5 ML lidocaine hydrochloride 20 MG/ML Injection

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 are recommended for each type of block indicated to produce local or regional anesthesia or analgesia [see Dosage and Administration (2.2)] . Lidocaine Hydrochloride Injection, USP contains lidocaine, an amide local anesthetic 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. For each type of block indicated to produce local or regional anesthesia or analgesia, specific concentrations and presentations are recommended. (1, 2.2) 1.1 Hypertension Amlodipine and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.

DOSAGE AND ADMINISTRATION Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of Lidocaine Hydrochloride Injection, USP for various types of anesthetic procedures. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. When larger volumes are required only solutions containing epinephrine should be used, except in those cases where vasopressor drugs may be contraindicated. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Lidocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION ). These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures. The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient. In all cases the lowest concentration and smallest dose that will produce the desired result should be given. Dosages should be reduced for children and for elderly and debilitated patients and patients with cardiac and/or liver disease. The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (i.e., total dose) of local anesthetic used. Thus, an increase in volume and concentration of Lidocaine Hydrochloride Injection will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia. However, increasing the volume and concentration of Lidocaine Hydrochloride Injection may result in a more profound fall in blood pressure when used in epidural anesthesia. Although the incidence of side effects with lidocaine is quite low, caution should be exercised when employing large volumes and concentrations, since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected. For intravenous regional anesthesia, only the 50 mL single-dose vial containing 0.5% Lidocaine Hydrochloride Injection, USP should be used. Epidural Anesthesia For epidural anesthesia, only the following available specific products of Lidocaine Hydrochloride Injection by Hospira are recommended: 1%. . . . . . . . . . . . . . . . . . . . 30 mL single-dose teartop vials 1.5%. . . . . . . . . . . . . . . . . . . . . . . 20 mL single-dose ampuls 2%. . . . . . . . . . . . . . . . . . . . . . . . . 10 mL single-dose ampuls Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block provided they are employed as single dose units. These solutions contain no bacteriostatic agent. In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2−3 mL of the indicated concentration per dermatome). Caudal and Lumbar Epidural Block: As a precaution against the adverse experiences sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2−3 mL of 1.5% lidocaine hydrochloride should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block. The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter. Epinephrine, if contained in the test dose (10−15 mcg have been suggested), may serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient "epinephrine response" within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure. Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of Lidocaine Hydrochloride Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered. In the event of the known injection of a large volume of local anesthetic solutions into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter. Maximum Recommended Dosages NOTE: The products accompanying this insert do not contain epinephrine. Adults: For normal healthy adults, the individual maximum recommended dose of lidocaine HCl with epinephrine should not exceed 7 mg/kg (3.5 mg/lb) of body weight and in general it is recommended that the maximum total dose not exceed 500 mg. When used without epinephrine, the maximum individual dose should not exceed 4.5 mg/kg (2 mg/lb) of body weight and in general it is recommended that the maximum total dose does not exceed 300 mg. For continuous epidural or caudal anesthesia, the maximum recommended dosage should not be administered at intervals of less than 90 minutes. When continuous lumbar or caudal epidural anesthesia is used for non-obstetrical procedures, more drug may be administered if required to produce adequate anesthesia. The maximum recommended dose per 90 minute period of lidocaine hydrochloride for paracervical block in obstetrical patients and non-obstetrical patients is 200 mg total. One-half of the total dose is usually administered to each side. Inject slowly five minutes between sides. (See also discussion of paracervical block in PRECAUTIONS ). For intravenous regional anesthesia, the dose administered should not exceed 4 mg/kg in adults. Children: It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight. For example, in a child of 5 years weighing 50 lbs., the dose of lidocaine HCl should not exceed 75 — 100 mg (1.5 — 2 mg/lb). The use of even more dilute solutions (i.e., 0.25 — 0.5%) and total dosages not to exceed 3 mg/kg (1.4 mg/lb) are recommended for induction of intravenous regional anesthesia in children. In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. In some cases it will be necessary to dilute available concentrations with 0.9% sodium chloride injection in order to obtain the required final concentration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions that are discolored and/or contain particulate matter should not be used. Table 1 Recommended Dosages of Lidocaine Hydrochloride Injection, USP for Various Anesthetic Procedures in Normal Healthy Adults Lidocaine Hydrochloride Injection, USP (without Epinephrine) Procedure Conc. (%) Vol. (mL) Total Dose (mg) Infiltration Percutaneous 0.5 or 1.0 1−60 5−300 Intravenous Regional 0.5 10−60 50−300 Peripheral Nerve Blocks, e.g. Brachial 1.5 15−20 225−300 Dental 2.0 1−5 20−100 Intercostal 1.0 3 30 Paravertebral 1.0 3−5 30−50 Pudendal (each side) 1.0 10 100 Paracervical Obstetrical Analgesia (each side) 1.0 10 100 Sympathetic Nerve Blocks, e.g. Cervical (stellate ganglion) 1.0 5 50 Lumbar 1.0 5−10 50−100 Central Neural Blocks Epidural* Thoracic 1.0 20−30 200−300 Lumbar Analg

