Bupivacine Hydrochloride

Indications and Usage MARCAINE / MARCAINE WITH EPINEPHRINE is indicated in adults 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 MARCAINE / MARCAINE WITH EPINEPHRINE are recommended for each type of block indicated to produce local or regional anesthesia or analgesia [see Dosage and Administration (2.2)]. Limitations of Use Not all blocks are indicated for use with MARCAINE / MARCAINE WITH EPINEPHRINE given clinically significant risks associated with use [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1, 5.4, 5.5, 5.7, 5.9)]. MARCAINE contains bupivacaine, an amide local anesthetic, and MARCAINE WITH EPINEPHRINE is a combination of bupivacaine, an amide local anesthetic, and epinephrine, an alpha and beta-adrenergic agonist. MARCAINE / MARCAINE WITH EPINEPHRINE is indicated in adults 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) Limitations of Use Not all blocks are indicated for use with MARCAINE / MARCAINE WITH EPINEPHRINE given clinically significant risks associated with use. (1, 2.2, 4, 5.1, 5.4, 5.5, 5.7, 5.9)

Dosage and Administration 2.1 Important Dosage and Administration Information •MARCAINE / MARCAINE WITH EPINEPHRINE is not for intrathecal use. •Avoid use of MARCAINE / MARCAINE WITH EPINEPHRINE solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [see Warnings and Precautions (5.4)]. •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. MARCAINE / MARCAINE WITH EPINEPHRINE are clear, colorless solutions. Do not administer solutions which are discolored or contain particulate matter. •Mixing or the prior or intercurrent use of any other local anesthetic with MARCAINE / MARCAINE WITH EPINEPHRINE is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions •MARCAINE / MARCAINE WITH EPINEPHRINE are 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 MARCAINE / MARCAINE WITH EPINEPHRINE 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 (5.2), 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 MARCAINE / MARCAINE WITH EPINEPHRINE [see Warnings and Precautions (5.2), Drug Interactions (7.1), Overdosage (10)]. •Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting MARCAINE / MARCAINE WITH EPINEPHRINE, 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 (5.9)]. •Avoid rapid injection of a large volume of MARCAINE / MARCAINE WITH EPINEPHRINE 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 MARCAINE / MARCAINE WITH EPINEPHRINE 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 MARCAINE WITH EPINEPHRINE 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 (5.12)]. 2.2 Recommended Concentrations and Dosages of MARCAINE / MARCAINE WITH EPINEPHRINE The dosage of MARCAINE / MARCAINE WITH EPINEPHRINE 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 MARCAINE / MARCAINE WITH EPINEPHRINE concentrations are shown in Table 1. At recommended dosages, MARCAINE / MARCAINE WITH EPINEPHRINE produces complete sensory block, but the effect on motor function differs among the three concentrations. Table 2 provides information on the expected effect on motor function for the three concentrations. The duration of anesthesia with MARCAINE / MARCAINE WITH EPINEPHRINE is such that for most indications, a single dose is sufficient. 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. The dosages in Table 3 are recommended as a guide for use in the average adult. These doses may be repeated once every three hours. Do not exceed a total daily dosage of 400 mg in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine. 2.3 Use in Epidural Anesthesia During the administration of epidural anesthesia, it is recommended that a test dose of MARCAINE WITH EPINEPHRINE without antimicrobial preservative (0.5% bupivacaine 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 MARCAINE / MARCAINE WITH EPINEPHRINE, 0.5% (5 mg/mL) and MARCAINE 0.75% (7.5 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. In obstetrics, use ONLY the 0.5% (5 mg/mL) and 0.25% (2.5 mg/mL) concentrations of MARCAINE / MARCAINE WITH EPINEPHRINE [see Warnings and Precautions (5.1)] ; incremental doses of 3 mL to 5 mL of the 0.5% (5 mg/mL) solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses 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 (5.4, 5.9)]. 2.4 Test Dose for Caudal and Lumbar Epidural Blocks Three mL of MARCAINE WITH EPINEPHRINE without antimicrobial preservative (0.5% bupivacaine 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 (5.9)]. 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 (5.2, 5.9), Overdosage (10)]. 2.5 Use in Dentistry MARCAINE WITH EPINEPHRINE 0.5% (5 mg/mL) is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthesia is desired, such as for procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after allowing 2 to 10 minutes for block onset [see Clinical Pharmacology (12.2

