients receiving dental injections of Lidocaine Hydrochloride not to chew solid foods or to test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours) [see Warnings and Precautions (5.15)]. 17.3 Methemoglobinemia Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to stop use and seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.2)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. For medical information about Lidocaine Hydrochloride and Epinephrine Injection, please visit www.pfizermedinfo.com or call 1-800-438-1985. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Hospira LAB-1298-8.0

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for recommended dosages and administration information for adult and pediatric patients ( 2 ) 2.1 Important Dosage and Administration Information Lidocaine Hydrochloride and Epinephrine Injection is not recommended for intrathecal use. Avoid use of Lidocaine Hydrochloride and Epinephrine solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [see Warnings and Precautions (5.3) ] . Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use. Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit. Lidocaine Hydrochloride and Epinephrine Injections are clear, colorless to slightly yellow solutions. Do not administer solutions which are discolored or contain particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions which are discolored (e.g., pinkish or darker than slightly yellow) or which contain particulate matter or precipitate should not be administered. Mixing or the prior or intercurrent use of any other local anesthetic with Lidocaine Hydrochloride and Epinephrine Injection is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions Lidocaine Hydrochloride and Epinephrine Injection is to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed. Use Lidocaine Hydrochloride and Epinephrine Injection only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Warnings and Precautions (5.1) , Adverse Reactions (6) , Overdosage (10) ] . The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with Lidocaine Hydrochloride and Epinephrine Injection [see Warnings and Precautions (5.1) , Drug Interactions (7.1) , Overdosage (10) ] . Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting Lidocaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection [see Warnings and Precautions (5.7) ] . Avoid rapid injection of a large volume of Lidocaine Hydrochloride and Epinephrine Injection and use fractional (incremental) doses when feasible. 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. The lowest dosage of Lidocaine Hydrochloride and Epinephrine Injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions.

the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access. The lowest dosage of Lidocaine Hydrochloride and Epinephrine Injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions. Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient’s level of consciousness after each local anesthetic injection. Use Lidocaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis [see Warnings and Precautions (5.10) ] . 2.2 Recommended Concentrations and Dosages of Lidocaine Hydrochloride and Epinephrine Injection/Lidocaine Hydrochloride Injection (without Epinephrine) in Adults The dosage of Lidocaine Hydrochloride and Epinephrine Injection administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. Administer the smallest dosage and concentration required to produce the desired result. The types of block and recommended Lidocaine Hydrochloride Injection (without epinephrine) concentrations are shown in Table 1. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. Consider administration of solutions containing epinephrine when large volumes are required. Table 1: Recommended Dosages in Adults Procedure Lidocaine Hydrochloride Injection (without epinephrine) Conc (%) Vol (mL) Total Dose (mg) Infiltration Percutaneous 0.5 or 1 1 to 60 5 to 300 Intravenous regional 0.5 10 to 60 50 to 300 Dose should not exceed 4 mg/kg. Peripheral Nerve Blocks, e.g., Brachial 1.5 15 to 20 225 to 300 Dental 2 1 to 5 20 to 100 Intercostal 1 3 30 Paravertebral 1 3 to 5 30 to 50 Pudendal (each side) 1 10 100 Paracervical Obstetrical analgesia (each side) 1 10 100 Sympathetic Nerve Blocks, e.g., Cervical (stellate ganglion) 1 5 50 Lumbar 1 5 to 10 50 to 100 Central Neural Blocks Epidural Dose determined by number of dermatomes to be anesthetized (2 to 3 mL/dermatome). Thoracic 1 20 to 30 200 to 300 Lumbar Analgesia 1 25 to 30 250 to 300 Anesthesia 1.5 15 to 20 225 to 300 2 10 to 15 200 to 300 Caudal Obstetrical analgesia 1 20 to 30 200 to 300 Surgical anesthesia 1.5 15 to 20 225 to 300 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 [see Dosage and Administration (2.5) ] . These recommended doses serve only as a guide to the amount of local anesthetic required for most indicated 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. The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site.

and smallest dose that will produce the desired result should be given. The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site. 2.3 Use in Epidural Anesthesia During the administration of epidural anesthesia, it is recommended that a test dose of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) be administered initially and the effects monitored before the full dose is given. When using a “continuous” catheter technique, test doses should be given prior to both the initial and all supplemental doses, because a catheter in the epidural space can migrate into a blood vessel or through the dura [see Dosage and Administration (2.4) ] . During epidural administration, administer Lidocaine Hydrochloride and Epinephrine Injection, 1.5% (15 mg/mL) and 2% (20 mg/mL) solutions in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Administer injections slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Perform syringe aspirations before and during each supplemental injection in continuous (intermittent) catheter techniques. Repeat doses of lidocaine should be preceded by a test dose containing epinephrine if not clinically contraindicated. Use only the single-dose vials for caudal or epidural anesthesia; avoid use of the multiple-dose vials for these procedures, which contain a preservative [see Dosage and Administration (2.1 , 2.4 ), Warnings and Precautions (5.7) ] . 2.4 Test Dose for Epidural Blocks 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. Three mL of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit. This test dose may serve as a warning of unintended intravascular or intrathecal injection. Closely monitor for early clinical signs of toxicity following each test dose [see Warnings and Precautions (5.7) ] . Allot adequate time for onset of spinal block to detect possible intrathecal injection. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. The test dose itself may produce a systemic toxic reaction, high spinal, or cardiovascular effects from the epinephrine [see Warnings and Precautions (5.1) , Overdosage (10) ] . 2.5 Maximum Recommended Dosage Adults For normal healthy adults, the individual maximum recommended dose of Lidocaine Hydrochloride and Epinephrine Injection should not exceed 7 mg/kg 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 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, a higher total dose may be administered if required to produce adequate anesthesia.

