Bupivacaine Hydrochloride in Dextrose Injection, USP is indicated for subarachnoid injection in adults for the production of subarachnoid block (spinal anesthesia).

{ "type": "p", "children": [], "text": "Bupivacaine Hydrochloride in Dextrose Injection, USP is indicated for subarachnoid injection in adults for the production of subarachnoid block (spinal anesthesia)." }

Administration Precautions

Conditions Which May Preclude Use of Spinal Anesthesia

The following conditions may preclude the use of spinal anesthesia, depending upon the physician’s evaluation of the patient:

The dosage of Bupivacaine Hydrochloride in Dextrose Injection, USP administered varies with the anesthetic procedure, 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 extent and degree of spinal anesthesia depend upon several factors including dosage, baricity of the anesthetic solution, volume of solution, force of injection, level of puncture, and position of the patient during and immediately after injection.

In recommended doses, Bupivacaine Hydrochloride in Dextrose Injection, USP produces complete motor and sensory block.

The following table summarizes general dosage guidelines for adult patients for the procedures described:

<div class="scrollingtable"><table width="539px"> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">PROCEDURES</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">DOSAGE GUIDELINES</span> <br/> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Vaginal Delivery</td><td align="center" class="Botrule Lrule Rrule Toprule"> Starting dose, 6 mg (0.8 mL)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Lower Extremity and Perineal Procedures, such as:</p> <ul class="Disk"> <li>transurethral resection of the prostate (TURP)</li> <li> vaginal hysterectomy </li> </ul> </td><td align="center" class="Botrule Lrule Rrule Toprule">7.5 mg (1 mL) </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Lower Abdominal Procedures, such as:</p> <ul class="Disk"> <li>abdominal hysterectomy</li> <li>tubal ligation</li> <li>appendectomy </li> </ul> </td><td align="center" class="Botrule Lrule Rrule Toprule">12 mg (1.6 mL) </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">Cesarean Section </td><td align="center" class="Botrule Lrule Rrule Toprule">7.5 mg to 10.5 mg (1 mL to 1.4 mL) </td> </tr> </tbody> </table></div>

Bupivacaine Hydrochloride in Dextrose Injection, USP is a clear, colorless solution available as:

{ "type": "p", "children": [], "text": "Bupivacaine Hydrochloride in Dextrose Injection, USP is a clear, colorless solution available as:" }

{ "type": "ul", "children": [ "15 mg/2 mL (7.5 mg/mL) in single-dose glass ampules." ], "text": "" }

Bupivacaine Hydrochloride in Dextrose Injection is contraindicated in:

{ "type": "p", "children": [], "text": "Bupivacaine Hydrochloride in Dextrose Injection is contraindicated in:" }

{ "type": "ul", "children": [ "intravenous regional anesthesia (Bier Block) [see Warnings and Precautions (5.8)].\n\n", "patients with septicemia.\n\n", "patients with severe hemorrhage, severe hypotension or shock, due to a reduced cardiac output.\n\n", "patients with clinically significant arrhythmias, such as complete heartblock, due a reduced cardiac output.\n\n", "patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of Bupivacaine Hydrochloride in Dextrose Injection." ], "text": "" }

{ "type": "ul", "children": [ " patients with local infection at the site of proposed lumbar puncture.\n" ], "text": "" }

Spinal anesthetics including Bupivacaine Hydrochloride in Dextrose Injection should not be injected during uterine contractions because cerebrospinal fluid current may carry the drug further cephalad than desired, resulting in a high motor block.

Sympathetic blockade due to spinal anesthesia may result in peripheral vasodilation and hypotension, the extent of which depends on the number of dermatomes blocked. Patients over 65 years, particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of Bupivacaine Hydrochloride in Dextrose Injection. Monitor blood pressure frequently, especially in the early phases of anesthesia. Hypotension may be controlled by administration of vasoconstrictor agents in titrated dosages depending on the severity of hypotension and response to treatment. Monitor the onset of adequate spinal anesthesia because it is not always possible to control the level of anesthesia after subarachnoid injection of Bupivacaine Hydrochloride in Dextrose Injection.

The safety and effectiveness of Bupivacaine Hydrochloride in Dextrose Injection depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient’s state of consciousness should be performed after injection of Bupivacaine Hydrochloride in Dextrose Injection solutions.

Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Delay in proper management of dose-related toxicity, hypoventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and possibly death.

The patient should have an indwelling intravenous catheter to assure adequate intravenous access. Use the lowest dosage of Bupivacaine Hydrochloride in Dextrose Injection that results in effective anesthesia to avoid serious adverse reactions. Avoid rapid injection of a large volume of Bupivacaine Hydrochloride in Dextrose Injection.

Injection of repeated doses of Bupivacaine Hydrochloride in Dextrose Injection may cause significant increases in plasma bupivacaine 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.

Reduced doses may be indicated in patients with increased intra-abdominal pressure (including obstetrical patients), if otherwise suitable for spinal anesthesia.

Unintended intravascular injection of Bupivacaine Hydrochloride in Dextrose Injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest [see Adverse Reactions (6)].

Aspirate for blood and cerebrospinal fluid before injecting Bupivacaine Hydrochloride in Dextrose Injection, for both the initial dose and all subsequent doses (where applicable), to confirm entry into the subarachnoid space and to avoid intravascular injection. Aspiration of cerebrospinal fluid into a Bupivacaine Hydrochloride in Dextrose Injection -filled syringe will result in an identifiable swirl in the solution. A negative aspiration for blood does not ensure against an intravascular injection.

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 (7.2)]. 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 Bupivacaine Hydrochloride in Dextrose Injection 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.

There have been reports of cardiac arrest with difficult resuscitation or death during use of Bupivacaine Hydrochloride for epidural anesthesia in obstetrical patients. In most cases, this has followed use of Bupivacaine Hydrochloride 0.75%, not Bupivacaine Hydrochloride in Dextrose Injection. The package insert for Bupivacaine Hydrochloride for epidural, nerve block, etc., has a more complete discussion of preparation for, and management of cardiac arrest following epidural administration. Bupivacaine Hydrochloride in Dextrose Injection is recommended for spinal anesthesia in obstetrical patients.

Intra-articular infusions of local anesthetics including bupivacaine 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 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 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

There have been reports of cardiac arrest and death during the use of bupivacaine for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of Bupivacaine Hydrochloride in Dextrose Injection in this procedure is lacking. Therefore, Bupivacaine Hydrochloride in Dextrose Injection is contraindicated for use with this technique [see Contraindications (4)].

Consider alternate anesthetic techniques in patients with severe disturbances of cardiac rhythm, shock, or heart block [see Contraindications (4)].

Because amide-type local anesthetics such as bupivacaine are metabolized by the liver, consider reduced dosing and increased monitoring for bupivacaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with Bupivacaine Hydrochloride in Dextrose Injection [see Use in Specific Populations (8.6)]. Most information regarding dose-related hepatic impairment is based on larger dosages of bupivacaine administered for other neuraxial, peripheral nerve, or fascial plane blocks.

Bupivacaine Hydrochloride in Dextrose Injection should be given in reduced doses in patients with impaired cardiovascular function (e.g., hypotension, heartblock, valvular abnormalities) because they may be less able to compensate for functional changes associated with the sympathetic blockade observed after subarachnoid administration of Bupivacaine Hydrochloride in Dextrose Injection and the prolongation of AV conduction produced by the drug. Monitor patients closely for blood pressure, heart rate, and ECG changes.

The following clinically significant adverse reactions have been reported and described in other sections of the labeling:

{ "type": "p", "children": [], "text": "The following clinically significant adverse reactions have been reported and described in other sections of the labeling:" }

{ "type": "ul", "children": [ "Allergic-Type Reactions [see Contraindications (4)]\n", "Dose-Related Toxicity [see Warnings and Precautions (5.3)]\n", "Systemic Toxicities with Unintended Intravascular Injection [see Warnings and Precautions (5.4)]\n", "Methemoglobinemia [see Warnings and Precautions (5.5)]\n", "Cardiac Arrest in Obstetrical Anesthesia [see Warnings and Precautions (5.6)]\n", "Chondrolysis with Intra-Articular Infusion [see Warnings and Precautions (5.7)]\n", "Cardiac Arrest with Intravenous Regional Anesthesia Use [see Contraindications (4), Warnings and Precautions (5.8)]\n" ], "text": "" }

The following adverse reactions from voluntary reports or clinical studies have been reported with bupivacaine. 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.

{ "type": "p", "children": [], "text": "The following adverse reactions from voluntary reports or clinical studies have been reported with bupivacaine. 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 Bupivacaine Hydrochloride in Dextrose Injection are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to Bupivacaine Hydrochloride in Dextrose Injection is due to cephalad extension of the motor level of anesthesia and/or excessive plasma levels, which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation.

{ "type": "p", "children": [], "text": "Adverse reactions to Bupivacaine Hydrochloride in Dextrose Injection are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to Bupivacaine Hydrochloride in Dextrose Injection is due to cephalad extension of the motor level of anesthesia and/or 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 following the administration of spinal anesthesia were hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia. These have led to cardiac arrest if untreated. In addition, dose-related convulsions and cardiovascular collapse have resulted from diminished tolerance, rapid absorption from the injection site, or from unintentional intravascular injection of a local anesthetic solution.

{ "type": "p", "children": [], "text": "The most commonly encountered acute adverse reactions that demand immediate counter-measures following the administration of spinal anesthesia were hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia. These have led to cardiac arrest if untreated. In addition, dose-related convulsions and cardiovascular collapse have resulted from diminished tolerance, rapid absorption from the injection site, or from unintentional intravascular injection of a local anesthetic solution." }

Respiratory System: Respiratory paralysis or underventilation have been noted as a result of cephalad spread of spinal anesthesia and has led to secondary hypoxic cardiac arrest when untreated. Preanesthetic medication, intraoperative anesthetics, analgesics, and sedatives, as well as surgical manipulation, may contribute to underventilation. This has usually been noted within minutes of the injection of spinal anesthetic solution, but because of differing maximal onset times, differing intercurrent drug usage, and differing surgical manipulation, it may occur at any time during surgery or the immediate recovery period.

{ "type": "p", "children": [], "text": "\nRespiratory System: Respiratory paralysis or underventilation have been noted as a result of cephalad spread of spinal anesthesia and has led to secondary hypoxic cardiac arrest when untreated. Preanesthetic medication, intraoperative anesthetics, analgesics, and sedatives, as well as surgical manipulation, may contribute to underventilation. This has usually been noted within minutes of the injection of spinal anesthetic solution, but because of differing maximal onset times, differing intercurrent drug usage, and differing surgical manipulation, it may occur at any time during surgery or the immediate recovery period." }

Cardiac Disorders: Hypotension due to loss of sympathetic tone has been commonly encountered following spinal anesthesia. This has been more commonly observed in elderly patients, particularly those with hypertension, and patients with reduced blood volume, reduced interstitial fluid volume, cephalad spread of the local anesthetic, and/or mechanical obstruction of venous return. Nausea and vomiting have been frequently associated with hypotensive episodes following the administration of spinal anesthesia. High doses, or inadvertent intravascular injection, have led to high plasma levels and related depression of the myocardium, decreased cardiac output, bradycardia, heart block, ventricular arrhythmias, and cardiac arrest [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "\nCardiac Disorders: Hypotension due to loss of sympathetic tone has been commonly encountered following spinal anesthesia. This has been more commonly observed in elderly patients, particularly those with hypertension, and patients with reduced blood volume, reduced interstitial fluid volume, cephalad spread of the local anesthetic, and/or mechanical obstruction of venous return. Nausea and vomiting have been frequently associated with hypotensive episodes following the administration of spinal anesthesia. High doses, or inadvertent intravascular injection, have led to high plasma levels and related depression of the myocardium, decreased cardiac output, bradycardia, heart block, ventricular arrhythmias, and cardiac arrest [see Warnings and Precautions (5.4)]." }

Nervous System Disorders: Respiratory paralysis or underventilation secondary to cephalad spread of the level of spinal anesthesia (see Respiratory System) and hypotension for the same reason (see Cardiac Disorders) have been the two most commonly encountered CNS-related adverse observations which demand immediate counter-measures.

{ "type": "p", "children": [], "text": "\nNervous System Disorders: Respiratory paralysis or underventilation secondary to cephalad spread of the level of spinal anesthesia (see Respiratory System) and hypotension for the same reason (see Cardiac Disorders) have been the two most commonly encountered CNS-related adverse observations which demand immediate counter-measures." }

High doses or inadvertent intravascular injection have led to high plasma levels and related CNS toxicity. Adverse reactions were characterized by excitation and/or depression of the CNS and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, and respiratory arrest.

{ "type": "p", "children": [], "text": "High doses or inadvertent intravascular injection have led to high plasma levels and related CNS toxicity. Adverse reactions were characterized by excitation and/or depression of the CNS and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, and respiratory arrest." }

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.

{ "type": "p", "children": [], "text": "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." }

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.