Boxed Warning WARNING: RISK OF CARDIAC ARREST WITH USE OF MARCAINE IN OBSTETRICAL ANESTHESIA There have been reports of cardiac arrest with difficult resuscitation or death during use of MARCAINE for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of MARCAINE is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary [see Warnings and Precautions (5.1)]. WARNING: RISK OF CARDIAC ARREST WITH USE OF MARCAINE IN OBSTETRICAL ANESTHESIA See full prescribing information for complete boxed warning. There have been reports of cardiac arrest with difficult resuscitation or death during use of MARCAINE for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of MARCAINE is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary (5.1). 5 Warnings and Precautions 5.1 Risk of Cardiac Arrest with Use of MARCAINE in Obstetrical Anesthesia There have been reports of cardiac arrest with difficult resuscitation or death during use of MARCAINE for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of MARCAINE is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary. 5.2 Dose-Related Toxicity The safety and effectiveness of MARCAINE / MARCAINE WITH EPINEPHRINE 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 MARCAINE / MARCAINE WITH EPINEPHRINE 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 MARCAINE / MARCAINE WITH EPINEPHRINE that results in effective anesthesia to avoid high plasma levels and serious adverse effects. Avoid rapid injection of a large volume of MARCAINE / MARCAINE WITH EPINEPHRINE solution and administer fractional (incremental) doses when feasible. Injection of repeated doses of MARCAINE / MARCAINE WITH EPINEPHRINE 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. 5.3 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/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious CNS and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue MARCAINE / MARCAINE WITH EPINEPHRINE 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. 5.4 Antimicrobial Preservatives in Multiple-Dose Vials Avoid use of MARCAINE / MARCAINE WITH EPINEPHRINE 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. 5.5 Chondrolysis with Intra-Articular Infusion Intra-articular infusions of local anesthetics including MARCAINE 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 associated with chondrolysis. 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. 5.6 Risk of Adverse Reactions Due to Drug Interactions with MARCAINE WITH EPINEPHRINE Risk of Severe, Persistent Hypertension Due to Drug Interactions Between MARCAINE WITH EPINEPHRINE and Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Administration of MARCAINE WITH EPINEPHRINE (containing a vasoconstrictor) 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 MARCAINE WITH EPINEPHRINE and Ergot-Type Oxytocic Drugs Concurrent administration of MARCAINE WITH EPINEPHRINE and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

Contraindications MARCAINE / MARCAINE WITH EPINEPHRINE is contraindicated in: •obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. •intravenous regional anesthesia (Bier Block) [see Warnings and Precautions (5.7)]. •patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of MARCAINE / MARCAINE WITH EPINEPHRINE. Obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. (4) Intravenous regional anesthesia (Bier Block). (4) Known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of MARCAINE / MARCAINE WITH EPINEPHRINE. (4)

Drug Interactions 7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with MARCAINE / MARCAINE WITH EPINEPHRINE 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 (5.2)]. 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants The administration of MARCAINE 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 situations when concurrent therapy is necessary, careful monitoring of the patient's hemodynamic status is essential [see Warnings and Precautions (5.6)]. 7.3 Ergot-Type Oxytocic Drugs Concurrent administration of MARCAINE WITH EPINEPHRINE and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of MARCAINE WITH EPINEPHRINE concomitantly with ergot-type oxytocic drugs [see Warnings and Precautions (5.6)]. 7.4 Nonselective Beta-Adrenergic Antagonists Administration of MARCAINE WITH EPINEPHRINE (containing a vasoconstrictor) 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 (5.6)]. 7.5 Drugs Associated with Methemoglobinemia Patients who are administered MARCAINE / MARCAINE WITH EPINEPHRINE are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions (5.3)]. 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., MARCAINE WITH EPINEPHRINE) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13)]. 7.7 Phenothiazines and Butyrophenones Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of MARCAINE 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 MARCAINE 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. (5.6, 7.2) Ergot-Type Oxytocic Drugs : Concurrent administration of MARCAINE WITH EPINEPHRINE and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. (5.6, 7.3) Nonselective Beta-Adrenergic Antagonists : Administration of MARCAINE WITH EPINEPHRINE (containing a vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. (5.6, 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. (5.13, 7.6) Image5.jpg