3 DOSAGE FORMS AND STRENGTHS Lidocaine Hydrochloride and Epinephrine Injection 1:100,000, USP is a clear, colorless to slightly yellow solution available as: 1% (200 mg/20 mL) (10 mg/mL), 20 mL multiple-dose vials 1% (500 mg/50 mL) (10 mg/mL), 50 mL multiple-dose vials Lidocaine Hydrochloride and Epinephrine 1:100,000 Injection, USP, Multiple-dose Vials: 1%

5 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.

travascular or intrathecal injection, 3 mL of Lidocaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (1.5% lidocaine with 1:200,000 epinephrine) may be used as a test dose prior to administration of the full dose in caudal and lumbar epidural blocks [see Dosage and Administration (2.4) ] . Three mL of Lidocaine Hydrochloride and Epinephrine Injection (1.5% lidocaine with 1:200,000 epinephrine) without antimicrobial preservative contains 45 mg lidocaine and 15 mcg epinephrine. An intravascular or intrathecal injection is still possible even if results of the test dose are negative. Signs/symptoms of unintended intravascular or intrathecal injection of the test dose of Lidocaine Hydrochloride and Epinephrine Injection and monitoring recommendations are described below. Unintended intravascular injection: Likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and/or 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. Therefore, following the test dose, the heart rate should be monitored for increases. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure. Unintended intrathecal injection: Evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk). The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects [see Overdosage (10) ] . 5.8 Risk of Toxicity in Patients with Hepatic Impairment Because amide local anesthetics such as lidocaine are metabolized by the liver, consider reduced dosing and increased monitoring for lidocaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with lidocaine hydrochloride, especially with repeat doses [see Use in Specific Populations (8.6) ] . 5.9 Risk of Use in Patients with Impaired Cardiovascular Function Lidocaine should also be given in reduced doses in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Monitor patients closely for blood pressure, heart rate, and ECG changes. 5.10 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood Supply Use Lidocaine Hydrochloride and Epinephrine Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply, such as digits, nose, external ear, or penis. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. 5.11 Risk of Cardiac Arrhythmias with Concomitant Use of Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., Lidocaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see Drug Interactions (7.6) ] . In deciding whether to concurrently use Lidocaine Hydrochloride and Epinephrine Injection with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account.

6 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.

s 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.

7 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) ] .

<table width="100%" styleCode="Noautorules"><col width="50%"/><col width="50%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Class</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Examples</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nitrates/Nitrites</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>nitroglycerin, nitroprusside, nitric oxide, nitrous oxide</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Local anesthetics</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Antineoplastic agents</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>cyclophosphamide, flutamide, rasburicase, ifosfamide, hydroxyurea</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Antibiotics</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>dapsone, sulfonamides, nitrofurantoin, para- aminosalicylic acid</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Antimalarials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>chloroquine, primaquine</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anticonvulsants</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>phenytoin, sodium valproate, phenobarbital</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Other drugs</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>acetaminophen, metoclopramide, quinine, sulfasalazine</paragraph></td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Geriatric Use : Elderly patients should be given reduced doses commensurate with their age and physical condition. ( 8.5 ) Hepatic Impairment : Consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with hepatic impairment. ( 8.6 ) 8.1 Pregnancy Risk Summary Available published data and decades of clinical use with lidocaine hydrochloride in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone and cardiac function (see Clinical Considerations ) . In a published animal reproduction study, pregnant rats administered lidocaine by continuous subcutaneous infusion at a dose approximately 9.6 times the maximum recommended human dose (MRHD) of 500 mg in lidocaine hydrochloride during the period of organogenesis resulted in lower fetal body weights [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal adverse reactions Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient’s legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Labor or delivery Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity [see Clinical Pharmacology (12.3) ] . The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. However, dosage recommendations for spinal anesthesia are much lower than dosage recommendations for other major blocks. Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life.

e parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. Data Animal Data Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine hydrochloride. In a published study, lidocaine administered to pregnant rats by continuous subcutaneous infusion during the period of organogenesis at 100, 250, and 500 mg/kg/day, did not produce any structural abnormalities, but did result in lower fetal weights at 500 mg/kg/day dose (approximately 9.6 times the maximum recommended human dose [MRHD] of 500 mg lidocaine on a mg/m 2 basis) in the absence of maternal toxicity. 8.2 Lactation Risk Summary Published data report the presence of lidocaine and its metabolites in human milk in low amounts, along with poor oral bioavailability. There are no data on the effect of lidocaine on the breastfed infant or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lidocaine Hydrochloride and Epinephrine Injection and any potential adverse effects on the breastfed child from Lidocaine Hydrochloride and Epinephrine Injection or from the underlying maternal condition. 8.4 Pediatric Use Dosages in children should be reduced, commensurate with age, body weight and physical condition [see Dosage and Administration (2.5) ] . 8.5 Geriatric Use Elderly patients should be given reduced doses commensurate with their age and physical condition [see Dosage and Administration (2.5) ] . 8.6 Hepatic Impairment Amide-type local anesthetics such as lidocaine are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with hepatic impairment treated with Lidocaine Hydrochloride and Epinephrine Injection, especially with repeat doses [see Warnings and Precautions (5.8) ] .