{ "type": "p", "children": [], "text": "\nConvulsions: 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." }

Neurologic effects following spinal anesthesia have included loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness and paralysis of the lower extremities, and loss of sphincter control with slow, incomplete, or no recovery; hypotension, high or total spinal block; urinary retention; headache; backache; septic meningitis, meningismus; arachnoiditis; slowing of labor; increased incidence of forceps delivery; shivering; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid; and fecal and urinary incontinence.

{ "type": "p", "children": [], "text": "Neurologic effects following spinal anesthesia have included loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness and paralysis of the lower extremities, and loss of sphincter control with slow, incomplete, or no recovery; hypotension, high or total spinal block; urinary retention; headache; backache; septic meningitis, meningismus; arachnoiditis; slowing of labor; increased incidence of forceps delivery; shivering; cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid; and fecal and urinary incontinence." }

Immune System Disorders: Allergic-type reactions have occurred as a result of sensitivity to bupivacaine. 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.

{ "type": "p", "children": [], "text": "\nImmune System Disorders: Allergic-type reactions have occurred as a result of sensitivity to bupivacaine. 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." }

The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with Bupivacaine Hydrochloride in Dextrose Injection 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 (5.3)].

Patients who are administered Bupivacaine Hydrochloride in Dextrose Injection are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions (5.5)].

Examples of Drugs Associated with Methemoglobinemia:

<div class="scrollingtable"><table width="640.2px"> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Class</span></td><td class="Botrule Lrule Rrule Toprule"><span class="Bold">Examples</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Nitrates/Nitrites</td><td class="Botrule Lrule Rrule Toprule">nitric oxide, nitroglycerin, nitroprusside, nitrous oxide</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Local anesthetics</td><td class="Botrule Lrule Rrule Toprule">articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Antineoplastic agents</td><td class="Botrule Lrule Rrule Toprule">cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Antibiotics</td><td class="Botrule Lrule Rrule Toprule">dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Antimalarials</td><td class="Botrule Lrule Rrule Toprule">chloroquine, primaquine </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Anticonvulsants</td><td class="Botrule Lrule Rrule Toprule">phenobarbital, phenytoin, sodium valproate </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">Other drugs</td><td class="Botrule Lrule Rrule Toprule">acetaminophen, metoclopramide, quinine, sulfasalazine </td> </tr> </tbody> </table></div>

The available data on the use of Bupivacaine Hydrochloride in Dextrose Injection in pregnant women do not establish the presence or absence of developmental toxicity related to the use of Bupivacaine Hydrochloride in Dextrose Injection.

In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis and decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning). These effects were observed at dose levels approximately 30 times the daily maximum recommended human dose (MRHD) on a body surface area (BSA) basis. Based on animal data, advise pregnant women of the potential risk to a fetus (see Data).

Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal 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 CNS, peripheral vascular tone, and cardiac function.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Maternal Adverse Reactions

Maternal hypotension has resulted from regional and neuraxial anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension, or fetal bradycardia following regional or neuraxial 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 and right-side-up positioning will 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

Spinal anesthesia is commonly used during labor and delivery. Bupivacaine hydrochloride, when administered properly, via the epidural route in doses 10 to 12 times the amount used in spinal anesthesia has been used for obstetrical analgesia and anesthesia without evidence of adverse effects on the fetus.

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. This has not been reported with bupivacaine.

It is extremely important to avoid aortocaval compression by the gravid uterus during administrations of regional or neuraxial block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and the gravid uterus displaced to the left.

Data

Animal Data

Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at doses 30-times the MHRD.

Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, and 40 mg/kg and to rabbits at doses of 1.3, 5.8, and 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are approximately 30-times the daily MRHD of 12 mg/day on a mg dose/m2 BSA basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level being approximately 8-times the MRHD on a BSA basis.

In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, and 40 mg/kg, decreased pup survival was observed at the high dose. The high dose is approximately 30-times the daily MRHD of 12 mg/day on a BSA basis.

Risk Summary

Lactation studies have not been conducted with bupivacaine. Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Bupivacaine Hydrochloride in Dextrose Injection should be administered to lactating women only if clearly indicated. Studies assessing the effects of Bupivacaine Hydrochloride in Dextrose Injection in breastfed children have not been performed. Studies to assess the effect of Bupivacaine Hydrochloride in Dextrose Injection on milk production or excretion have not been performed. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for bupivacaine and any potential adverse effects on the breastfed child from bupivacaine or from the underlying maternal condition.

Bupivacaine Hydrochloride in Dextrose Injection is approved for use in adults only. Administration of Bupivacaine Hydrochloride in Dextrose Injection in patients younger than 18 is not recommended.

Patients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing spinal anesthesia with Bupivacaine Hydrochloride in Dextrose Injection.

In clinical studies of bupivacaine, elderly patients exhibited a greater spread and higher maximal level of anesthesia than younger patients. Elderly patients also reached the maximal level of anesthesia more rapidly than younger patients, and exhibited a faster onset of motor blockade.

Differences in various pharmacokinetic parameters have been observed between elderly and younger patients [see Clinical Pharmacology (12.3)].

This product is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients may require lower doses of Bupivacaine Hydrochloride in Dextrose Injection.

Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment treated with Bupivacaine Hydrochloride in Dextrose Injection [see Warnings and Precautions (5.10)].

Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. This should be considered when selecting the Bupivacaine Hydrochloride in Dextrose Injection dosage [see Use in Specific Populations (8.5)].

Clinical Presentation

{ "type": "p", "children": [], "text": "\nClinical Presentation\n" }

Acute emergencies from Bupivacaine Hydrochloride in Dextrose Injection are generally related to hypoventilation (and perhaps apnea) secondary to upward extension of spinal anesthesia or high plasma levels encountered during therapeutic use [see Warnings and Precautions (5.3), Adverse Reactions (6)]. Hypotension is commonly encountered during the conduct of spinal anesthesia due to loss of sympathetic tone, and sometimes, contributory mechanical obstruction of venous return due to the gravid uterus exerting pressure on the great vessels [see Warnings and Precautions (5.2), Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Acute emergencies from Bupivacaine Hydrochloride in Dextrose Injection are generally related to hypoventilation (and perhaps apnea) secondary to upward extension of spinal anesthesia or high plasma levels encountered during therapeutic use [see Warnings and Precautions (5.3), Adverse Reactions (6)]. Hypotension is commonly encountered during the conduct of spinal anesthesia due to loss of sympathetic tone, and sometimes, contributory mechanical obstruction of venous return due to the gravid uterus exerting pressure on the great vessels [see Warnings and Precautions (5.2), Adverse Reactions (6)]." }

If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Hypoventilation or apnea due to a high or total spinal may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts.

{ "type": "p", "children": [], "text": "If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of the local anesthetic may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Hypoventilation or apnea due to a high or total spinal may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts." }

Management

{ "type": "p", "children": [], "text": "\nManagement\n" }

The first step in the management of systemic toxic reactions, as well as hypoventilation or apnea due to a high or total spinal, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated.

{ "type": "p", "children": [], "text": "The first step in the management of systemic toxic reactions, as well as hypoventilation or apnea due to a high or total spinal, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated." }

If necessary, use drugs to manage the convulsions. A bolus intravenous dose of benzodiazepine will counteract the CNS stimulation related to Bupivacaine Hydrochloride in Dextrose Injection. Immediately after the institution of ventilatory measures, evaluate the adequacy of the circulation. Supportive treatment of circulatory depression may require Advanced Cardiac Life Support measures.

{ "type": "p", "children": [], "text": "If necessary, use drugs to manage the convulsions. A bolus intravenous dose of benzodiazepine will counteract the CNS stimulation related to Bupivacaine Hydrochloride in Dextrose Injection. Immediately after the institution of ventilatory measures, evaluate the adequacy of the circulation. Supportive treatment of circulatory depression may require Advanced Cardiac Life Support measures." }

Hypotension due to sympathetic relaxation may be managed by giving intravenous fluids (such as isotonic saline or lactated Ringer’s solution), in an attempt to relieve mechanical obstruction of venous return, or by using vasopressor agents (such as ephedrine which increases myocardial contractility) and, if indicated, by giving plasma expanders or blood products.

{ "type": "p", "children": [], "text": "Hypotension due to sympathetic relaxation may be managed by giving intravenous fluids (such as isotonic saline or lactated Ringer’s solution), in an attempt to relieve mechanical obstruction of venous return, or by using vasopressor agents (such as ephedrine which increases myocardial contractility) and, if indicated, by giving plasma expanders or blood products." }

Bupivacaine Hydrochloride in Dextrose Injection, USP is an amide-local anesthetic and sterile hyperbaric aqueous solution. The route of administration for Bupivacaine Hydrochloride in Dextrose Injection, USP is by subarachnoid injection. Bupivacaine Hydrochloride contains bupivacaine hydrochloride, as the active pharmaceutical ingredient and also contains Dextrose, as baricity agent.

{ "type": "p", "children": [], "text": "Bupivacaine Hydrochloride in Dextrose Injection, USP is an amide-local anesthetic and sterile hyperbaric aqueous solution. The route of administration for Bupivacaine Hydrochloride in Dextrose Injection, USP is by subarachnoid injection. Bupivacaine Hydrochloride contains bupivacaine hydrochloride, as the active pharmaceutical ingredient and also contains Dextrose, as baricity agent." }

Bupivacaine Hydrochloride (monohydrate) chemical name is 2-piperidinecarboxamide, 1-butyl-N-(2,6- dimethylphenyl)-, monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. Bupivacaine Hydrochloride (monohydrate) has a molecular formula of C18H28N2O·HCl·H2O and molecular weight of 342.90 g/mol and has the following structural formula:

{ "type": "p", "children": [], "text": "Bupivacaine Hydrochloride (monohydrate) chemical name is 2-piperidinecarboxamide, 1-butyl-N-(2,6- dimethylphenyl)-, monohydrochloride, monohydrate, a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. Bupivacaine Hydrochloride (monohydrate) has a molecular formula of C18H28N2O·HCl·H2O and molecular weight of 342.90 g/mol and has the following structural formula:" }

Dextrose chemical name is D-glucopyranose. Dextrose (anhydrous) has a molecular formula of C6H12O6, molecular weight of 180.16 g/mol and has the following structural formula:

{ "type": "p", "children": [], "text": "Dextrose chemical name is D-glucopyranose. Dextrose (anhydrous) has a molecular formula of C6H12O6, molecular weight of 180.16 g/mol and has the following structural formula:" }

Bupivacaine Hydrochloride in Dextrose Injection, USP is a clear and colorless sterile hyperbaric solution.

{ "type": "p", "children": [], "text": "Bupivacaine Hydrochloride in Dextrose Injection, USP is a clear and colorless sterile hyperbaric solution." }

Each mL of Bupivacaine Hydrochloride in Dextrose Injection, USP contains 7.5 mg bupivacaine hydrochloride (anhydrous) (equivalent to 7.9 mg of bupivacaine hydrochloride monohydrate), 82.5 mg dextrose (anhydrous) as baricity agent, and sodium hydroxide and hydrochloric acid as pH adjusters in water for injection.

{ "type": "p", "children": [], "text": "Each mL of Bupivacaine Hydrochloride in Dextrose Injection, USP contains 7.5 mg bupivacaine hydrochloride (anhydrous) (equivalent to 7.9 mg of bupivacaine hydrochloride monohydrate), 82.5 mg dextrose (anhydrous) as baricity agent, and sodium hydroxide and hydrochloric acid as pH adjusters in water for injection." }

Bupivacaine Hydrochloride in Dextrose Injection, USP pH is between 4.0 and 6.5.

{ "type": "p", "children": [], "text": "Bupivacaine Hydrochloride in Dextrose Injection, USP pH is between 4.0 and 6.5." }

The specific gravity of Bupivacaine Hydrochloride in Dextrose Injection, USP is between 1.030 and 1.035 at 25°C and 1.03 at 37°C.

{ "type": "p", "children": [], "text": "The specific gravity of Bupivacaine Hydrochloride in Dextrose Injection, USP is between 1.030 and 1.035 at 25°C and 1.03 at 37°C." }

Bupivacaine Hydrochloride in Dextrose Injection, USP does not contain any preservatives.

{ "type": "p", "children": [], "text": "Bupivacaine Hydrochloride in Dextrose Injection, USP does not contain any preservatives." }

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.

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 (5.4)].

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 stage.

The duration of local anesthesia after administration of Bupivacaine Hydrochloride in Dextrose Injection is longer than that observed after administration of other commonly used short-acting local anesthetic. There appears to be a period of analgesia that persists after the resolution of the block and the return of sensation.

