Lidocaine Hydrochloride

1 INDICATIONS AND USAGE Lidocaine Hydrochloride Injection, USP 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 Injection, USP is recommended for each type of block indicated to produce local or regional anesthesia or analgesia [see Dosage and Administration ( 2.2 )] .

2 DOSAGE AND ADMINISTRATION 2.1 Important Dosage and Administration Information Lidocaine Hydrochloride Injection, USP is not recommended for intrathecal use. Avoid use of Lidocaine Hydrochloride Injection, USP 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 Injection, USP are clear, colorless 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 Injection, USP is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions Lidocaine Hydrochloride Injection, USP 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 Injection, USP 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 Injection, USP [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 Injection, USP, 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 Injection, USP 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 Injection, USP 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 Injection, USP 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 Dosages of Lidocaine Hydrochloride Injection, USP in Adults The dosage of Lidocaine Hydrochloride Injection, USP 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 …

MAXIMUM RECOMMENDED DOSAGES Normal Healthy Adults The maximum recommended dose of Lidocaine Hydrochloride Topical Solution, USP 4% should be such that the dose of lidocaine hydrochloride is kept below 300 mg and in any case should not exceed 4.5 mg/kg (2 mg/lb) body weight. Children It is difficult to recommend a maximum dose of any drug for children since this varies as a function of age and weight. For children of less than ten years who have a normal lean body mass and normal body development, the maximum dose may be determined by the application of one of the standard pediatric drug formulas (e.g., Clark's rule). For example, in a child of five years weighing 50 lbs., the dose of lidocaine hydrochloride should not exceed 75 to 100 mg when calculated according to Clark's rule. In any case, the maximum dose of Lidocaine Hydrochloride with epinephrine should not exceed 7 mg/kg (3.2 mg/lb) of body weight. When used without epinephrine, the amount of Lidocaine Hydrochloride administered should be such that the dose of lidocaine is kept below 300 mg and in any case should not exceed 4.5 mg/kg (2 mg/lb) of body weight.

Normal Healthy Adults The maximum recommended dose of Lidocaine Hydrochloride Topical Solution, USP 4% should be such that the dose of lidocaine hydrochloride is kept below 300 mg and in any case should not exceed 4.5 mg/kg (2 mg/lb) body weight.

Children It is difficult to recommend a maximum dose of any drug for children since this varies as a function of age and weight. For children of less than ten years who have a normal lean body mass and normal body development, the maximum dose may be determined by the application of one of the standard pediatric drug formulas (e.g., Clark's rule). For example, in a child of five years weighing 50 lbs., the dose of lidocaine hydrochloride should not exceed 75 to 100 mg when calculated according to Clark's rule. In any case, the maximum dose of Lidocaine Hydrochloride with epinephrine should not exceed 7 mg/kg (3.2 mg/lb) of body weight. When used without epinephrine, the amount of Lidocaine Hydrochloride administered should be such that the dose of lidocaine is kept below 300 mg and in any case should not exceed 4.5 mg/kg (2 mg/lb) of body weight.

4 CONTRAINDICATIONS Lidocaine Hydrochloride Injection, USP 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 Injection, USP.

6 ADVERSE REACTIONS The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions 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 Injection, USP 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. In addition to systemic does-related toxicity, unintentional intrathecal injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) has resulted in underventilation or apnea (“Total or High Spinal”). Also, hypertension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia have occurred. This has led to secondary cardiac arrest when untreated. When used for dental injections, paresthesia of the lips, tongue, and oral tissues have been reported. Persistent paresthesia lasting weeks to months and, in some instances, lasting greater than one year, have also been reported. Nervous System Disorders Adverse reactions were characterized by excitation and/or depression of the central nervous system and included lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. In a prospective review of 10,440 patients who received lidocaine hydrochloride for spinal anesthesia, the incidences of adverse reactions were reported to be about 3 percent each for positional headaches, hypotension and backache; 2 percent for shivering; and less than 1 percent each for peripheral nerve symptoms, nausea, respiratory inadequacy and double vision. Persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances when caudal or lumbar epidural block has been attempted. Backache and headache have also been noted following use of these anesthetic procedures. There …

7 DRUG INTERACTIONS 7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with Lidocaine Hydrochloride Injection, USP 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 Injection, USP with 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 situation 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 Injection, USP with Epinephrine concomitantly with ergot-type oxytocic drugs [see Warnings and Precautions ( 5.5 )] . 7.4 Nonselective Beta-Adrenergic Antagonists Administration of Lidocaine Hydrochloride Injection, USP with 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 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 Injection, USP with Epinephrine) 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 Injection, USP with Epinephrine and these agents should generally be avoided. In situation when concurrent therapy is necessary, careful patient monitoring is essential.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available published data and decades of clinical use with Lidocaine Hydrochloride Injection, USP 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 Injection, USP 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. 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 develop …

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 Injection, USP 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.