8.1 Pregnancy Risk Summary Available published data and decades of clinical use with lidocaine hydrochloride in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone and cardiac function (see Clinical Considerations ) . In a published animal reproduction study, pregnant rats administered lidocaine by continuous subcutaneous infusion at a dose approximately 9.6 times the maximum recommended human dose (MRHD) of 500 mg in lidocaine hydrochloride during the period of organogenesis resulted in lower fetal body weights [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal adverse reactions Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient’s legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Labor or delivery Local anesthetics rapidly cross the placenta, and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity [see Clinical Pharmacology (12.3) ] . The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. However, dosage recommendations for spinal anesthesia are much lower than dosage recommendations for other major blocks. Spinal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Spinal anesthesia has also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. Data Animal Data Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine hydrochloride.

11 DESCRIPTION Lidocaine Hydrochloride and Epinephrine Injection, USP is a sterile, nonpyrogenic solution of lidocaine hydrochloride and epinephrine in water for injection for parenteral administration in various concentrations with characteristics as follows: Concentration Lidocaine hydrochloride Epinephrine Lidocaine hydrochloride (anhyd.) mg/mL Epinephrine mcg/mL Sodium Chloride mg/mL 1% 1:100,000 10 10 7 Sodium metabisulfite 0.5 mg/mL and citric acid, anhydrous 0.2 mg/mL added as stabilizers. The headspace of Lists 3178 are nitrogen gassed. May contain sodium hydroxide and/or hydrochloric acid to adjust pH; pH is 4.5 (3.3 to 5.5). See HOW SUPPLIED section for various sizes and strengths. Multiple-dose vials contain methylparaben 1 mg/mL added as preservative. Lidocaine is a local anesthetic of the amide-type. Lidocaine Hydrochloride, USP is chemically designated 2-(diethyl-amino)-2',6'-acetoxylidide monohydrochloride monohydrate, a white powder freely soluble in water. It has the following structural formula: Epinephrine is a vasoconstrictor. Epinephrine, USP is a sympathomimetic (adrenergic) agent designated chemically as 4-[1-hydroxy-2 (methylamino) ethyl]-1,2 benzenediol, a white, microcrystalline powder. It has the following structural formula: lidocaine-01.jpg lidocaine-02.jpg

<table width="100%"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="bottom"><paragraph><content styleCode="bold">Concentration</content></paragraph><paragraph><content styleCode="bold">Lidocaine hydrochloride</content></paragraph></td><td align="center" styleCode="Botrule Lrule Rrule Toprule" valign="bottom"><paragraph><content styleCode="bold">Epinephrine</content></paragraph></td><td align="center" styleCode="Botrule Lrule Rrule Toprule" valign="middle"><paragraph><content styleCode="bold">Lidocaine hydrochloride</content></paragraph><paragraph><content styleCode="bold">(anhyd.) mg/mL</content></paragraph></td><td align="center" styleCode="Botrule Lrule Rrule Toprule" valign="bottom"><paragraph><content styleCode="bold">Epinephrine</content></paragraph><paragraph><content styleCode="bold">mcg/mL</content></paragraph></td><td align="center" styleCode="Botrule Lrule Rrule Toprule" valign="bottom"><paragraph><content styleCode="bold">Sodium Chloride</content></paragraph><paragraph><content styleCode="bold">mg/mL</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Botrule Lrule Rrule Toprule" valign="middle"><paragraph>1:100,000</paragraph></td><td align="center" styleCode="Botrule Lrule Rrule Toprule" valign="middle"><paragraph>10</paragraph></td><td align="center" styleCode="Botrule Lrule Rrule Toprule" valign="middle"><paragraph>10</paragraph></td><td align="center" styleCode="Botrule Lrule Rrule Toprule" valign="middle"><paragraph>7</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Do not autoclave. Storage : All solutions should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light . For single-dose vials and ampules: Discard unused portion. Lidocaine Hydrochloride and Epinephrine Injection 1:100,000, USP is a clear, colorless to slightly yellow solution available as: Unit of Sale Concentration 1% Contains 10 mg lidocaine hydrochloride per mL NDC 85766-073-01 [relabeled from 0409-3178-16] Multiple-dose fliptop vials 200 mg/20 mL (10 mg/mL) NDC 85766-073-25 [relabeled from 0409-3178-01] Tray of 25 multiple-dose fliptop vials 200 mg/20 mL (10 mg/mL) NDC 85766-073-50 [relabeled from 0409-3178-18] Multiple-dose fliptop vials 500 mg/50 mL (10 mg/mL)