The onset of sensory blockade following spinal block with Bupivacaine Hydrochloride in Dextrose Injection is rapid (generally within one minute); maximum motor blockade and maximum dermatome level are achieved within 15 minutes in most cases. Duration of sensory blockade (time to return of complete sensation in the operative site or regression of two dermatomes) following Bupivacaine Hydrochloride in Dextrose Injection 12 mg averages 2 hours with or without 0.2 mg epinephrine. The time to return of complete motor ability with Bupivacaine Hydrochloride in Dextrose Injection 12 mg averages 3.5 hours without the addition of epinephrine and 4.5 hours if 0.2 mg epinephrine is added. When compared to equal milligram doses of hyperbaric tetracaine, the duration of sensory blockade was the same, but the time to complete motor recovery was longer for tetracaine. Addition of 0.2 mg epinephrine prolongs the motor blockade and time to first postoperative opioid with Bupivacaine Hydrochloride in Dextrose Injection.

Systemic plasma levels of bupivacaine following administration of Bupivacaine Hydrochloride in Dextrose Injection 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.

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 profiles of bupivacaine after direct intravenous injection (Bupivacaine Hydrochloride in Dextrose Injection is not approved for intravenous use, and contraindicated for intravenous regional block, i.e. Bier Block) 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 ability 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

The total plasma clearance was decreased and the terminal half-life was lengthened in these patients.

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)].

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted.

Mutagenesis

The mutagenic potential of bupivacaine hydrochloride has not been determined.

Impairment of Fertility

 The effect of bupivacaine on fertility has not been determined.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]" }

Bupivacaine Hydrochloride in Dextrose Injection, USP solution may be autoclaved once at 15 pound pressure, 121°C (250°F) for 15 minutes. This product is clear and colorless. Do not use the solution if it is discolored or contains particulate matter.

{ "type": "p", "children": [], "text": "Bupivacaine Hydrochloride in Dextrose Injection, USP solution may be autoclaved once at 15 pound pressure, 121°C (250°F) for 15 minutes. This product is clear and colorless. Do not use the solution if it is discolored or contains particulate matter." }

Single-dose ampules of 2 mL Bupivacaine Hydrochloride in Dextrose Injection, USP (15 mg bupivacaine hydrochloride with 165 mg dextrose) are supplied as follows:

{ "type": "p", "children": [], "text": "Single-dose ampules of 2 mL Bupivacaine Hydrochloride in Dextrose Injection, USP (15 mg bupivacaine hydrochloride with 165 mg dextrose) are supplied as follows:" }

<div class="scrollingtable"><table width="284px"> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule"> <span class="Bold">Unit of Sale</span></td><td align="center" class="Botrule Lrule Rrule Toprule"> <span class="Bold">Concentration</span></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">NDC 0264-9379-88</span> <br/> Carton of 10 single-dose ampules</td><td align="center" class="Botrule Lrule Rrule Toprule"> 15 mg/2 mL<br/> (7.5 mg/mL)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"284px\">\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> <span class=\"Bold\">Unit of Sale</span></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> <span class=\"Bold\">Concentration</span></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\"><span class=\"Bold\">NDC 0264-9379-88</span>\n<br/> Carton of 10 single-dose ampules</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\"> 15 mg/2 mL<br/> (7.5 mg/mL)</td>\n</tr>\n</tbody>\n</table></div>" }

Discard the unused portion.

{ "type": "p", "children": [], "text": "Discard the unused portion.\n" }

Allergic-Type Reactions

{ "type": "p", "children": [], "text": "\nAllergic-Type Reactions\n" }

Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients [see Contraindications (4), Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients [see Contraindications (4), Adverse Reactions (6)].\n" }

Temporary Loss of Sensation and Motor Activity After Spinal Anesthesia

{ "type": "p", "children": [], "text": "\nTemporary Loss of Sensation and Motor Activity After Spinal Anesthesia\n" }

When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, including the inability to move the legs, following proper administration of spinal anesthesia.

{ "type": "p", "children": [], "text": "When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, including the inability to move the legs, following proper administration of spinal anesthesia." }

Methemoglobinemia

{ "type": "p", "children": [], "text": "\nMethemoglobinemia\n" }

 Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis), headache, rapid heart rate, shortness of breath, lightheadedness, or fatigue [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "\n Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis), headache, rapid heart rate, shortness of breath, lightheadedness, or fatigue [see Warnings and Precautions (5.5)]." }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

B. Braun Medical Inc. Bethlehem, PA 18018-3524 USA

{ "type": "p", "children": [], "text": "\nB. Braun Medical Inc.\nBethlehem, PA 18018-3524 USA" }

Manufactured by: Solupharm Pharmazeutische Erzeugnisse GmbH

{ "type": "p", "children": [], "text": "Manufactured by: Solupharm Pharmazeutische Erzeugnisse GmbH" }

Prepared in Germany.

{ "type": "p", "children": [], "text": "Prepared in Germany." }

API from Switzerland.

{ "type": "p", "children": [], "text": "API from Switzerland." }

A4805964-2

{ "type": "p", "children": [], "text": " A4805964-2\n" }

LD-560-1

{ "type": "p", "children": [], "text": "LD-560-1" }

NDC 0264-9379-88

{ "type": "p", "children": [], "text": "NDC 0264-9379-88" }

Bupivacaine HCl            0.75%

{ "type": "p", "children": [], "text": "\nBupivacaine HCl            0.75%\n" }

in Dextrose                    8.25%

{ "type": "p", "children": [], "text": "\nin Dextrose                    8.25%\n" }

Injection, USP

{ "type": "p", "children": [], "text": "\nInjection, USP\n" }

SPINAL

{ "type": "p", "children": [], "text": "\nSPINAL\n" }

Contains 7.5 mg bupivacaine HCl (anhydrous) and 82.5 mg dextrose (anhydrous) per mL. pH adjusted between 4.0 and 6.5 with NaOH or HCl.

{ "type": "p", "children": [], "text": "Contains 7.5 mg bupivacaine HCl (anhydrous) and 82.5 mg dextrose (anhydrous) per mL. pH adjusted between 4.0 and 6.5 with NaOH or HCl." }

2 mL

{ "type": "p", "children": [], "text": "\n2 mL\n" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

B. Braun Medical Inc.

{ "type": "p", "children": [], "text": "\nB. Braun Medical Inc.\n" }

Bethlehem, PA 18018-3524 USA

{ "type": "p", "children": [], "text": "Bethlehem, PA 18018-3524 USA" }

Prepared in Germany.API from Switzerland.

{ "type": "p", "children": [], "text": "Prepared in Germany.API from Switzerland." }

LOT

{ "type": "p", "children": [], "text": "LOT" }

EXP

{ "type": "p", "children": [], "text": "EXP" }

10 x 2 mL Single-dose Ampoules

{ "type": "p", "children": [], "text": "\n10 x 2 mL Single-dose Ampoules\n" }

NDC 0264-9379-88

{ "type": "p", "children": [], "text": "\nNDC 0264-9379-88\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

 STERILE HYPERBARIC SOLUTION FOR SPINAL ANESTHESIA

{ "type": "p", "children": [], "text": "\n STERILE HYPERBARIC SOLUTION FOR SPINAL ANESTHESIA\n" }

Bupivacaine Hydrochloride in 8.25% Dextrose Injection, USP

{ "type": "p", "children": [], "text": "\nBupivacaine Hydrochloride in \n8.25% Dextrose Injection, USP\n" }

SPINAL  0.75% (15 mg/2 mL) (7.5 mg/mL)

{ "type": "p", "children": [], "text": "\nSPINAL  0.75%\n(15 mg/2 mL)\n(7.5 mg/mL)\n" }

Store at 20 to 25°C (68 to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Each mL contains 7.5 mg bupivacaine HCl (anhydrous) and 82.5 mg dextrose (anhydrous) per mL. pH adjusted between 4.0 and 6.5 with NaOH or HCl. These ampoules bear a color band signifying that they are Easy Break Ampoules. The tops snap off at constriction, regardless of the position of the color band. Usual dosage: See Insert.

{ "type": "p", "children": [], "text": "Store at 20 to 25°C (68 to 77°F); excursions permitted between 15° to 30°C (59° to\n86°F). [See USP Controlled Room Temperature.]\nEach mL contains 7.5 mg bupivacaine HCl (anhydrous) and 82.5 mg dextrose\n(anhydrous) per mL. pH adjusted between 4.0 and 6.5 with NaOH or HCl.\nThese ampoules bear a color band signifying that they are Easy Break Ampoules.\nThe tops snap off at constriction, regardless of the position of the color band.\nUsual dosage: See Insert." }

LD-618-2

{ "type": "p", "children": [], "text": "LD-618-2" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

B. Braun Medical Inc.

{ "type": "p", "children": [], "text": "\nB. Braun Medical Inc.\n" }

Bethlehem, PA 18018-3524 USA

{ "type": "p", "children": [], "text": "Bethlehem, PA 18018-3524 USA" }

1-800-227-2862

{ "type": "p", "children": [], "text": "1-800-227-2862" }

Prepared in Germany. API from Switzerland.

{ "type": "p", "children": [], "text": "Prepared in Germany.\nAPI from Switzerland." }

Bupivacaine HCl  0.75% in Dextrose          8.25% Injection, USP SPINAL

{ "type": "p", "children": [], "text": "Bupivacaine HCl  0.75%\nin Dextrose          8.25%\nInjection, USP\nSPINAL" }

LOT

{ "type": "p", "children": [], "text": "LOT" }

EXP

{ "type": "p", "children": [], "text": "EXP" }

XARACOLL is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair.

{ "type": "p", "children": [], "text": "XARACOLL is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair." }

Limitations of Use

{ "type": "p", "children": [], "text": "\nLimitations of Use\n" }

Safety and effectiveness have not been established in other surgical procedures, including orthopedic and boney procedures [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Safety and effectiveness have not been established in other surgical procedures, including orthopedic and boney procedures [see Warnings and Precautions (5.5)]." }

Administration of additional local anesthetics, including bupivacaine HCl, into the surgical site with XARACOLL has not been studied.

Studies conducted with XARACOLL demonstrated that commonly used surgical materials (nonabsorbable surgical suture, delayed absorbable surgical suture, and surgical mesh) are not affected by the presence of XARACOLL.

When a topical antiseptic such as povidone iodine (e.g., Betadine®) is applied, allow the surgical site to dry before XARACOLL is administered.

XARACOLL (bupivacaine HCl) implant

{ "type": "p", "children": [], "text": "XARACOLL (bupivacaine HCl) implant" }

{ "type": "ul", "children": [ "100 mg bupivacaine HCl (equivalent to 88.8 mg bupivacaine) per implant; each implant is white to off-white in color and is approximately 5 cm × 5 cm × 0.5 cm in size" ], "text": "" }

XARACOLL is contraindicated in:

{ "type": "p", "children": [], "text": "XARACOLL is contraindicated in:" }

{ "type": "ul", "children": [ "patients with a known hypersensitivity to any local anesthetic agent of the amide-type or to any of the other components of XARACOLL.", "patients undergoing obstetrical paracervical block anesthesia.  The use of bupivacaine in this technique has resulted in fetal bradycardia and death." ], "text": "" }

The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. The toxic effects of local anesthetics are additive. Avoid additional local anesthetic administration within 96 hours following XARACOLL implantation.  If additional local anesthetic administration with XARACOLL cannot be avoided based on clinical need, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity.  Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be performed after administration of XARACOLL.

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.  Consider surgical removal of XARACOLL depending on the clinical situation.

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious CNS and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Consider removal of XARACOLL and discontinue 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.

Because amide local anesthetics such as bupivacaine are metabolized by the liver, consider increased monitoring for bupivacaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with XARACOLL [see Use in Specific Populations (8.6)].

Patients with impaired cardiovascular function (e.g., hypotension, heart block) may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by XARACOLL. Monitor patients closely for blood pressure, heart rate, and ECG changes.

The safety and effectiveness of XARACOLL in surgical procedures other than open inguinal hernia repair have not been established, and XARACOLL is not approved for use in these other surgical procedures (e.g., orthopedic procedures). A study evaluating the effects of bupivacaine HCl implant in rats following an osteotomy procedure demonstrated inhibition of bone healing [see Nonclinical Toxicology (13.2)].

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety of XARACOLL was evaluated in 11 clinical studies, including two Phase 3 double-blind, placebo implant-controlled studies in patients undergoing open, unilateral inguinal hernia repair. Overall, 612 patients were treated with a single dose of XARACOLL, total dose ranged from 100 mg to 300 mg bupivacaine HCl.  Patients treated with XARACOLL ranged in age from 18 to 85 years (median age 51 years), with 88% male, 88% White, 9% African-American, and 3% all other races. 

Across the XARACOLL drug development program, which included evaluations in various surgery models, there was one patient death reported in the placebo implant treatment group, and 16 patients who experienced one or more serious adverse events; 11 patients in the XARACOLL treatment group and 5 patients in the placebo implant or comparator treatment groups.  Serious adverse reactions reported in the XARACOLL treatment group included wound infection and seroma. There was a single patient who experienced signs and symptoms consistent with local anesthetic systemic toxicity (LAST) approximately four hours after administration of an early formulation of the bupivacaine collagen implant 150 mg during bladder sling surgery.  LAST treatment included administration of lipid emulsion and surgical removal of the XARACOLL implants. 