Adverse Reactions The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling: •Cardiac Arrest in Obstetrical Anesthesia [see Warnings and Precautions (5.1)] •Dose-Related Toxicity [see Warnings and Precautions (5.2)] •Methemoglobinemia [see Warnings and Precautions (5.3)] •Chondrolysis with Intra-Articular Infusion [see Warnings and Precautions (5.5)] •Severe, Persistent Hypertension, Cerebrovascular Accidents, and Bradycardia Due to Drug Interactions [see Warnings and Precautions (5.6)] •Cardiac Arrest with Intravenous Regional Anesthesia Use [see Contraindications (4), Warnings and Precautions (5.7)] •Allergic-Type Reactions [see Warnings and Precautions (5.8)] •Systemic Toxicities with Unintended Intravascular or Intrathecal Injection [see Warnings and Precautions (5.9)] •Respiratory Arrest Following Retrobulbar Block [see Warnings and Precautions (5.15)] The following adverse reactions from voluntary reports or clinical studies have been reported with bupivacaine or bupivacaine 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 MARCAINE / MARCAINE WITH EPINEPHRINE 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 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, hypotension 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. Nervous System Disorders : Adverse reactions were characterized by excitation and/or depression of the central nervous system and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, respiratory arrest, nausea, vomiting, chills, pupillary constriction. 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-type reactions have occurred as a result of sensitivity to bupivacaine or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions. These reactions were characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and severe hypotension. Cross sensitivity among members of the amide-type local anesthetic group has been reported [see Warnings and Precautions (5.8)]. Most common adverse reactions are related to the central nervous system and the cardiovascular system. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Clinical Pharmacology 12.1 Mechanism of Action Bupivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Epinephrine is a vasoconstrictor added to bupivacaine to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration. 12.2 Pharmacodynamics Systemic absorption of bupivacaine produces effects on the cardiovascular system and CNS. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. These cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine [see Warnings and Precautions (5.9)]. Following systemic absorption, bupivacaine can produce CNS stimulation, CNS depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by CNS depression and coma progressing ultimately to respiratory arrest. However, bupivacaine has a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state. The duration of local anesthesia after administration of MARCAINE is longer than that observed after administration of other commonly used short-acting local anesthetics. There appears to be a period of analgesia that persists after the resolution of the block and return of sensation. The onset of action following dental injections is usually 2 to 10 minutes and may last up to 7 hours. The duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000. 12.3 Pharmacokinetics Systemic plasma levels of bupivacaine following administration of MARCAINE do not correlate with local efficacy. Absorption The rate of systemic absorption of bupivacaine is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000) usually reduces the rate of absorption and peak plasma concentration of bupivacaine, permitting the use of moderately larger total doses and sometimes prolonging the duration of action [see Dosage and Administration (2)]. After injection of MARCAINE for caudal, epidural, or peripheral nerve block, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours. Distribution Bupivacaine appears to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/ maternal ratios of bupivacaine appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. Depending upon the route of administration, bupivacaine is distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Pharmacokinetic studies on the plasma profile of bupivacaine after direct intravenous injection (MARCAINE is not approved for intravenous use) suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. Elimination The half-life of bupivacaine in adults is 2.7 hours. Metabolism Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecoloxylidine is the major metabolite of bupivacaine. The elimination of drug from tissue distribution depends largely upon the availability of binding sites in the circulation to carry it to the liver where it is metabolized. Excretion The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine. Specific Populations Geriatric Patients Elderly patients exhibited higher peak plasma concentrations than younger patients following administration of MARCAINE. The total plasma clearance was decreased in these patients [see Use in Specific Populations (8.5)]. Patients with Hepatic Impairment Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic disease. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics [see Use in Specific Populations (8.6)]. Patients with Renal Impairment Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow [see Use in Specific Populations (8.5, 8.7)].