<table width="70%"><colgroup><col width="41%"/><col width="40%"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"><paragraph><content styleCode="bold">Concentration</content></paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Botrule Lrule Rrule" valign="top"><paragraph>1% Contains 10 mg lidocaine hydrochloride per mL</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>NDC 85766-073-01 [relabeled from 0409-3178-16]</paragraph><paragraph>Multiple-dose fliptop vials</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"><paragraph>200 mg/20 mL</paragraph><paragraph>(10 mg/mL)</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>NDC 85766-073-25 [relabeled from 0409-3178-01]</paragraph><paragraph>Tray of 25 multiple-dose fliptop vials</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"><paragraph>200 mg/20 mL</paragraph><paragraph>(10 mg/mL)</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>NDC 85766-073-50 [relabeled from 0409-3178-18]</paragraph><paragraph>Multiple-dose fliptop vials</paragraph></td><td styleCode="Botrule Lrule Rrule Toprule" valign="top"> 500 mg/50 mL <paragraph>(10 mg/mL)</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION 17.1 Allergic-Type Reactions Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions [see Contraindications (4) , Warnings and Precautions (5.6) , Adverse Reactions (6) ] . 17.2 Temporary Loss of Sensation and Motor Activity After Caudal or Epidural Anesthesia When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Instructions After Dental Injection of Lidocaine Hydrochloride Advise patients receiving dental injections of Lidocaine Hydrochloride not to chew solid foods or to test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours) [see Warnings and Precautions (5.15) ] . 17.3 Methemoglobinemia Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to stop use and seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.2) ] . This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . For medical information about Lidocaine Hydrochloride and Epinephrine Injection, please visit www.pfizermedinfo.com or call 1-800-438-1985. Distributed by: Sportpharm LLC 379 Van Ness Ave 1401, Torrance, CA 90501 Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501

3 DOSAGE FORMS AND STRENGTHS For Epidural test dose, Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: 1.5% (75 mg/5 mL) (15 mg/mL), 5 mL single-dose ampuls Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: 1.5% (450 mg/30 mL) (15 mg/mL), 30 mL single-dose vials 2% (400 mg/20 mL) (20 mg/mL), 20 mL single-dose vials Lidocaine Hydrochloride and Epinephrine Injection 1:200,000, USP is a clear, colorless to slightly yellow solution available as: 0.5% (250 mg/mL) (5 mg/mL), 50 mL multiple-dose vials Lidocaine Hydrochloride and Epinephrine Injection 1:100,000, USP is a clear, colorless to slightly yellow solution available as: 1% (200 mg/20 mL) (10 mg/mL), 20 mL multiple-dose vials 1% (300 mg/30 mL) (10 mg/mL), 30 mL multiple-dose vials 1% (500 mg/50 mL) (10 mg/mL), 50 mL multiple-dose vials 2% (400 mg/20 mL) (20 mg/mL), 20 mL multiple-dose vials 2% (600 mg/30 mL) (20 mg/mL), 30 mL multiple-dose vials 2% (1000 mg/50 mL) (20 mg/mL), 50 mL multiple-dose vials For epidural test dose, Lidocaine Hydrochloride and Epinephrine 1:200,000 Injection, USP, Single-dose Ampuls: 1.5% Lidocaine Hydrochloride and Epinephrine 1:200,000 Injection, USP, Single-dose Vials: 1.5%, 2% Lidocaine Hydrochloride and Epinephrine 1:200,000 Injection, USP, Multiple-dose Vials: 0.5% Lidocaine Hydrochloride and Epinephrine 1:100,000 Injection, USP, Multiple-dose Vials: 1%, 2%

<table width="100%" styleCode="Noautorules"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Concentration</content></paragraph><paragraph><content styleCode="bold">Lidocaine hydrochloride</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Epinephrine</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Lidocaine hydrochloride</content></paragraph><paragraph><content styleCode="bold">(anhyd.) mg/mL</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Epinephrine</content></paragraph><paragraph><content styleCode="bold">mcg/mL</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Sodium Chloride</content></paragraph><paragraph><content styleCode="bold">mg/mL</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:200,000</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:200,000</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:200,000</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:200,000</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1:100,000</paragraph></td><td align="center" styleCode="Rrul

16 HOW SUPPLIED/STORAGE AND HANDLING Do not autoclave. Storage : All solutions should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light . For single-dose vial: Discard unused portion. For Epidural test dose, Lidocaine Hydrochloride and Epinephrine Injection, USP 1:200,000 is a clear, colorless to slightly yellow solution available as: Lidocaine Hydrochloride and Epinephrine Injection 1:100,000, USP is a clear, colorless to slightly yellow solution available as: Unit of Sale Concentration 2% Contains 20 mg lidocaine hydrochloride per mL NDC 84549-182-03 multiple-dose fliptop vials 1000 mg/50 mL (20 mg/mL)

<table width="70%" styleCode="Noautorules"><colgroup><col width="41%"/><col width="40%"/></colgroup><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Concentration</content></paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph/></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2% Contains 20 mg lidocaine hydrochloride per mL</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph/></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>NDC 84549-182-03</paragraph><paragraph>multiple-dose fliptop vials</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1000 mg/50 mL</paragraph><paragraph>(20 mg/mL)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph/></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION 17.1 Allergic-Type Reactions Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions [see Contraindications (4) , Warnings and Precautions (5.6) , Adverse Reactions (6) ] . 17.2 Temporary Loss of Sensation and Motor Activity After Caudal or Epidural Anesthesia When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia. Instructions After Dental Injection of Lidocaine Hydrochloride Advise patients receiving dental injections of Lidocaine Hydrochloride not to chew solid foods or to test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours) [see Warnings and Precautions (5.15) ] . 17.3 Methemoglobinemia Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to stop use and seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.2) ] . This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . For medical information about Lidocaine Hydrochloride and Epinephrine Injection, please visit www.pfizermedinfo.com or call 1-800-438-1985. lidocaine-03.jpg

1 INDICATIONS AND USAGE FLAVALTA solution is indicated for the production of local anesthesia for dental procedures by nerve block or infiltration techniques [see Dosage and Administration (2.2) ]. FLAVALTA solution is a combination of lidocaine, an amide local anesthetic, and epinephrine, an alpha and beta adrenergic agonist indicated for the production of local anesthesia for dental procedures by nerve block or infiltration techniques.