The most common adverse reactions (incidence greater than or equal to 2% and higher than placebo implant) following XARACOLL administration were dysgeusia, headache, scrotal swelling, tremor, pyrexia, vision blurred, and seroma.  Common incision site adverse reactions (incidence greater than or equal to 2% and higher in either the XARACOLL or placebo implant groups compared to non-implant comparator treatment groups) were swelling pain, other complication, post-procedural discharge, erythema, dehiscence, and inflammation.

Adverse Reactions Reported in Phase 3 Placebo-controlled Trials

There were 619 patients who underwent open inguinal hernia repair in the two Phase 3 studies.  Patients received general anesthesia intra-operatively, and a standard acetaminophen regimen, in addition to intravenous and oral morphine as needed, post-operatively.  The most common adverse reactions (incidence greater than or equal to 2% and higher than placebo implants) following XARACOLL administration were incision site swelling, dysgeusia, headache, tremor, vision blurred, seroma, scrotal swelling, pyrexia, hypoesthesia oral, and post procedural discharge shown in Table 1.

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 1: Adverse Reactions (ARs) with Incidence Greater Than or Equal to 2% and Greater Than Placebo Reported in the Phase 3 Placebo-controlled Studies</span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Placebo consisted of three collagen implants.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td></td><td align="center"><span class="Bold"> XARACOLL 300 mg</span> <br/> <span class="Bold">N=411</span> <br/> <span class="Bold">n (%)</span></td><td align="center"><span class="Bold"> Placebo<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></span> <br/> <span class="Bold">N=208</span> <br/> <span class="Bold">n (%)</span></td> </tr> <tr> <td> Subjects Reporting Treatment Emergent Adverse Events</td><td align="center"> 256 (62.3%)</td><td align="center"> 143 (68.8%)</td> </tr> <tr> <td> Injury, Poisoning and Procedural Complications</td><td></td><td></td> </tr> <tr> <td>     Incision Site Swelling</td><td align="center"> 60 (14.6%)</td><td align="center"> 30 (14.4%)</td> </tr> <tr> <td>     Post Procedural Discharge</td><td align="center"> 20 (4.9%)</td><td align="center"> 10 (4.8%)</td> </tr> <tr> <td>    Seroma</td><td align="center"> 12 (2.9%)</td><td align="center"> 5 (2.4%)</td> </tr> <tr> <td> Nervous System Disorders</td><td></td><td></td> </tr> <tr> <td>    Dysgeusia</td><td align="center"> 31 (7.5%)</td><td align="center"> 13 (6.3%)</td> </tr> <tr> <td>    Headache</td><td align="center"> 17 (4.1%)</td><td align="center"> 1 (0.5%)</td> </tr> <tr> <td>    Tremor</td><td align="center"> 15 (3.6%)</td><td align="center"> 6 (2.9%)</td> </tr> <tr> <td> Gastrointestinal Disorders</td><td></td><td></td> </tr> <tr> <td>    Hypoaesthesia Oral</td><td align="center"> 9 (2.2%)</td><td align="center"> 4 (1.9%)</td> </tr> <tr> <td> Reproductive System and Breast Disorders</td><td></td><td></td> </tr> <tr> <td>    Scrotal Swelling</td><td align="center"> 12 (2.9%)</td><td align="center"> 2 (1.0%)</td> </tr> <tr> <td> General Disorders and Administration Site Conditions</td><td></td><td></td> </tr> <tr> <td>    Pyrexia</td><td align="center"> 10 (2.4%)</td><td align="center"> 1 (0.5%)</td> </tr> <tr> <td> Eye Disorders</td><td></td><td></td> </tr> <tr class="Last"> <td>    Vision Blurred</td><td align="center"> 15 (3.6%)</td><td align="center"> 6 (2.9%)</td> </tr> </tbody> </table></div>

The following adverse reactions from voluntary reports have been reported with various formulations of bupivacaine, administered via different routes and for different indications. 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 bupivacaine 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.

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. 

Neurological effects following routes of administration other than epidural or caudal have included persistent anesthesia, paresthesia, weakness, and paralysis, all with slow, incomplete, or no recovery. 

The incidence 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 have led to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest.

Immune System Disorders: Allergic-type reactions have occurred as a result of sensitivity to bupivacaine or to other formulation ingredients. 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.

The toxic effects of local anesthetics are additive.  Avoid additional local anesthetic administration within 96 hours following XARACOLL implantation.  If additional local anesthetic administration with XARACOLL cannot be avoided based on clinical need, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration (2.1), Warnings and Precautions (5.1), Overdosage (10)].

Patients who are administered local anesthetics may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:

<div class="scrollingtable"><table width="100%"> <caption> <span>Examples of Drugs Associated with Methemoglobinemia </span> </caption> <tbody class="Headless"> <tr class="First"> <td><span class="Bold"> Class</span></td><td><span class="Bold"> Examples</span></td> </tr> <tr> <td> Nitrates/Nitrites</td><td> nitric oxide, nitroglycerin, nitroprusside, nitrous oxide</td> </tr> <tr> <td> Local anesthetics</td><td> articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine</td> </tr> <tr> <td> Antineoplastic agents</td><td> cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase</td> </tr> <tr> <td> Antibiotics</td><td> dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides</td> </tr> <tr> <td> Antimalarials</td><td> chloroquine, primaquine</td> </tr> <tr> <td> Anticonvulsants</td><td> phenobarbital, phenytoin, sodium valproate</td> </tr> <tr class="Last"> <td> Other drugs</td><td> acetaminophen, metoclopramide, quinine, sulfasalazine</td> </tr> </tbody> </table></div>

Risk Summary

There are no studies conducted with XARACOLL in pregnant women to inform a drug-associated risk of adverse development outcomes. In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at clinically relevant doses. Decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning) at a dose level comparable to the daily maximum recommended human dose (MRHD). Based on animal data, advise pregnant women of the potential risks to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Labor or Delivery

Local anesthetics rapidly cross the placenta [see Pharmacokinetics (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 CNS, peripheral vascular tone, and cardiac function.

Data

Animal Data

Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses.

Bupivacaine HCl was administered subcutaneously to rats at doses of 4.4, 13.3 and 40 mg/kg and to rabbits at doses of 1.3, 5.8 and 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). No embryo-fetal effects were observed in rats at up to 40 mg/kg, a dose that caused increased maternal lethality. This dose is approximately 1.3 times the daily maximum recommended human dose (MRHD) of 300 mg when calculated on a mg/m2 body surface area (BSA) for a 60 kg woman. An increase in embryo-fetal deaths was observed in rabbits at the high dose (1.4 times the MHRD based on BSA) in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 0.4 times the MRHD on a BSA basis.

In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, and 40 mg/kg/day, decreased pup survival was observed at the high dose. The high dose is approximately 1.3 times the daily MRHD on a BSA basis.

Risk Summary

Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. There is no available information on effects of the drug in the breastfed infant or effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XARACOLL and any potential adverse effects on the breastfed infant from XARACOLL or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established. 

Of the total number of patients in the Phase 3 XARACOLL studies (N=411), 60 patients were greater than or equal to 65 years of age and 14 patients were greater than or equal to 75 years of age. No overall differences in efficacy and safety were observed between these patients and younger patients.  Clinical experience with XARACOLL has not identified differences in efficacy or safety between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In clinical studies of bupivacaine, differences in various pharmacokinetic parameters have been observed between elderly and younger patients.  Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function,  it may be useful to monitor renal function. The effects of age (elderly versus younger) on the pharmacokinetics of XARACOLL have not been studied.

Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations and potentially local anesthetic systemic toxicity. Consider increased monitoring for local anesthetic systemic toxicity in subjects with moderate to severe hepatic disease [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].

Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Patients with severe renal disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Consider increased monitoring for local anesthetic systemic toxicity in subjects with renal disease [see Clinical Pharmacology (12.3)].

Clinical Presentation

{ "type": "p", "children": [], "text": "\nClinical Presentation\n" }

Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics [see Warnings and Precautions (5.1), Adverse Reactions (6)]. 

{ "type": "p", "children": [], "text": "Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics [see Warnings and Precautions (5.1), Adverse Reactions (6)]. " }

If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of bupivacaine may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. If cardiac arrest occurs, successful outcome may require prolonged resuscitative efforts.

{ "type": "p", "children": [], "text": "If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of bupivacaine may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. If cardiac arrest occurs, successful outcome may require prolonged resuscitative efforts." }

Management

{ "type": "p", "children": [], "text": "\nManagement\n" }

The first step in the management of systemic toxic reactions consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated.

{ "type": "p", "children": [], "text": "The first step in the management of systemic toxic reactions consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated." }

If necessary, use drugs to manage the convulsions. A bolus intravenous dose of a benzodiazepine will counteract CNS stimulation related to XARACOLL. Immediately after the institution of ventilatory measures, evaluate the adequacy of the circulation. Supportive treatment of circulatory depression may require Advance Cardiac Life Support measures.

{ "type": "p", "children": [], "text": "If necessary, use drugs to manage the convulsions. A bolus intravenous dose of a benzodiazepine will counteract CNS stimulation related to XARACOLL. Immediately after the institution of ventilatory measures, evaluate the adequacy of the circulation. Supportive treatment of circulatory depression may require Advance Cardiac Life Support measures." }

Consider surgical removal of XARACOLL depending on the clinical situation.

{ "type": "p", "children": [], "text": "Consider surgical removal of XARACOLL depending on the clinical situation." }

Bupivacaine HCl is a 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide hydrochloride monohydrate, white crystalline powder that is freely soluble in 95% ethanol, soluble in water, and slightly soluble in acetone. The molecular formula of bupivacaine is C18H28N2O and its molecular weight is 288.4. It has the following structural formula:

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. Clinically, the order of loss of nerve function is (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

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 liquid formulations of bupivacaine.

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 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.

Local placement of XARACOLL within the surgical site during open inguinal hernia repair resulted in detectable plasma levels of bupivacaine at the first measured time point (0.5 hours) and throughout the 96-hour observation period [see Warnings and Precautions (5.1)]. Systemic plasma levels of bupivacaine following application of XARACOLL do not correlate with local efficacy.

Absorption

The rate of systemic absorption of bupivacaine is dependent on the total dose administered, the route of administration, and the vascularity of the administration site.

Pharmacokinetic parameters for XARACOLL following placement in the surgical site during hernioplasty are presented in Table 2.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2: Pharmacokinetic Parameters for Bupivacaine After Placement of XARACOLL in the Surgical Site During Open Inguinal Hernia Repair</span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Arithmetic mean (SD)</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>Median (SD)</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td><span class="Bold"> Parameter</span></td><td align="center"><span class="Bold">XARACOLL 300 mg</span> <br/> <span class="Bold">N=34</span></td> </tr> <tr> <td>C<span class="Sub">max</span> (ng/mL)<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a> [minimum, maximum]</td><td align="center">663 (264) [274, 1230]</td> </tr> <tr> <td>T<span class="Sub">max</span> (hours) <a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a> [minimum, maximum]</td><td align="center">3 [1.5, 24]</td> </tr> <tr> <td>AUC<span class="Sub">0-last</span> (h•ng/mL)<span class="Sup">*</span></td><td align="center">19493 (7564)</td> </tr> <tr> <td>AUC<span class="Sub">0-∞</span> (h•ng/mL)<span class="Sup">*</span></td><td align="center">20368 (7912)</td> </tr> <tr class="Last"> <td>t<span class="Sub">1/2</span> (hours)<span class="Sup">*</span></td><td align="center">19 (6)</td> </tr> </tbody> </table></div>

The highest individual bupivacaine plasma concentration observed in the XARACOLL clinical program was 1230 ng/mL, which occurred 2 hours after placement of the three XARACOLL 100 mg implants (total bupivacaine HCl dose 300 mg) in the surgical site of one patient.

Distribution

After bupivacaine is released from XARACOLL it is absorbed systemically. Local anesthetics including bupivacaine are distributed to some extent to all body tissues, with higher concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

Local anesthetics including bupivacaine appear 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 local anesthetics 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, non-ionized drugs such as bupivacaine readily enter the fetal blood from the maternal circulation.

Elimination

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

After bupivacaine has been released from XARACOLL and is absorbed systemically, bupivacaine excretion is expected to be the same as for other bupivacaine formulations.

The kidney is the main excretory organ for most local anesthetics and their metabolites. Only 6% of bupivacaine is excreted unchanged in the urine.

Specific Populations

Age

Various pharmacokinetic parameters of the local anesthetics such as bupivacaine can be significantly altered by the age of the patient [see Geriatric Use (8.5)].

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)].

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 Warnings and Precautions (5.1), Use in Specific Populations (8.7), Geriatric Use (8.5)].

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted.