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.

11 DESCRIPTION: Lidocaine Hydrochloride Injection, USP contains lidocaine hydrochloride, an amide local anesthetic, as the active pharmaceutical ingredient. The route of administration for Lidocaine Hydrochloride Injection, USP is by injection, for infiltration, nerve block, epidural and caudal use. Multiple dose vials contain methylparaben and they should not be used for caudal and lumbar epidural blocks. Dosage forms listed as Lidocaine Hydrochloride Injection-Methylparaben Free indicate single-dose solutions that are Methylparaben Free (MPF). Lidocaine hydrochloride, is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-, monohydrochloride monohydrate and has the molecular weight of 288.8 g/mol. Lidocaine hydrochloride molecular formula is C 14 H 22 N 2 O • HCl•H 2 O, and has the following structural formula: Lidocaine Hydrochloride Injection, USP in multiple dose vials is a sterile, nonpyrogenic, isotonic, clear, colorless solution containing lidocaine hydrochloride and sodium chloride. Each mL contains 1 mg methylparaben as an antiseptic preservative. The pH of these solutions is adjusted to approximately 6.5 (5.0 to 7.0) with sodium hydroxide and hydrochloric acid. Ingredients Strength 1% 2% Amount (Per mL) Amount (Per mL) Lidocaine Hydrochloride (Anhydrous) 10 mg* 20 mg£ Sodium Chloride 7 mg 6 mg Methylparaben 1 mg 1 mg Sodium Hydroxide Added for pH Adjustment to approximately 6.5 (5.0 to 7.0) Hydrochloric Acid * Quantity is equivalent to 10.7 mg/ mL Lidocaine Hydrochloride, USP (Monohydrate). £ Quantity is equivalent to 21.3 mg/ mL Lidocaine Hydrochloride, USP (Monohydrate). Lidocaine Hydrochloride Injection, USP-Methylparaben Free is a sterile, nonpyrogenic, isotonic, clear, colorless, and preservative-free solution. The pH of these solutions is adjusted to approximately 6.5 (5.0 to 7.0) with sodium hydroxide and hydrochloric acid. Ingredients Strength 1% 2% Amount (Per mL) Amount (Per mL) Lidocaine Hydrochloride (Anhydrous) 10 mg* 20 mg£ Sodium Chloride 7 mg 6 mg Sodium Hydroxide Added for pH Adjustment to approximately 6.5 (5.0 to 7.0) Hydrochloric Acid figure 1

OVERDOSAGE Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics. (see ADVERSE REACTIONS , WARNINGS , and PRECAUTIONS ). Management of Local Anesthetic Emergencies 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 administration. At the first sign of change, oxygen should be administered. The first step in the management of convulsions 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, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to 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. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine. The intravenous LD 50 of lidocaine hydrochloride in female mice is 26 (21 to 31) mg/kg and the subcutaneous LD 50 is 264 (203 to 304) mg/kg.

Management of Local Anesthetic Emergencies 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 administration. At the first sign of change, oxygen should be administered. The first step in the management of convulsions 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, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to 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. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine. The intravenous LD 50 of lidocaine hydrochloride in female mice is 26 (21 to 31) mg/kg and the subcutaneous LD 50 is 264 (203 to 304) mg/kg.

HOW SUPPLIED Lidocaine Hydrochloride Topical Solution, USP 4% is supplied in 50 mL bottle (NDC 0116-4025-50) and packaged in a carton (NDC 0116-4025-50). An aqueous solution for topical application. NOT FOR INJECTION. RECOMMENDED STORAGE RECOMMENDED STORAGE Store at 20 ° to 25 °C (68 ° to 77 °F) [see USP Controlled Room Temperature]. AVOID FREEZING Rx Only Product No.: 4025 Manufactured By: GROUPE PARIMA Inc. 4450 Cousens Montreal, Quebec, Canada H4S 1X6 Manufactured For: Xttrium Laboratories, Inc. 1200 E. Business Center Dr. Mount Prospect, IL 60056 4025LIDOINST REV. 03-25

RECOMMENDED STORAGE RECOMMENDED STORAGE Store at 20 ° to 25 °C (68 ° to 77 °F) [see USP Controlled Room Temperature]. AVOID FREEZING Rx Only Product No.: 4025 Manufactured By: GROUPE PARIMA Inc. 4450 Cousens Montreal, Quebec, Canada H4S 1X6 Manufactured For: Xttrium Laboratories, Inc. 1200 E. Business Center Dr. Mount Prospect, IL 60056 4025LIDOINST REV. 03-25