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for recommended dosages and administration information for adult and pediatric patients. 2.1 Important Dosage and Administration Information Visually inspect this product for particulate matter and discoloration prior to administration. Solution that is discolored and/or contains particulate matter should not be used and any unused portion of a cartridge of FLAVALTA should be discarded. Local anesthetic procedures should not be performed when there is inflammation and/or sepsis in the region of the proposed injection. The dosage of FLAVALTA (lidocaine HCl and epinephrine) depends on the physical status of the patient, the area of the oral cavity to be anesthetized, the vascularity of the oral tissues, and the technique of anesthesia used. The least volume of solution that results in effective local anesthesia should be administered; time should be allowed between injections to observe the patient for manifestations of an adverse reaction. Mixing or the prior or intercurrent use of any other local anesthetic with FLAVALTA is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions FLAVALTA should be in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise. Use FLAVALTA only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Warnings and Precautions (5.1) , Adverse Reactions (6) , Overdosage (10) ]. The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with FLAVALTA [see Warnings and Precautions (5.1) , Drug Interactions (7.1) , Overdosage (10) ]. Aspirate for blood prior to injecting FLAVALTA, both the initial dose and all subsequent doses, to avoid intravascular injection. However, a negative aspiration for blood does not ensure against an intravascular injection [see Warnings and Precautions (5.9) ]. Avoid rapid injection of a large volume of FLAVALTA and use fractional (incremental) doses when feasible. Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient’s level of consciousness after each local anesthetic injection. Use FLAVALTA in carefully restricted quantities in areas that may have compromised blood supply [see Warnings and Precautions (5.7) ]. 2.2 Recommended Concentration and Dosages of FLAVALTA Adult: For normal healthy adults, the amount of lidocaine HCl administered should be kept below 500 mg and should not exceed 7 mg/kg of body weight. Dosage requirements should be determined on an individual basis. In oral infiltration and/or mandibular block, initial dosages of 1 mL to 5 mL (½ to 2 ½ cartridges) of FLAVALTA (lidocaine HCl 2% solution with a 1:100,000 epinephrine concentration) are usually effective. Pediatric: For pediatric patients who have a normal lean body mass and normal body development, the dose of lidocaine HCl is determined by the child’s body weight. The lowest effective dose should be used. The maximum dose of lidocaine hydrochloride should not exceed 7 mg/kg.

hrine concentration) are usually effective. Pediatric: For pediatric patients who have a normal lean body mass and normal body development, the dose of lidocaine HCl is determined by the child’s body weight. The lowest effective dose should be used. The maximum dose of lidocaine hydrochloride should not exceed 7 mg/kg. In children under 10 years of age, it is rarely necessary to administer more than one-half cartridge (0.9 mL to 1 mL or 18 mg to 20 mg of lidocaine) per procedure to achieve local anesthesia for a procedure involving a single tooth. In maxillary infiltration, this amount will often suffice for the treatment of two or even three teeth. In the mandibular block, however, satisfactory anesthesia achieved with this amount of drug will allow treatment of the teeth of an entire quadrant. Aspiration is recommended since it reduces the possibility of intravascular injection, thereby keeping the incidence of adverse events and anesthetic failures to a minimum. Injection should always be made slowly.

3 DOSAGE FORMS AND STRENGTHS Injection: lidocaine hydrochloride 2% (34 mg/1.7 mL) (20 mg/mL) and epinephrine 1:100,000 (0.017 mg/1.7 mL) (0.01 mg/mL) as a clear, colorless solution in single-dose glass cartridges Injection: lidocaine hydrochloride 2% (34 mg/1.7 mL) (20 mg/mL) and epinephrine 1:100,000 (0.017 mg/1.7 mL) (0.01 mg/mL) as a clear, colorless solution in single-dose glass cartridges

4 CONTRAINDICATIONS FLAVALTA is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type or to any components of the injectable formulations. Known history of hypersensitivity to lidocaine or to any local anesthetics of the amide-type or to other components of FLAVALTA ( 4 )

5 WARNINGS AND PRECAUTIONS Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after injection of FLAVALTA. ( 5.1 ) Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. See full prescribing information for more detail on managing these risks. ( 5.2 ) Allergic-Type Reactions to Sulfites in FLAVALTA and Anaphylactic Reactions: FLAVALTA contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people ( 5.4 ) Risk of Systemic Toxicities with Unintended Intravascular Injection: Unintended intravascular injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Aspirate for blood prior to each dose ( 5.9 ) 5.1 Dose-Related Toxicity The safety and effectiveness of FLAVALTA depends 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 each local anesthetic injection. Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Signs and symptoms of depressed cardiovascular function may commonly result from a vasovagal reaction, particularly if the patient is in an upright position: placing the patient in the recumbent position is recommended when an adverse response is noted after injection of a local anesthetic. Vasovagal reactions may elicit a range of clinical manifestations, from prodrome signs of pre-syncope (e.g. lightheadedness, pallor, nausea, sweating, visual disturbances, weakness) to brief loss of consciousness (i.e. syncope). 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. Resuscitative equipment, oxygen and other resuscitative drugs should be available for immediate use [see Adverse Reactions (6) ] . The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest. Drowsiness following the administration of lidocaine is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption. Use the lowest dosage of FLAVALTA that results in effective anesthesia to avoid high plasma levels and serious adverse effects. Avoid rapid injection of a large volume of FLAVALTA solution and administer fractional (incremental) doses when feasible. Injection of repeated doses of lidocaine may cause significant increases in blood 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, acutely ill patients, and children should be given reduced doses commensurate with their age and physical status.