Mutagenesis

Bupivacaine was not mutagenic or clastogenic in a bacterial reverse mutation assay, an in vitro mammalian cell gene mutation test, and an in vivo mammalian erythrocyte micronucleus assay.

Impairment of Fertility

The effect of bupivacaine on fertility has not been determined.

Bupivacaine collage-matrix implants delayed bone healing in a rat osteotomy model compared to saline, bupivacaine, or placebo collagen implant alone. The clinical significance of these delays is not known.

The efficacy and safety of XARACOLL were evaluated in two randomized, multi-center, double-blind, placebo-controlled Phase 3 trials in patients undergoing open inguinal repair under general anesthesia.

{ "type": "p", "children": [], "text": "The efficacy and safety of XARACOLL were evaluated in two randomized, multi-center, double-blind, placebo-controlled Phase 3 trials in patients undergoing open inguinal repair under general anesthesia." }

In Study 1, 298 patients were enrolled. The mean age was 53.2 years (range 19 to 86) and patients were predominantly male (96%). In Study 2, 312 patients were enrolled. The mean age was 49.7 years (range 18 to 85) and patients were predominantly male (98%). In each study, three XARACOLL implants, containing 100 mg bupivacaine HCl each, were cut in half. Three halves were placed into the hernia repair site below the site of mesh placement. The muscle/fascial layer was closed and the remaining three halves were placed between the fascia/muscle closure and the skin closure. The placebo consisted of three implants without bupivacaine HCl, similarly prepared and placed.  Use of low-dose lidocaine, administered topically or subcutaneously for intravenous catheter placement, or administered intravenously during the induction of general anesthesia prior to surgery and placement of XARACOLL, was reported.

{ "type": "p", "children": [], "text": "In Study 1, 298 patients were enrolled. The mean age was 53.2 years (range 19 to 86) and patients were predominantly male (96%). In Study 2, 312 patients were enrolled. The mean age was 49.7 years (range 18 to 85) and patients were predominantly male (98%). In each study, three XARACOLL implants, containing 100 mg bupivacaine HCl each, were cut in half. Three halves were placed into the hernia repair site below the site of mesh placement. The muscle/fascial layer was closed and the remaining three halves were placed between the fascia/muscle closure and the skin closure. The placebo consisted of three implants without bupivacaine HCl, similarly prepared and placed.  Use of low-dose lidocaine, administered topically or subcutaneously for intravenous catheter placement, or administered intravenously during the induction of general anesthesia prior to surgery and placement of XARACOLL, was reported." }

Pain intensity was rated by the patients using a 0 to 10 numerical rating scale at multiple time points up to 72 hours. Immediately postoperatively, patients were allowed parenteral morphine rescue medication as needed.  Once tolerating oral intake, patients received a standard acetaminophen regimen (650 mg orally three times daily) and immediate-release oral morphine (15 mg) was available as needed.

{ "type": "p", "children": [], "text": "Pain intensity was rated by the patients using a 0 to 10 numerical rating scale at multiple time points up to 72 hours. Immediately postoperatively, patients were allowed parenteral morphine rescue medication as needed.  Once tolerating oral intake, patients received a standard acetaminophen regimen (650 mg orally three times daily) and immediate-release oral morphine (15 mg) was available as needed." }

The primary outcome measure was the time-weighted sum of pain intensity from Time 0 through 24 hours (SPI24). The secondary endpoints were total use of opioid analgesia from Time 0 through 24 hours (TOpA24), time-weighted sum of pain intensity from Time 0 through 48 hours (SPI48), total use of opioid analgesia from Time 0 through 48 hours (TOpA48), time-weighted sum of pain intensity from Time 0 through 72 hours (SPI72), and total use of opioid analgesia from Time 0 through 72 hours (TOpA72).

{ "type": "p", "children": [], "text": "The primary outcome measure was the time-weighted sum of pain intensity from Time 0 through 24 hours (SPI24). The secondary endpoints were total use of opioid analgesia from Time 0 through 24 hours (TOpA24), time-weighted sum of pain intensity from Time 0 through 48 hours (SPI48), total use of opioid analgesia from Time 0 through 48 hours (TOpA48), time-weighted sum of pain intensity from Time 0 through 72 hours (SPI72), and total use of opioid analgesia from Time 0 through 72 hours (TOpA72)." }

In both Study 1 and Study 2, there was a statistically significant treatment effect for XARACOLL compared to placebo in SPI 24 and TOpA24. There was no statistically significant treatment effect for XARACOLL compared to placebo in SPI72 and TOpA72. Table 3 shows the mean sum of pain intensity over the first 24 hours after surgery.

{ "type": "p", "children": [], "text": "In both Study 1 and Study 2, there was a statistically significant treatment effect for XARACOLL compared to placebo in SPI 24 and TOpA24. There was no statistically significant treatment effect for XARACOLL compared to placebo in SPI72 and TOpA72. Table 3 shows the mean sum of pain intensity over the first 24 hours after surgery." }

<div class="scrollingtable"><table width="100%"> <caption> <span> Table 3: Mean Sum of Pain Intensity Over the First 24 Hours After Surgery (Primary Endpoint)</span> </caption> <tfoot> <tr> <td align="left" colspan="0"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>Placebo consisted of three collagen implants.</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">†</a> </dt> <dd>Primary endpoint</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">‡</a> </dt> <dd>Treatment compared with placebo</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td></td><td align="center" colspan="2"><span class="Bold">  Study 1</span></td><td align="center" colspan="2"><span class="Bold">  Study 2</span></td> </tr> <tr> <td></td><td align="center"> XARACOLL<br/>N=197</td><td align="center"> Placebo<span class="Sup">1</span> <br/>N=101</td><td align="center"> XARACOLL<br/>N=207</td><td align="center"> Placebo<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a> <br/>N=105</td> </tr> <tr> <td> SPI24<a class="Sup" href="#footnote-5" name="footnote-reference-5">†</a> <br/>Mean (SD)</td><td align="center"> <br/>85.9 (47.2)</td><td align="center"> 106.8 (48.2)</td><td align="center"> 88.3 (47.0)</td><td align="center"> 116.2 (44.0)</td> </tr> <tr class="Last"> <td> Difference<a class="Sup" href="#footnote-6" name="footnote-reference-6">‡</a> <br/>95% CI</td><td align="center"> -20.8<br/>(-32.2, -9.4)</td><td></td><td align="center">-27.8<br/>(-38.6, -17.1)</td><td></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span> Table 3: Mean Sum of Pain Intensity Over the First 24 Hours After Surgery (Primary Endpoint)</span>\n</caption>\n<tfoot>\n<tr>\n<td align=\"left\" colspan=\"0\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-4\" name=\"footnote-4\">*</a>\n</dt>\n<dd>Placebo consisted of three collagen implants.</dd>\n<dt>\n<a href=\"#footnote-reference-5\" name=\"footnote-5\">†</a>\n</dt>\n<dd>Primary endpoint</dd>\n<dt>\n<a href=\"#footnote-reference-6\" name=\"footnote-6\">‡</a>\n</dt>\n<dd>Treatment compared with placebo</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td></td><td align=\"center\" colspan=\"2\"><span class=\"Bold\">  Study 1</span></td><td align=\"center\" colspan=\"2\"><span class=\"Bold\">  Study 2</span></td>\n</tr>\n<tr>\n<td></td><td align=\"center\"> XARACOLL<br/>N=197</td><td align=\"center\"> Placebo<span class=\"Sup\">1</span>\n<br/>N=101</td><td align=\"center\"> XARACOLL<br/>N=207</td><td align=\"center\"> Placebo<a class=\"Sup\" href=\"#footnote-4\" name=\"footnote-reference-4\">*</a>\n<br/>N=105</td>\n</tr>\n<tr>\n<td> SPI24<a class=\"Sup\" href=\"#footnote-5\" name=\"footnote-reference-5\">†</a>\n<br/>Mean (SD)</td><td align=\"center\">\n<br/>85.9 (47.2)</td><td align=\"center\"> 106.8 (48.2)</td><td align=\"center\"> 88.3 (47.0)</td><td align=\"center\"> 116.2 (44.0)</td>\n</tr>\n<tr class=\"Last\">\n<td> Difference<a class=\"Sup\" href=\"#footnote-6\" name=\"footnote-reference-6\">‡</a>\n<br/>95% CI</td><td align=\"center\"> -20.8<br/>(-32.2, -9.4)</td><td></td><td align=\"center\">-27.8<br/>(-38.6, -17.1)</td><td></td>\n</tr>\n</tbody>\n</table></div>" }

SD=standard deviation; CI=confidence interval;SPI (sum of pain intensity):

{ "type": "p", "children": [], "text": "SD=standard deviation; CI=confidence interval;SPI (sum of pain intensity):" }

The proportion of patients who did not receive opioid rescue analgesia through 72 hours in the XARACOLL and placebo treatment groups was 36% and 22%, respectively, in Study 1, and 28% and 12%, respectively, in Study 2.  The median time to first opioid rescue analgesia in the XARACOLL and placebo treatment groups was 11 hours and 1 hour, respectively, in Study 1, and 6 hours and 1 hour, respectively in Study 2.

{ "type": "p", "children": [], "text": "The proportion of patients who did not receive opioid rescue analgesia through 72 hours in the XARACOLL and placebo treatment groups was 36% and 22%, respectively, in Study 1, and 28% and 12%, respectively, in Study 2.  The median time to first opioid rescue analgesia in the XARACOLL and placebo treatment groups was 11 hours and 1 hour, respectively, in Study 1, and 6 hours and 1 hour, respectively in Study 2." }

XARACOLL (bupivacaine HCl) implant is supplied as three white to off-white sterile surgical implants (approximately 5 cm × 5 cm × 0.5 cm), each containing 100 mg bupivacaine HCl in individually sealed blister packages. A tray of three blister packages in a sterile pouch is provided in one carton. XARACOLL is available as:

{ "type": "p", "children": [], "text": "XARACOLL (bupivacaine HCl) implant is supplied as three white to off-white sterile surgical implants (approximately 5 cm × 5 cm × 0.5 cm), each containing 100 mg bupivacaine HCl in individually sealed blister packages. A tray of three blister packages in a sterile pouch is provided in one carton. XARACOLL is available as:" }

{ "type": "ul", "children": [ "Four single-use cartons, each containing one pouch containing 3 x 100 mg implants  (NDC 51715-100-04)", "Ten single-use cartons, each containing one pouch containing 3 x 100 mg implants  (NDC 51715-100-10)" ], "text": "" }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

XARACOLL should be stored at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F). Brief exposure to temperatures up to 40°C (104°F) may be tolerated provided the mean kinetic temperature does not exceed 25°C (77°F); however, such exposure should be minimized.

{ "type": "p", "children": [], "text": "XARACOLL should be stored at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F). Brief exposure to temperatures up to 40°C (104°F) may be tolerated provided the mean kinetic temperature does not exceed 25°C (77°F); however, such exposure should be minimized." }

Handling

{ "type": "p", "children": [], "text": "\nHandling\n" }

Prior to surgical placement:

{ "type": "p", "children": [], "text": "Prior to surgical placement:" }

{ "type": "ul", "children": [ "Do not use if pouch or blister packaging has been compromised", "Avoid excessive handling", "Keep away from moisture", "Maintain sterility" ], "text": "" }

Allergic-Type Reactions

{ "type": "p", "children": [], "text": "\nAllergic-Type Reactions\n" }

Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients [see Contraindications (4), Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients [see Contraindications (4), Adverse Reactions (6)]." }

Methemoglobinemia

{ "type": "p", "children": [], "text": "\nMethemoglobinemia\n" }

Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

{ "type": "p", "children": [], "text": "Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue." }

Innocoll Pharmaceuticals Limited Athlone, Ireland N37 VW42

{ "type": "p", "children": [], "text": "Innocoll Pharmaceuticals Limited Athlone, Ireland N37 VW42" }

USA Patent Number: RE47,826 E

{ "type": "p", "children": [], "text": "USA Patent Number: RE47,826 E" }

Sep 2020; Version 1.6

{ "type": "p", "children": [], "text": "Sep 2020; Version 1.6" }

NDC 51715-100-03

{ "type": "p", "children": [], "text": "\nNDC 51715-100-03\n" }

xaracoll®

{ "type": "p", "children": [], "text": "\nxaracoll®\n" }

(bupivacaine HCl) implant

{ "type": "p", "children": [], "text": "\n(bupivacaine HCl) implant\n" }

100 mg per implant

{ "type": "p", "children": [], "text": "\n100 mg per implant\n" }

Pharmacist: Please dispense as 1 pouch

{ "type": "p", "children": [], "text": "\nPharmacist: Please dispense as 1 pouch\n" }

For surgical implantation

{ "type": "p", "children": [], "text": "\nFor surgical implantation\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

1 POUCH CONTAINING

{ "type": "p", "children": [], "text": "\n1 POUCH CONTAINING\n" }

3 x 100 mg STERILE IMPLANTS

{ "type": "p", "children": [], "text": "\n3 x 100 mg STERILE IMPLANTS\n" }

LOT:       EXP: 

{ "type": "p", "children": [], "text": "LOT:       EXP: " }

NDC 51715-100-03

{ "type": "p", "children": [], "text": "\nNDC 51715-100-03\n" }

xaracoll®

{ "type": "p", "children": [], "text": "\nxaracoll®\n" }

(bupivacaine HCl) implant

{ "type": "p", "children": [], "text": "\n(bupivacaine HCl) implant\n" }

100 mg per implant

{ "type": "p", "children": [], "text": "\n100 mg per implant\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

1 POUCH CONTAINING 3 x 100 mg STERILE IMPLANTS

{ "type": "p", "children": [], "text": "\n1 POUCH CONTAINING 3 x 100 mg STERILE IMPLANTS\n" }

Each implant contains: bupivacaine HCl 100 mg (equivalent to 88.8 mg bupivacaine)

{ "type": "p", "children": [], "text": "\nEach implant contains: bupivacaine HCl 100 mg (equivalent to 88.8 mg bupivacaine)\n" }

Dosage: 3 implants equivalent to 300 mg of bupivacaine HCl

{ "type": "p", "children": [], "text": "\nDosage: 3 implants equivalent to 300 mg of bupivacaine HCl\n" }

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F).

