Marcaine

1 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)

2 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 co…

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 …

4 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)

7 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 anest…

6 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. Neurolog…