WARNINGS AND PRECAUTIONS Dose-Related Toxicity : Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after injection of lidocaine hydrochloride (5.1) Methemoglobinemia: Casesofmethemoglobinemiahavebeenreportedinassociationwithlocalanestheticsuse.Seefullprescribinginformationformore 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) Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal I njection : 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 (5.7) 5.1 Dose-Related Toxicity The safety and effectiveness of Lidocaine Hydrochloride 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 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 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 Injection solution and administer fractional (incremental) doses when feasible. Injection of repeated doses of Lidocaine Hydrochloride 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 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 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 Injection Risk of Severe, Persistent Hypertension Due to Drug Interactions Between Lidocaine Hydrochloride Injection and Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Administration of Lidocaine Hydrochloride 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 Injection and Ergot-Type Oxytocic Drugs Concurrent administration of Lidocaine Hydrochloride Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of Lidocaine Hydrochloride Injection concomitantly with ergot-type oxytocic drugs [see Drug Interactions (7.3) ]. Risk of Hypertension and Bradycardia Due to Drug Interactions Between Lidocaine Hydrochloride Injection and Nonselective Beta-Adrenergic Antagonists Administration of Lidocaine Hydrochloride 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 Injection and Anaphylactic Reactions Lidocaine Hydrochloride Injection without epinephrine does not contain sodium metabisulfite. 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 Injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Unintentional intrathecal injecti

CONTRAINDICATIONS Known hypersensitivity to any local anesthetic agent of the amide-type or to other components of GLYDO 2% Jelly ( 4.1 ) Infected and/or Severely Traumatized Mucosa ( 4.2 ) Severe shock or heart block ( 4.3 ) 4.1 Hypersensitivity GLYDO 2% Jelly is contraindicated in patients with a known history of hypersensitivity to lidocaine or to any local anesthetics of the amide type or to other components of GLYDO 2% Jelly. 4.2 Use on Infected and/or Severely Traumatized Mucosa GLYDO 2% Jelly should not be used on infected and/or severely traumatized mucosa in the area of application. 4.3 Use in Severe Shock or Heart Block GLYDO 2% Jelly should not be used in patients with severe shock or heart block.