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F)." }

Do not use if pouch or blister packaging is damaged.

{ "type": "p", "children": [], "text": "Do not use if pouch or blister packaging is damaged." }

Pharmacist: Please dispense as 1 pouch

{ "type": "p", "children": [], "text": "\nPharmacist: Please dispense as 1 pouch\n" }

For surgical implantation

{ "type": "p", "children": [], "text": "\nFor surgical implantation\n" }

innocoll

{ "type": "p", "children": [], "text": "\ninnocoll\n" }

Distributed by: Innocoll Pharmaceuticals Ltd. Athlone, Ireland N37 VW42

{ "type": "p", "children": [], "text": "Distributed by: Innocoll Pharmaceuticals Ltd. Athlone, Ireland N37 VW42" }

NDC 51715-100-10

{ "type": "p", "children": [], "text": "\nNDC 51715-100-10\n" }

xaracoll®

{ "type": "p", "children": [], "text": "\nxaracoll®\n" }

(bupivacaine HCl) implant

{ "type": "p", "children": [], "text": "\n(bupivacaine HCl) implant\n" }

100 mg per implant

{ "type": "p", "children": [], "text": "\n100 mg per implant\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

CONTAINS 10 SINGLE-USE CARTONS, EACH CONTAINING 1 POUCH CONTAINING 3 x 100 mg STERILE IMPLANTS

{ "type": "p", "children": [], "text": "\nCONTAINS 10 SINGLE-USE CARTONS, EACH CONTAINING 1 POUCH CONTAINING 3 x 100 mg STERILE IMPLANTS\n" }

Each implant contains: bupivacaine HCl 100 mg (equivalent to 88.8 mg bupivacaine)

{ "type": "p", "children": [], "text": "\nEach implant contains: bupivacaine HCl 100 mg (equivalent to 88.8 mg bupivacaine)\n" }

Dosage: 3 implants equivalent to 300 mg of bupivacaine HCl

{ "type": "p", "children": [], "text": "\nDosage: 3 implants equivalent to 300 mg of bupivacaine HCl\n" }

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F).

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F)." }

Do not use if pouch or blister packaging is damaged.

{ "type": "p", "children": [], "text": "Do not use if pouch or blister packaging is damaged." }

Pharmacist: Please dispense as a single-use carton containing 1 pouch

{ "type": "p", "children": [], "text": "\nPharmacist: Please dispense as a single-use carton containing 1 pouch\n" }

For surgical implantation

{ "type": "p", "children": [], "text": "\nFor surgical implantation\n" }

Distributed by:

{ "type": "p", "children": [], "text": "Distributed by:" }

Innocoll Pharmaceuticals Ltd. Athlone, Ireland N37 VW42

{ "type": "p", "children": [], "text": "Innocoll Pharmaceuticals Ltd. Athlone, Ireland N37 VW42" }

innocoll

{ "type": "p", "children": [], "text": "\ninnocoll\n" }

NDC 51715-100-04

{ "type": "p", "children": [], "text": "\nNDC 51715-100-04\n" }

xaracoll®

{ "type": "p", "children": [], "text": "\nxaracoll®\n" }

(bupivacaine HCl) implant

{ "type": "p", "children": [], "text": "\n(bupivacaine HCl) implant\n" }

100 mg per implant

{ "type": "p", "children": [], "text": "\n100 mg per implant\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

CONTAINS 4 SINGLE-USE CARTONS, EACH CONTAINING 1 POUCH CONTAINING 3 x 100 mg STERILE IMPLANTS

{ "type": "p", "children": [], "text": "\nCONTAINS 4 SINGLE-USE CARTONS, EACH CONTAINING 1 POUCH CONTAINING 3 x 100 mg STERILE IMPLANTS\n" }

Each implant contains: bupivacaine HCl 100 mg (equivalent to 88.8 mg bupivacaine)

{ "type": "p", "children": [], "text": "\nEach implant contains: bupivacaine HCl 100 mg (equivalent to 88.8 mg bupivacaine)\n" }

Dosage: 3 implants equivalent to 300 mg of bupivacaine HCl

{ "type": "p", "children": [], "text": "\nDosage: 3 implants equivalent to 300 mg of bupivacaine HCl\n" }

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F).

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F)." }

Do not use if pouch or blister packaging is damaged.

{ "type": "p", "children": [], "text": "Do not use if pouch or blister packaging is damaged." }

Pharmacist: Please dispense as a single-use carton containing 1 pouch

{ "type": "p", "children": [], "text": "\nPharmacist: Please dispense as a single-use carton containing 1 pouch\n" }

For surgical implantation

{ "type": "p", "children": [], "text": "\nFor surgical implantation\n" }

innocoll

{ "type": "p", "children": [], "text": "\ninnocoll\n" }

Distributed by: Innocoll Pharmaceuticals Ltd. Athlone, Ireland N37 VW42

{ "type": "p", "children": [], "text": "Distributed by: Innocoll Pharmaceuticals Ltd. Athlone, Ireland N37 VW42" }

Limitations of Use

The safety and effectiveness of EXPAREL have not been established to produce postsurgical regional analgesia via other nerve blocks besides an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block.

Local Analgesia via Infiltration in Adults

The recommended dose of EXPAREL for local infiltration in adults is up to a maximum dose of 266 mg, and is based on the following factors:

As general guidance in selecting the proper EXPAREL dose for local infiltration in adults, two examples are provided [see Clinical Studies (14.2)]. In adult patients undergoing:

Local Analgesia via Infiltration in Pediatric Patients

The recommended dose of EXPAREL for one-time infiltration in pediatric patients, aged 6 to less than 17 years, is 4 mg/kg (up to a maximum of 266 mg), and is based upon two studies of pediatric patients undergoing either spine surgery or cardiac surgery [see Use in Specific Populations (8.4)].

The maximum recommended dose of EXPAREL via perineural use for interscalene brachial plexus nerve block, sciatic nerve block in the popliteal fossa, and adductor canal block is 133 mg. For all these nerve blocks, administer additional analgesics, which may include other immediate-release local anesthetics, as appropriate (for example, Mayo field block for bunionectomy, infiltration between the popliteal artery and capsule of the knee (IPACK) block for total knee arthroplasty).

Regional Analgesia via Interscalene Brachial Plexus Nerve Block in Adults

The recommended dose of EXPAREL for interscalene brachial plexus nerve block in adults is 133 mg and is based upon one study of patients undergoing either total shoulder arthroplasty or rotator cuff repair [see Clinical Studies (14.3)].

Regional Analgesia via Sciatic Nerve Block in the Popliteal Fossa in Adults

The recommended dose of EXPAREL for sciatic nerve block in the popliteal fossa in adults is 133 mg and is based upon one study of patients undergoing bunionectomy [see Clinical Studies (14.3)].

Regional Analgesia via Adductor Canal Block in Adults

The recommended dose of EXPAREL for adductor canal block in adults is 133 mg (10 mL) admixed with 50 mg (10 mL) 0.5% bupivacaine HCl, for a total volume of 20 mL, and is based upon one study of patients undergoing total knee arthroplasty [see Clinical Studies (14.3)].

Some physicochemical incompatibilities exist between EXPAREL and certain other drugs. Direct contact of EXPAREL with these drugs results in a rapid increase in free (unencapsulated) bupivacaine, altering EXPAREL characteristics and potentially affecting the safety and efficacy of EXPAREL. Therefore, admixing EXPAREL with other drugs prior to administration is not recommended [see Drug Interactions (7)].

Studies conducted with EXPAREL demonstrated that the most common implantable materials (polypropylene, PTFE, silicone, stainless steel, and titanium) are not affected by the presence of EXPAREL any more than they are by saline. None of the materials studied had an adverse effect on EXPAREL.

EXPAREL (bupivacaine liposome injectable suspension) is a white to off-white, milky aqueous suspension that is available in the following vial sizes:

{ "type": "p", "children": [], "text": "EXPAREL (bupivacaine liposome injectable suspension) is a white to off-white, milky aqueous suspension that is available in the following vial sizes:" }

{ "type": "ul", "children": [ "1.3% (266 mg/20 mL) (13.3 mg/mL) single-dose vial", "1.3% (133 mg/10 mL) (13.3 mg/mL) single-dose vial" ], "text": "" }

EXPAREL is contraindicated in obstetrical paracervical block anesthesia [see Use in Specific Populations (8.1)]. While EXPAREL has not been tested with this technique, the use of bupivacaine HCl with this technique has resulted in fetal bradycardia and death.

{ "type": "p", "children": [], "text": "EXPAREL is contraindicated in obstetrical paracervical block anesthesia [see Use in Specific Populations (8.1)]. While EXPAREL has not been tested with this technique, the use of bupivacaine HCl with this technique has resulted in fetal bradycardia and death." }

The safety and effectiveness of EXPAREL, other bupivacaine products, and other amide-containing products depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. As there is a potential risk of severe life-threatening adverse reactions associated with the administration of bupivacaine, any bupivacaine-containing product should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity [see Overdosage (10)].

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 bupivacaine and other amide-containing products. Restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity.

EXPAREL, other bupivacaine products, and other amide-containing products should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs.

Injection of multiple doses of EXPAREL, other bupivacaine products, and other amide-containing products may cause significant increases in plasma concentrations with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood concentrations varies with the status of the patient.

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations.

Central Nervous System Reactions

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. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. Neurologic effects following infiltration of soft tissue may include persistent anesthesia, paresthesia, weakness, and paralysis, all of which may have slow, incomplete, or no recovery.

Central nervous system reactions are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered.

Cardiovascular System Reactions

Toxic blood concentrations depress cardiac conductivity 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 [See Overdosage (10)].

Allergic Reactions

Allergic-type reactions are rare and may occur as a result of hypersensitivity to the local anesthetic or to other formulation ingredients. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly anaphylactoid-like symptoms (including severe hypotension). Cross-sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established.

Chondrolysis

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been postmarketing 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 patients 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 second month after surgery. Currently, there is no effective treatment for chondrolysis; patients who have experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

Methemoglobinemia

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue EXPAREL and any 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.

As there is a potential risk of severe life-threatening adverse reactions associated with the administration of bupivacaine, EXPAREL should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity [See Overdosage (10)].

Caution should be taken to avoid accidental intravascular injection of EXPAREL. Convulsions and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and other amide-containing products.

Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

EXPAREL has not been evaluated for the following uses and, therefore, is not recommended for these routes of administration or types of analgesia:

EXPAREL has not been evaluated for use in the following patient populations and, therefore, is not recommended for administration to these groups.