eated 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, acutely ill patients, and children 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. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue FLAVALTA and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. 5.3 Risk of Adverse Reactions Due to Drug Interactions with FLAVALTA Risk of Severe, Persistent Hypertension Due to Drug Interactions Between FLAVALTA and Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Administration of FLAVALTA (containing a vasoconstrictor, epinephrine) 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 FLAVALTA and Ergot-Type Oxytocic Drugs Concurrent administration of FLAVALTA and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of FLAVALTA concomitantly with ergot-type oxytocic drugs [see Drug Interactions (7.3) ]. Risk of Hypertension and Bradycardia Due to Drug Interactions Between FLAVALTA and Nonselective Beta-Adrenergic Antagonists Administration of FLAVALTA (containing a vasoconstrictor, epinephrine) 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) ]. 5.4 Allergic-Type Reactions to Sulfites in FLAVALTA FLAVALTA solution contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non asthmatic people.

type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non asthmatic people. 5.5 Risk of Toxicity in Patients with Hepatic Impairment Because amide-type local anesthetics such as lidocaine are metabolized by the liver, consider using reduced dosing and increased monitoring in patients with moderate and severe hepatic impairment who are treated with FLAVALTA, especially with repeat doses [see Uses in Specific Populations (8.6) ]. 5.6 Risk of Use in Patients with Impaired Cardiovascular Function FLAVALTA should also be given in reduced doses in patients with impaired cardiovascular function (e.g., hypotension, heart block) because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by FLAVATA. Monitor patients closely for blood pressure, heart rate, and ECG changes. 5.7 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood Supply Use FLAVALTA in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease or hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury (such as exfoliating or ulcerating lesions) or necrosis may result. 5.8 Risk of Adverse Reactions with Use in Head and Neck Area Small doses of local anesthetics injected into the head and neck area for dental treatment may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injection of larger doses. Confusion, convulsions, respiratory depression and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Monitor circulation and respiration and constantly observe patients receiving FLAVALTA. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see Dosage and Administration (2.2) ]. 5.9 Risk of Systemic Toxicities with Unintended Intravascular Injection Unintended intravascular injection of FLAVALTA may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Aspirate for blood before all injections of FLAVALTA to avoid intravascular injection. However, a negative aspiration for blood does not ensure against an intravascular injection. 5.10 Risk of Cardiac Arrythmias with Concomitant Use of Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics [see Drug Interactions (7.6) ]. In deciding whether to concurrently use FLAVALTA with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account. 5.11 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa Because of the long duration of anesthesia when FLAVALTA is administered, warn patients about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns [see Patient Counseling Information (17) ].

6 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) ] Severe, Persistent Hypertension, Cerebrovascular Accidents, and Bradycardia Due to Drug Interactions [see Warnings and Precautions (5.3) ] Allergic-Type Reactions [see Warnings and Precautions (5.4) ] Systemic Toxicities with Unintended Intravascular Injection [see Warnings and Precautions (5.9) ] 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 FLAVALTA are characteristic of those associated with other amide-type local anesthetics. 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. Persistent paresthesias of the lips, tongue, and oral tissues have been reported with the use of lidocaine, with slow, incomplete, or no recovery. These adverse events have been reported primarily following nerve blocks in the mandible involving the trigeminal nerve and its branches. 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. Neurologic effects following 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. 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 of lidocaine and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest [see Warnings and Precautions (5.9) ].

ntravascular injection have led to high plasma levels of lidocaine and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest [see Warnings and Precautions (5.9) ]. In addition, the beta-adrenergic receptor stimulating action of epinephrine may lead to excitatory cardiovascular responses, such as tachycardia, palpitations, and hypertension. Vasovagal Reactions: dizziness, loss of consciousness, nausea, diaphoresis, syncope, and hypotension. 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 sulfites in epinephrine-containing solutions. [see Warnings and Precautions (5.4) ]. 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 related to the central nervous system and the cardiovascular system. To report SUSPECTED ADVERSE REACTIONS, contact Septodont at 1-888-888-1441 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 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 FLAVALTA, which contains epinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. ( 5.3 , 7.2 ) Ergot-Type Oxytocic Drugs: Concurrent administration FLAVALTA, which contains epinephrine, and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. ( 5.3 , 7.3 ) Nonselective Beta-Adrenergic Antagonists: Administration of FLAVALTA (containing a vasoconstrictor, epinephrine), in patients receiving nonselective beta-adrenergic antagonist may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided ( 5.3 , 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 a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics. ( 5.10 , 7.6) 7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with FLAVALTA cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ]. 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants The administration of local anesthetic solutions containing epinephrine 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 patient monitoring is essential [see Warnings and Precautions (5.3) ]. 7.3 Ergot-Type Oxytocic Drugs Concurrent administration of FLAVALTA and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of FLAVALTA concomitantly with ergot-type oxytocic drugs [see Warnings and Precautions (5.3) ]. 7.4 Nonselective Beta-Adrenergic Antagonists Administration of FLAVALTA solution (containing a vasoconstrictor, epinephrine), in patients receiving a nonselective beta-adrenergic antagonist may result in dose-dependent hypertension and bradycardia with possible heart block. 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 (5.3) ]. 7.5 Drugs Associated with Methemoglobinemia Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions (5.2) ].

al [see Warnings and Precautions (5.3) ]. 7.5 Drugs Associated with Methemoglobinemia Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions (5.2) ]. Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 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 [see Warnings and Precautions (5.10) ] . 7.7 Phenothiazines and Butyrophenones Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of FLAVALTA and these agents should generally be avoided. In situation when concurrent therapy is necessary, careful patient monitoring is essential.