CLINICAL PHARMACOLOGY Mechanism of Action: Lidocaine and prilocaine cream, applied to intact skin under occlusive dressing, provides dermal analgesia by the release of lidocaine and prilocaine from the cream into the epidermal and dermal layers of the skin and by the accumulation of lidocaine and prilocaine in the vicinity of dermal pain receptors and nerve endings. Lidocaine and prilocaine are amide-type local anesthetic agents. Both lidocaine and prilocaine stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. The onset, depth and duration of dermal analgesia on intact skin provided by lidocaine and prilocaine cream depends primarily on the duration of application. To provide sufficient analgesia for clinical procedures such as intravenous catheter placement and venipuncture, lidocaine and prilocaine cream should be applied under an occlusive dressing for at least 1 hour. To provide dermal analgesia for clinical procedures such as split skin graft harvesting, lidocaine and prilocaine cream should be applied under occlusive dressing for at least 2 hours. Satisfactory dermal analgesia is achieved 1 hour after application, reaches maximum at 2 to 3 hours, and persists for 1 to 2 hours after removal. Absorption from the genital mucosa is more rapid and onset time is shorter (5 to 10 minutes) than after application to intact skin. After a 5 to 10 minute application of lidocaine and prilocaine cream to female genital mucosa, the average duration of effective analgesia to an argon laser stimulus (which produced a sharp, pricking pain) was 15 to 20 minutes (individual variations in the range of 5 to 45 minutes). Dermal application of lidocaine and prilocaine cream may cause a transient, local blanching followed by a transient, local redness or erythema. Pharmacokinetics Lidocaine and prilocaine cream is a eutectic mixture of lidocaine 2.5% and prilocaine 2.5% formulated as an oil in water emulsion. In this eutectic mixture, both anesthetics are liquid at room temperature (see DESCRIPTION) and the penetration and subsequent systemic absorption of both prilocaine and lidocaine are enhanced over that which would be seen if each component in crystalline form was applied separately as a 2.5% topical cream. Absorption: The amount of lidocaine and prilocaine systemically absorbed from lidocaine and prilocaine cream is directly related to both the duration of application and to the area over which it is applied. In two pharmacokinetic studies, 60 g of lidocaine and prilocaine cream (1.5 g lidocaine and 1.5 g prilocaine) was applied to 400 cm 2 of intact skin on the lateral thigh and then covered by an occlusive dressing. The subjects were then randomized such that one-half of the subjects had the occlusive dressing and residual cream removed after 3 hours, while the remainder left the dressing in place for 24 hours. The results from these studies are summarized below. TABLE 1 Absorption of Lidocaine and Prilocaine from Lidocaine and Prilocaine Cream: Normal Volunteers (N=16 ) Lidocaine and Prilocaine Cream (g) Area (cm 2 ) Time On (hrs) Drug Content (mg) Absorbed (mg) C max (mcg/mL) T max (hr) 60 400 3 lidocaine 1500 54 0.12 4 prilocaine 1500 92 0.07 4 60 400 24* lidocaine 1500 243 0.28 10 prilocaine 1500 503 0.14 10 *Maximum recommended duration of exposure is 4 hours. When 60 g of lidocaine and prilocaine cream was applied over 400 cm 2 for 24 hours, peak blood levels of lidocaine are approximately 1/20 the systemic toxic level. Likewise, the maximum prilocaine level is about 1/36 the toxic level. In a pharmacokinetic study, lidocaine and prilocaine cream was applied to penile skin in 20 adult male patients in doses ranging from 0.5 g to 3.3 g for 15 minutes. Plasma concentrations of lidocaine and prilocaine following lidocaine and prilocaine cream application in this study were consistently low (2.5 to 16 ng/mL for lidocaine and 2.5 to 7 ng/mL for prilocaine). The application of lidocaine and prilocaine cream to broken or inflamed skin, or to 2,000 cm 2 or more of skin where more of both anesthetics are absorbed, could result in higher plasma levels that could, in susceptible individuals, produce a systemic pharmacologic response. The absorption of lidocaine and prilocaine cream applied to genital mucous membranes was studied in two open-label clinical trials. Twenty-nine patients received 10 g of lidocaine and prilocaine cream applied for 10 to 60 minutes in the vaginal fornices. Plasma concentrations of lidocaine and prilocaine following lidocaine and prilocaine cream application in these studies ranged from 148 to 641 ng/mL for lidocaine and 40 to 346 ng/mL for prilocaine and time to reach maximum concentration (t max ) ranged from 21 to 125 minutes for lidocaine and from 21 to 95 minutes for prilocaine. These levels are well below the concentrations anticipated to give rise to systemic toxicity (approximately 5000 ng/mL for lidocaine and prilocaine). Distribution: When each drug is administered intravenously, the steady-state volume of distribution is 1.1 to 2.1 L/kg (mean 1.5, ±0.3 SD, n=13) for lidocaine and is 0.7 to 4.4 L/kg (mean 2.6, ±1.3 SD, n=13) for prilocaine. The larger distribution volume for prilocaine produces the lower plasma concentrations of prilocaine observed when equal amounts of prilocaine and lidocaine are administered. At concentrations produced by application of lidocaine and prilocaine cream, lidocaine is approximately 70% bound to plasma proteins, primarily alpha-1-acid glycoprotein. At much higher plasma concentrations (1 to 4 mcg/mL of free base) the plasma protein binding of lidocaine is concentration dependent. Prilocaine is 55% bound to plasma proteins. Both lidocaine and prilocaine cross the placental and blood brain barrier, presumably by passive diffusion. Metabolism: It is not known if lidocaine or prilocaine are metabolized in the skin. Lidocaine is metabolized rapidly by the liver to a number of metabolites including monoethylglycinexylidide (MEGX) and glycinexylidide (GX), both of which have pharmacologic activity similar to, but less potent than that of lidocaine. The metabolite, 2,6-xylidine, has unknown pharmacologic activity. Following intravenous administration, MEGX and GX concentrations in serum range from 11 to 36% and from 5 to 11% of lidocaine concentrations, respectively. Prilocaine is metabolized in both the liver and kidneys by amidases to various metabolites including ortho -toluidine and N-n-propylalanine. It is not metabolized by plasma esterases. The ortho -toluidine metabolite has been shown to be carcinogenic in several animal models (see Carcinogenesis subsection of PRECAUTIONS). In addition, ortho -toluidine can produce methemoglobinemia following systemic doses of prilocaine approximating 8 mg/kg (see ADVERSE REACTIONS). Very young patients, patients with glucose-6-phosphate dehydrogenase deficiencies and patients taking oxidizing drugs such as antimalarials and sulfonamides are more susceptible to methemoglobinemia (see Methemoglobinemia subsection of PRECAUTIONS). Elimination: The terminal elimination half-life of lidocaine from the plasma following IV administration is approximately 65 to 150 minutes (mean 110, ±24 SD, n=13). More than 98% of an absorbed dose of lidocaine can be recovered in the urine as metabolites or parent drug. The systemic clearance is 10 to 20 mL/min/kg (mean 13, ±3 SD, n=13). The elimination half-life of prilocaine is approximately 10 to 150 minutes (mean 70, ±48 SD, n=13). The systemic clearance is 18 to 64 mL/min/kg (mean 38, ±15 SD, n=13). During intravenous studies, the elimination half-life of lidocaine was statistically significantly longer in elderly patients (2.5 hours) than in younger patients (1.5 hours). No studies are available on the intravenous pharmacokinetics of prilocaine in elderly patients. Pediatrics: Some pharmacokinetic (PK) data are available i