The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dose administered and may last for up to 5 days as seen in clinical trials.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adverse Reactions Reported in All Local Infiltration Clinical Studies in Adults

The safety of EXPAREL (local administration into the surgical site) was evaluated in 10 randomized, double-blind, clinical studies (including Studies 1 and 2 [see Clinical Studies (14.2)]) that included 823 adult patients who had various surgical procedures. Patients were administered an EXPAREL dose ranging from 66 to 532 mg (two times the maximum recommended dose of 266 mg). In these studies, following EXPAREL administration, the:

Neurological and Cardiac Adverse Reactions

In the EXPAREL surgical site infiltration studies, following EXPAREL administration adverse reactions with an incidence greater than or equal to 1% in the:

Adverse Reactions Reported in All Local Infiltration Placebo-Controlled Trials in Adults

Adverse reactions with an incidence greater than or equal to 2% reported by adult patients in clinical studies who underwent a bunionectomy (Study 1) or hemorrhoidectomy (Study 2) [see Clinical Studies (14.2)] that compared 106 mg of EXPAREL (8 mL) to placebo and 266 mg of EXPAREL (20 mL) to placebo are shown in Table 1.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 1: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Local Infiltration Placebo-Controlled Studies in Adults (Studies 1 and 2) </span> </caption> <col align="left" valign="top" width="34%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="15%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="15%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="3" valign="middle">System Organ Class<br/>  Preferred Term</th><th align="center" class="Rrule" colspan="2">Study 1<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></th><th align="center" class="Rrule" colspan="2">Study 2<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></th> </tr> <tr class="Botrule"> <th align="center" class="Lrule Rrule">EXPAREL</th><th align="center" class="Rrule">Placebo</th><th align="center" class="Rrule">EXPAREL</th><th align="center" class="Rrule">Placebo</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule" valign="middle">106 mg<br/>(N=97)<br/>n (%)</th><th align="center" class="Rrule" valign="middle">(N=96)<br/>n (%)</th><th align="center" class="Rrule" valign="middle">266 mg<br/>(N=95)<br/>n (%)</th><th align="center" class="Rrule" valign="middle">(N=94)<br/>n (%)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">TEAE = treatment-emergent adverse event. <br/>At each level of summation (overall, system organ class, preferred term), patients are only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Study 1: Bunionectomy; </dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>Study 2: Hemorrhoidectomy; </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Any TEAE</td><td align="center" class="Rrule">53 (54.6)</td><td align="center" class="Rrule">59 (61.5)</td><td align="center" class="Rrule">10 (10.5)</td><td align="center" class="Rrule">17 (18.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Gastrointestinal Disorders</td><td align="center" class="Rrule">41 (42.3)</td><td align="center" class="Rrule">38 (39.6)</td><td align="center" class="Rrule">7 (7.4)</td><td align="center" class="Rrule">13 (13.8)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">39 (40.2)</td><td align="center" class="Rrule">36 (37.5)</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">1 (1.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Vomiting</td><td align="center" class="Rrule">27 (27.8)</td><td align="center" class="Rrule">17 (17.7)</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">4 (4.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Constipation</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">1 (1.0)</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">2 (2.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anal Hemorrhage</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">3 (3.2)</td><td align="center" class="Rrule">4 (4.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Painful Defecation</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">5 (5.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Rectal Discharge</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">1 (1.1)</td><td align="center" class="Rrule">3 (3.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nervous System Disorders</td><td align="center" class="Rrule">20 (20.6)</td><td align="center" class="Rrule">30 (31.3)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dizziness</td><td align="center" class="Rrule">11 (11.3)</td><td align="center" class="Rrule">25 (26.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">5 (5.2)</td><td align="center" class="Rrule">8 (8.3)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Somnolence</td><td align="center" class="Rrule">5 (5.2)</td><td align="center" class="Rrule">1 (1.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Syncope</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Skin And Subcutaneous Tissue Disorders</td><td align="center" class="Rrule">8 (8.2)</td><td align="center" class="Rrule">7 (7.3)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Generalized Pruritus</td><td align="center" class="Rrule">5 (5.2)</td><td align="center" class="Rrule">6 (6.3)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pruritus</td><td align="center" class="Rrule">3 (3.1)</td><td align="center" class="Rrule">1 (1.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Investigations</td><td align="center" class="Rrule">5 (5.2)</td><td align="center" class="Rrule">3 (3.1)</td><td align="center" class="Rrule">4 (4.2)</td><td align="center" class="Rrule">3 (3.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Increased Alanine Aminotransferase</td><td align="center" class="Rrule">3 (3.1)</td><td align="center" class="Rrule">3 (3.1)</td><td align="center" class="Rrule">1 (1.1)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Increased Aspartate Aminotransferase</td><td align="center" class="Rrule">3 (3.1)</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Increased Blood Creatinine</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Increased Body Temperature</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">3 (3.2)</td><td align="center" class="Rrule">3 (3.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">General Disorders And Administration Site Conditions</td><td align="center" class="Rrule">4 (4.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">1 (1.1)</td><td align="center" class="Rrule">1 (1.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Feeling Hot</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pyrexia</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">1 (1.1)</td><td align="center" class="Rrule">1 (1.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Infections And Infestations</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">1 (1.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fungal Infection</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">1 (1.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Injury, Poisoning And Procedural Complications</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Post Procedural Swelling</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Metabolism And Nutrition Disorders</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Decreased Appetite</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0 (0.0)</td><td align="center" class="Rrule">0 (0.0)</td> </tr> </tbody> </table></div>

Adverse Reactions Reported in All Local Infiltration Clinical Studies in Pediatric Patients Aged 6 to Less Than 17 Years

The safety of EXPAREL in 110 pediatric patients between the age of 6 and 17 years old who had spine or cardiac surgical procedures was evaluated in one randomized, open-label, clinical study in which EXPAREL was administered by infiltration into the surgical site (Study Peds-1) and one single-arm, open-label study in which EXPAREL was administered by infiltration into the surgical site (Study Peds-2) [see Use in Specific Populations (8.4)]. Patients were administered a weight-based dose of EXPAREL at 4 mg/kg (maximum dose of 266 mg) or bupivacaine HCl 2 mg/kg (maximum dose of 175 mg).

In these studies, following EXPAREL administration the:

Neurological and Cardiac Adverse Reactions in Pediatric Patients Aged 6 to Less than 17 Years Old

In the EXPAREL infiltration studies in pediatric patients aged 6 to less than 17 years old (Studies Peds-1 and Peds-2), following EXPAREL administration adverse reactions with an incidence greater than or equal to 1% in the:

Adverse Reactions Reported in All Local Infiltration Trials in Pediatric Patients Aged 6 to Less than 17 Years Old

Adverse reactions with an incidence greater than or equal to 2% reported by patients in clinical studies (Studies Peds-1 and Peds-2) studying 4 mg/kg EXPAREL are shown in Table 2.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2: Treatment-Emergent Adverse Reactions (TEAE) with an Incidence Greater than or Equal to 2%: Local Infiltration Studies in Pediatric Patients Aged 6 to Less than 17 Years Old (Study Peds-1 and Peds-2)</span> </caption> <col align="left" valign="top" width="40%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2" valign="middle">System Organ Class<br/>Preferred Term</th><th align="center" class="Rrule" colspan="2">Study Peds-1<a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a></th><th align="center" class="Rrule">Study Peds-2<a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">Spine Surgery<br/>EXPAREL<br/>4 mg/kg<a class="Sup" href="#footnote-5" name="footnote-reference-5">‡</a> <br/>(N=36)<br/>n (%)</th><th align="center" class="Rrule">Cardiac Surgery<br/>EXPAREL<br/>4 mg/kg<a class="Sup" href="#footnote-5">‡</a> <br/>(N=29)<br/>n (%)</th><th align="center" class="Rrule">Spine Surgery<br/>EXPAREL<br/>4 mg/kg<a class="Sup" href="#footnote-5">‡</a> <br/>(N=15)<br/>n (%)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4">At each level of summation (overall, system organ class, preferred term), patients are only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group.<br/>TEAE = treatment-emergent adverse event.</td> </tr> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>Study 1: Includes spine surgery patients aged 6 to less than 17 years old, and cardiac surgery patients aged 6 to less than 12 years old.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>Study 2: Includes spine surgery patients aged 12 to less than 17 years old.</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">‡</a> </dt> <dd>Patients received EXPAREL 4 mg/kg, not to exceed 266 mg.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Patients with at least one TEAE</td><td align="center" class="Rrule">24 (66.7)</td><td align="center" class="Rrule">9 (31.0)</td><td align="center" class="Rrule">15 (100.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Blood and lymphatic system disorders</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">15 (100)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anemia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">15 (100)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Cardiac disorders</td><td align="center" class="Rrule">3 (8.3)</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">12 (80.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Bradycardia</td><td align="center" class="Rrule">2 (5.6)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">5 (33.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Sinus tachycardia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Tachycardia </td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">8 (53.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Ventricular extrasystoles</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Ear and labyrinth disorders</td><td align="center" class="Rrule">2 (5.6)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (13.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Ear discomfort</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypoacusis</td><td align="center" class="Rrule">2 (5.6)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Eye disorders</td><td align="center" class="Rrule">10 (27.8)</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">4 (26.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Diplopia</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Eye swelling</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Increased Lacrimation</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Blurred Vision</td><td align="center" class="Rrule">7 (19.4)</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">3 (20.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Visual impairment</td><td align="center" class="Rrule">2 (5.6)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Gastrointestinal disorders</td><td align="center" class="Rrule">18 (50.0)</td><td align="center" class="Rrule">7 (24.1)</td><td align="center" class="Rrule">14 (93.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Abdominal Pain</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Constipation</td><td align="center" class="Rrule">9 (25.0)</td><td align="center" class="Rrule">4 (13.8)</td><td align="center" class="Rrule">7 (46.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">11 (30.6)</td><td align="center" class="Rrule">2 (6.9)</td><td align="center" class="Rrule">9 (60.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Diarrhea</td><td align="center" class="Rrule">3 (8.3)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dyspepsia</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Flatulence</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Hypoesthesia</td><td align="center" class="Rrule">4 (11.1)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (13.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Lip Swelling</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Vomiting</td><td align="center" class="Rrule">10 (27.8)</td><td align="center" class="Rrule">4 (13.8)</td><td align="center" class="Rrule">8 (53.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">General disorders and administration site conditions</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">3 (20.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Chest pain</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Face edema</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Gait disturbance</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Generalized edema</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pyrexia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3 (20.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Infections and infestations</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Ear infection</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fungal wound infection</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Injury, poisoning and procedural complications</td><td align="center" class="Rrule">8 (22.2)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Postoperative Anemia</td><td align="center" class="Rrule">5 (13.9)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Delayed recovery from anesthesia</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fall</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Incision site hemorrhage</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Joint dislocation</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Procedural hemorrhage</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Seroma</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Metabolism and nutrition disorders</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3 (10.3)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Acidosis</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hyperglycemia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypomagnesaemia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Metabolic acidosis</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Musculoskeletal and connective tissue disorders</td><td align="center" class="Rrule">8 (22.2)</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">12 (80.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Back pain</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (13.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Flank pain</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Muscle twitching</td><td align="center" class="Rrule">3 (8.3)</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">9 (60.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Muscle spasms</td><td align="center" class="Rrule">4 (11.1)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3 (20.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Muscular weakness</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (13.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Musculoskeletal pain</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Musculoskeletal chest pain</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pain in extremity</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nervous system disorders</td><td align="center" class="Rrule">3 (8.3)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">7 (46.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Burning sensation</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dizziness</td><td align="center" class="Rrule">2 (5.6)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3 (20.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dysgeusia</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypoesthesia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3 (20.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Paresthesia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Syncope</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Psychiatric disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (13.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anxiety</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Panic attack</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Renal and urinary disorders</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (13.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hematuria</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (13.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Respiratory, thoracic and mediastinal disorders</td><td align="center" class="Rrule">3 (8.3)</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">7 (46.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Atelectasis</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Bradypnea</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dyspnea</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypopnea</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypoxia</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pleural effusion</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Tachypnea</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">6 (40.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Skin and subcutaneous tissue disorders</td><td align="center" class="Rrule">4 (11.1)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">6 (40.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pruritus</td><td align="center" class="Rrule">3 (8.3)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">6 (40.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Generalized Pruritus</td><td align="center" class="Rrule">1 (2.8)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Rash</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (6.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Vascular disorders</td><td align="center" class="Rrule">4 (11.1)</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">14 (93.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hot flush</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypotension</td><td align="center" class="Rrule">4 (11.1)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">14 (93.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypertension</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (3.4)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Systolic hypertension</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> </tbody> </table></div>

Adverse Reactions Reported in Placebo-Controlled Nerve Block Clinical Studies in Adults

The safety of EXPAREL was evaluated in four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) [see Clinical Studies (14.3, 14.4)] involving 469 EXPAREL-treated adult patients and 357 placebo-treated patients who had various surgical procedures. Patients were administered placebo or an EXPAREL dose of either 133 or 266 mg (two times the maximum recommended dose for these nerve blocks). In these studies, following EXPAREL administration via nerve block (perineural use) the:

The most common and common adverse reactions for the four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) are shown in Table 3.