<table width="100%" border="1.1"><caption/><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold"> Class</content></td><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold"> Examples</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Nitrates/Nitrites</td><td> nitric oxide, nitroglycerin, nitroprusside, nitrous oxide</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Local anesthetics</td><td styleCode="Lrule Rrule Toprule Botrule"> articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Antineoplastic agents</td><td styleCode="Botrule Lrule Rrule Toprule"> cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Antibiotics</td><td styleCode="Botrule Lrule Rrule Toprule"> dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Antimalarials</td><td styleCode="Botrule Lrule Rrule Toprule"> chloroquine, primaquine</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Anticonvulsants</td><td styleCode="Botrule Lrule Rrule Toprule"> phenobarbital, phenytoin, sodium valproate</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"> Other drugs</td><td styleCode="Botrule Lrule Rrule Toprule"> acetaminophen, metoclopramide, quinine, sulfasalazine</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Pediatric Use: Dosages in pediatric population should be reduced, commensurate with body weight and physical condition. ( 8.4 ) Geriatric Use: Elderly patients should be given reduced doses commensurate with their age and physical condition ( 8.5 ) Hepatic Impairment: Consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with hepatic impairment ( 8.6 ) 8.1 Pregnancy Risk Summary Available published data and decades of clinical use with lidocaine in pregnant women have not identified any drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Local anesthetics may cause varying degrees of toxicity to the mother and fetus and adverse reactions include alterations of the central nervous system, peripheral vascular tone and cardiac function (see Clinical Considerations ). In published reproduction studies, performed in rats, lower fetal body weights were reported when dosed up to 9.7 times the maximum recommended daily dose during the period of organogenesis and developmental delays in neonates when dosed 0.1 times the maximum recommended daily dose on Gestation Day 11 (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Maternal Adverse Reactions During treatment of systemic toxicity, which may appear as maternal hypotension or fetal bradycardia, the parturient should be maintained in the left lateral decubitus position if possible or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient’s legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Data Animal Data Reproduction studies with lidocaine have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine. In a published study, lidocaine administered to pregnant rats by continuous subcutaneous infusion during the period of organogenesis at 100, 250, and 500 mg/kg/day, did not produce any structural abnormalities, but did result in lower fetal weights at 500 mg/kg/day dose (approximately 9.7 times the maximum daily dose [MDD] of 500 mg on a mg/m2 basis) in the absence of maternal toxicity. In a published study, lidocaine containing 1:100,000 epinephrine at a dose of 6 mg/kg (approximately 0.1 times the MDD for lidocaine on a mg/m2 basis) injected into the masseter muscle of the jaw or into the gum of the lower jaw of pregnant Long-Evans hooded rats on Gestation Day 11 resulted in developmental delays in the neonates. Developmental delays were observed for negative geotaxis, static righting reflex, visual discrimination response, sensitivity and response to thermal and electrical shock stimuli, and water maze acquisition. The developmental delays of the neonatal animals were transient, with responses becoming comparable to untreated animals later in life. The clinical relevance of these animal data is uncertain.

visual discrimination response, sensitivity and response to thermal and electrical shock stimuli, and water maze acquisition. The developmental delays of the neonatal animals were transient, with responses becoming comparable to untreated animals later in life. The clinical relevance of these animal data is uncertain. 8.2 Lactation Risk Summary Published data report the presence of lidocaine and its metabolites in human milk in low amounts, along with poor oral bioavailability. There are no data on the effect of lidocaine on the breastfed infant or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FLAVALTA and any potential adverse effects on the breastfed child from FLAVALTA or from the underlying maternal condition. 8.4 Pediatric Use Dosages in pediatric population should be reduced, commensurate with body weight and physical condition [see Dosage and Administration (2.2) ] . 8.5 Geriatric Use Elderly patients should be given reduced doses commensurate with their age and physical condition. 8.6 Hepatic Impairment Amide-type local anesthetics such as lidocaine are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment treated with FLAVALTA, especially with repeat doses [see Warnings and Precautions (5.5) ]

10 OVERDOSAGE 10.1 Clinical Presentation Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution [see Warnings and Precautions (5) , Adverse Reactions (6) ]. If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of lidocaine may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts. 10.2 Management of local anesthetic emergencies The first step in the management of systemic toxic reactions consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated. A bolus intravenous dose of a benzodiazepine will counteract central nervous system stimulation related to FLAVALTA. Immediately after the institution of ventilatory measures, evaluate the adequacy of circulation. Supportive treatment of circulatory depression may require Advanced Cardiac Life Support measures.

11 DESCRIPTION FLAVALTA is a clear and colorless sterile isotonic solution containing a local anesthetic agent, Lidocaine Hydrochloride, and a vasoconstrictor, Epinephrine (as bitartrate) and is administered parenterally by injection. FLAVALTA is available in single dose cartridges of 1.7 mL [see Indications and Usage (1) ]. FLAVALTA solution contains lidocaine hydrochloride which is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-monohydrochloride, and has the following structural formula: C 14 H 22 N 2 0 • HCl • H 2 0 M.W. 288.8 Epinephrine is ( - )-3,4-Dihydroxy- α -[(Methylamino) methyl] benzyl alcohol and has the following structural formula: C 9 H 13 NO 3 M.W. 183.21 Each mL of FLAVALTA contains 20 mg lidocaine hydrochloride (equivalent to 17.31 mg lidocaine), and 0.01 mg epinephrine (equivalent to 0.018 mg epinephrine bitartrate) with 0.25 mg edetate disodium, 1.2 mg potassium metabisulfite, 6.5 mg sodium chloride and 1 mL water for injections q.s. ad. The flavoring agents are 20.0 mg L-serine and 0.9 mg sodium saccharin. The pH of the FLAVALTA solution is adjusted with sodium hydroxide to 3.3 – 5.5. Lidocaine Hydrochloride Epinephrine

12 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.

al/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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of lidocaine and epinephrine. Mutagenesis The mutagenic potential of lidocaine and epinephrine has not been determined. Impairment of Fertility In a published study, female Sprague-Dawley rats were treated subcutaneously with lidocaine via osmotic pumps starting two weeks prior to mating, and reproductive effects were assessed. Rat doses up to the high dose of 500 mg/kg/day (approximately 9.7 times the maximum daily dose of 500 mg on a mg/m2 basis) showed no effects on copulatory rate, pregnancy rate, or the numbers of corpora lutea or implantations.

16 HOW SUPPLIED/STORAGE AND HANDLING FLAVALTA (lidocaine hydrochloride and epinephrine injection) contains lidocaine hydrochloride 2% (34 mg/1.7 mL) (20 mg/mL) and epinephrine 1:100,000 (0.017 mg/1.7 mL) (0.01 mg/mL) supplied in cardboard boxes containing five blisters of ten 1.7 mL single-dose cartridges. The solution is clear and colorless (NDC is 0362-1200-50). Store at 20° - 25°C (68° - 77°F). Excursions between 15° and 30°C (59° and 86°F) are allowed. Protect from light. Do not freeze. BOXES: For protection from light, retain in box until time of use. Once opened, the box should be reclosed by closing the end flap. Do not use if color is pinkish or darker than slightly yellow or if it contains a precipitate. Sterilization Storage and Technical Procedures Cartridges should not be autoclaved, because the closures employed cannot withstand autoclaving temperatures and pressures. If chemical disinfection of anesthetic cartridges is desired, either isopropyl alcohol (91%) or 70% ethyl alcohol is recommended. Many commercially available brands of rubbing alcohol, as well as solution of ethyl alcohol not of U.S.P grade, contain denaturants that are injurious to rubber and, therefore, are not to be used. It is recommended that chemical disinfection be accomplished just prior to use by wiping the cartridge cap thoroughly with a pledge of cotton that has been moistened with recommended alcohol. Certain metallic ions (mercury, zinc, copper, etc.) have been related to swelling and edema after local anesthesia in dentistry. Therefore, chemical disinfectants containing or releasing these ions are not recommended. Antirust tablets usually contain sodium nitrite or some similar agents that may be capable of releasing metal ions. Because of this, aluminium sealed cartridges should not be kept in such solution. Quaternary ammonium salts, such as benzalkonium chloride, are electrolytically incompatible with aluminium. Cartridges of FLAVALTA are sealed with aluminium caps and therefore should not be immersed in any solution containing these salts. To avoid leakage of solution during injection, be sure to penetrate the center of the rubber diaphragm when loading the syringe. An off-center penetration produces an oval shaped puncture that allows leakage around the needle. Other causes of leakage and breakage include badly worn syringes, aspirating syringes with bent harpoons, the use of syringes not designed to take 1.7 mL cartridges, and inadvertent freezing. Cracking of glass cartridges is most often the result of an attempt to use a cartridge with an extruded plunger. An extruded plunger loses its lubrication and can be forced back into the cartridge only with difficulty. Cartridges with extruded plungers should be discarded. Store at 20° - 25°C (68° - 77°F). Excursions between 15° and 30°C (59° and 86°F) are allowed.

17 PATIENT COUNSELING INFORMATION Allergic-Type Reactions Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the sulfites in epinephrine-containing solutions [see Contraindications (4) , Warnings and Precautions (5.4) , Adverse Reactions (6) ]. Instructions after FLAVALTA injection The patient should be informed of the possibility of temporary loss of sensation and muscle function following infiltration or nerve block injections. Advise patients not to chew solid foods or to test the anesthetized area by biting or probing until anesthesia has worn off (approximately 3 to 3.5 hours) to avoid inadvertent trauma to the lips, tongue, cheek mucosae or soft palate when these structures are anesthetized. Methemoglobinemia Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see Warnings and Precautions (5.2) ]. Manufactured for SEPTODONT, Inc., 205 Granite Run Dr., Suite 150, Lancaster, PA, USA 17601 by Novocol Pharmaceutical of Canada, Inc., 25 Wolseley Court, Cambridge, Ontario, Canada N1R 6X3 Rev. 03/2026 (20060-1)