Neurological and Cardiac Adverse Reactions

In the EXPAREL nerve block placebo-controlled studies, following EXPAREL administration adverse reactions with an incidence greater than or equal to 1% in the:

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Nerve Block Placebo-Controlled Studies (Studies 3, 6, 7, and 8)</span> </caption> <col align="left" valign="middle" width="50%"/> <col align="center" valign="middle" width="16%"/> <col align="center" valign="middle" width="17%"/> <col align="center" valign="middle" width="17%"/> <thead> <tr class="First Last"> <th align="left" valign="bottom">SYSTEM ORGAN CLASS<br/>  Preferred Term</th><th align="center" valign="bottom">EXPAREL<br/>133 mg<br/>(N=168)<br/>n (%)</th><th align="center" valign="bottom">EXPAREL<br/>266 mg<br/>(N=301)<br/>n (%)</th><th align="center" valign="bottom">Placebo<br/>(N=357)<br/>n (%)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4">At each level of summation (overall, system organ class, preferred term), patients are only counted once.<br/>Preferred terms are included where at least 2% of patients reported the event in any treatment group.<br/>TEAE = treatment-emergent adverse event.</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Number of Patients with at Least One TEAE</td><td align="center" class="Rrule">152 (90.5)</td><td align="center" class="Rrule">260 (86.4)</td><td align="center" class="Rrule">299 (83.8)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Blood and Lymphatic System Disorders</td><td align="center" class="Rrule">2 (1.2)</td><td align="center" class="Rrule">22 (7.3)</td><td align="center" class="Rrule">15 (4.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anemia</td><td align="center" class="Rrule">2 (1.2)</td><td align="center" class="Rrule">18 (6.0)</td><td align="center" class="Rrule">13 (3.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Cardiac Disorders</td><td align="center" class="Rrule">13 (7.7)</td><td align="center" class="Rrule">34 (11.3)</td><td align="center" class="Rrule">38 (10.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Atrial Fibrillation</td><td align="center" class="Rrule">1 (0.6)</td><td align="center" class="Rrule">4 (1.3)</td><td align="center" class="Rrule">8 (2.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Sinus Tachycardia</td><td align="center" class="Rrule">3 (1.8)</td><td align="center" class="Rrule">8 (2.7)</td><td align="center" class="Rrule">4 (1.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Tachycardia</td><td align="center" class="Rrule">3 (1.8)</td><td align="center" class="Rrule">11 (3.7)</td><td align="center" class="Rrule">10 (2.8)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Gastrointestinal Disorders</td><td align="center" class="Rrule">84 (50.0)</td><td align="center" class="Rrule">154 (51.2)</td><td align="center" class="Rrule">184 (51.5)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Constipation</td><td align="center" class="Rrule">29 (17.3)</td><td align="center" class="Rrule">66 (21.9)</td><td align="center" class="Rrule">68 (19.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dyspepsia</td><td align="center" class="Rrule">3 (1.8)</td><td align="center" class="Rrule">7 (2.3)</td><td align="center" class="Rrule">7 (2.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oral Hypoesthesia</td><td align="center" class="Rrule">6 (3.6)</td><td align="center" class="Rrule">8 (2.7)</td><td align="center" class="Rrule">7 (2.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">62 (36.9)</td><td align="center" class="Rrule">111 (36.9)</td><td align="center" class="Rrule">133 (37.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Vomiting</td><td align="center" class="Rrule">17 (10.1)</td><td align="center" class="Rrule">55 (18.3)</td><td align="center" class="Rrule">73 (20.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">General Disorders And Administration Site Conditions</td><td align="center" class="Rrule">52 (31.0)</td><td align="center" class="Rrule">102 (33.9)</td><td align="center" class="Rrule">91 (25.5)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fatigue</td><td align="center" class="Rrule">7 (4.2)</td><td align="center" class="Rrule">15 (5.0)</td><td align="center" class="Rrule">15 (4.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Feeling Cold</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">10 (3.3)</td><td align="center" class="Rrule">8 (2.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Peripheral Edema</td><td align="center" class="Rrule">4 (2.4)</td><td align="center" class="Rrule">6 (2.0)</td><td align="center" class="Rrule">8 (2.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Peripheral Swelling</td><td align="center" class="Rrule">3 (1.8)</td><td align="center" class="Rrule">8 (2.7)</td><td align="center" class="Rrule">4 (1.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pyrexia</td><td align="center" class="Rrule">36 (21.4)</td><td align="center" class="Rrule">70 (23.3)</td><td align="center" class="Rrule">64 (17.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Injury, Poisoning And Procedural Complications</td><td align="center" class="Rrule">18 (10.7)</td><td align="center" class="Rrule">44 (14.6)</td><td align="center" class="Rrule">32 (9.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Postoperative Anemia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">8 (2.7)</td><td align="center" class="Rrule">10 (2.8)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Contusion</td><td align="center" class="Rrule">4 (2.4)</td><td align="center" class="Rrule">1 (0.3)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fall</td><td align="center" class="Rrule">4 (2.4)</td><td align="center" class="Rrule">8 (2.7)</td><td align="center" class="Rrule">1 (0.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Post Procedural Hematoma</td><td align="center" class="Rrule">4 (2.4)</td><td align="center" class="Rrule">1 (0.3)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Procedural Hypotension</td><td align="center" class="Rrule">2 (1.2)</td><td align="center" class="Rrule">13 (4.3)</td><td align="center" class="Rrule">7 (2.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Investigations</td><td align="center" class="Rrule">18 (10.7)</td><td align="center" class="Rrule">31 (10.3)</td><td align="center" class="Rrule">31 (8.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Increased Body Temperature</td><td align="center" class="Rrule">1 (0.6)</td><td align="center" class="Rrule">10 (3.3)</td><td align="center" class="Rrule">4 (1.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Increased Hepatic Enzyme</td><td align="center" class="Rrule">7 (4.2)</td><td align="center" class="Rrule">1 (0.3)</td><td align="center" class="Rrule">3 (0.8)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Metabolism and Nutrition Disorders</td><td align="center" class="Rrule">13 (7.7)</td><td align="center" class="Rrule">18 (6.0)</td><td align="center" class="Rrule">25 (7.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypokalemia</td><td align="center" class="Rrule">7 (4.2)</td><td align="center" class="Rrule">9 (3.0)</td><td align="center" class="Rrule">14 (3.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Musculoskeletal And Connective Tissue Disorders</td><td align="center" class="Rrule">22 (13.1)</td><td align="center" class="Rrule">47 (15.6)</td><td align="center" class="Rrule">41 (11.5)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Decreased Mobility</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">6 (2.0)</td><td align="center" class="Rrule">5 (1.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Muscle Twitching</td><td align="center" class="Rrule">14 (8.3)</td><td align="center" class="Rrule">21 (7.0)</td><td align="center" class="Rrule">25 (7.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nervous System Disorders</td><td align="center" class="Rrule">72 (42.9)</td><td align="center" class="Rrule">101 (33.6)</td><td align="center" class="Rrule">112 (31.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dizziness</td><td align="center" class="Rrule">8 (4.8)</td><td align="center" class="Rrule">28 (9.3)</td><td align="center" class="Rrule">40 (11.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dysgeusia</td><td align="center" class="Rrule">12 (7.1)</td><td align="center" class="Rrule">22 (7.3)</td><td align="center" class="Rrule">21 (5.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">14 ( 8.3)</td><td align="center" class="Rrule">10 (3.3)</td><td align="center" class="Rrule">10 (2.8)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypoesthesia</td><td align="center" class="Rrule">6 (3.6)</td><td align="center" class="Rrule">5 (1.7)</td><td align="center" class="Rrule">2 (0.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Motor Dysfunction</td><td align="center" class="Rrule">35 (20.8)</td><td align="center" class="Rrule">35 (11.6)</td><td align="center" class="Rrule">37 (10.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Sensory Loss</td><td align="center" class="Rrule">4 (2.4)</td><td align="center" class="Rrule">7 (2.3)</td><td align="center" class="Rrule">1 (0.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Psychiatric Disorders</td><td align="center" class="Rrule">10 (6.0)</td><td align="center" class="Rrule">33 (11.0)</td><td align="center" class="Rrule">44 (12.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anxiety</td><td align="center" class="Rrule">3 (1.8)</td><td align="center" class="Rrule">9 (3.0)</td><td align="center" class="Rrule">6 (1.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Confusional State</td><td align="center" class="Rrule">3 (1.8)</td><td align="center" class="Rrule">15 (5.0)</td><td align="center" class="Rrule">14 (3.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Insomnia</td><td align="center" class="Rrule">5 (3.0)</td><td align="center" class="Rrule">10 (3.3)</td><td align="center" class="Rrule">19 (5.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Renal And Urinary Disorders</td><td align="center" class="Rrule">9 (5.4)</td><td align="center" class="Rrule">31 (10.3)</td><td align="center" class="Rrule">31 (8.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Urinary Retention</td><td align="center" class="Rrule">5 (3.0)</td><td align="center" class="Rrule">23 (7.6)</td><td align="center" class="Rrule">22 (6.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Respiratory, Thoracic And Mediastinal Disorders</td><td align="center" class="Rrule">18 (10.7)</td><td align="center" class="Rrule">30 (10.0)</td><td align="center" class="Rrule">31 (8.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dyspnea</td><td align="center" class="Rrule">2 (1.2)</td><td align="center" class="Rrule">4 (1.3)</td><td align="center" class="Rrule">8 (2.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hiccups</td><td align="center" class="Rrule">4 (2.4)</td><td align="center" class="Rrule">4 (1.3)</td><td align="center" class="Rrule">1 (0.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypoxia</td><td align="center" class="Rrule">4 (2.4)</td><td align="center" class="Rrule">3 (1.0)</td><td align="center" class="Rrule">3 (0.8)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Skin And Subcutaneous Tissue Disorders</td><td align="center" class="Rrule">24 (14.3)</td><td align="center" class="Rrule">63 (20.9)</td><td align="center" class="Rrule">84 (23.5)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hyperhidrosis</td><td align="center" class="Rrule">1 (0.6)</td><td align="center" class="Rrule">14 (4.7)</td><td align="center" class="Rrule">15 (4.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pruritus</td><td align="center" class="Rrule">10 (6.0)</td><td align="center" class="Rrule">45 (15.0)</td><td align="center" class="Rrule">55 (15.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Generalized Pruritus</td><td align="center" class="Rrule">6 (3.6)</td><td align="center" class="Rrule">7 (2.3)</td><td align="center" class="Rrule">14 (3.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Vascular Disorders</td><td align="center" class="Rrule">16 (9.5)</td><td align="center" class="Rrule">30 (10.0)</td><td align="center" class="Rrule">44 (12.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypertension</td><td align="center" class="Rrule">3 (1.8)</td><td align="center" class="Rrule">15 (5.0)</td><td align="center" class="Rrule">21 (5.9)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Hypotension</td><td align="center" class="Rrule">11 (6.5)</td><td align="center" class="Rrule">8 (2.7)</td><td align="center" class="Rrule">19 (5.3)</td> </tr> </tbody> </table></div>

Adverse Reactions Reported in Active-Controlled Nerve Block Clinical Studies in Approved Populations

The safety of EXPAREL was evaluated in two randomized, double-blind, active-controlled nerve block clinical studies in 189 adult patients who had a bunionectomy or a total knee arthroplasty (Studies 4 and 5) [see Clinical Studies (14.3)]. Via nerve block, patients received 133 mg of EXPAREL, 266 mg of EXPAREL (two times the maximum recommended EXPAREL dose) [see Dosage and Administration (2.3)] or 133 mg of EXPAREL admixed with 50 mg of bupivacaine HCl. In both of these studies the active comparator was 50 mg of bupivacaine HCl.

The most common adverse reactions (incidence greater than or equal to 10%) in Studies 4 and 5 following:

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) in Studies 4 and 5 following:

The less common adverse reactions (incidence less than 2%) in Studies 4 and 5 following:

The most common and common adverse reactions in adult patients in the active-controlled clinical studies are shown in Table 4.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Nerve Block Active-Controlled Studies (Studies 4 and 5)</span> </caption> <col align="left" valign="top" width="36%"/> <col align="center" valign="top" width="16%"/> <col align="center" valign="top" width="16%"/> <col align="center" valign="top" width="16%"/> <col align="center" valign="top" width="16%"/> <thead> <tr class="First Last"> <th align="left" valign="bottom">SYSTEM ORGAN CLASS<br/>  Preferred Term</th><th align="center">EXPAREL<br/>133 mg<br/>(N=81)<br/>n (%)</th><th align="center">EXPAREL<br/>266 mg<br/>(N=22)<br/>n (%)</th><th align="center">EXPAREL<br/>133 mg + Bupi<br/>(N = 86)<br/>n (%)</th><th align="center"> Bupi<br/>(N=162)<br/>n (%)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">At each level of summation (overall, system organ class, preferred term), patients were only counted once.<br/>Preferred terms are included where at least 2% of patients reported the event in any treatment group.<br/>TEAE = treatment-emergent adverse event.</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Number of Patients with at Least One TEAE</td><td align="center" class="Rrule">42 (51.9)</td><td align="center" class="Rrule">13 (59.1)</td><td align="center" class="Rrule">77 (89.5)</td><td align="center" class="Rrule">116 (71.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Cardiac Disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Tachycardia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">4 (4.7)</td><td align="center" class="Rrule">5 (3.1)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Gastrointestinal Disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Constipation</td><td align="center" class="Rrule">10 (12.3)</td><td align="center" class="Rrule">3 (13.6)</td><td align="center" class="Rrule">30 (34.9)</td><td align="center" class="Rrule">47 (29.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dyspepsia</td><td align="center" class="Rrule">2 (2.5)</td><td align="center" class="Rrule">1 (4.5)</td><td align="center" class="Rrule">2 (2.3)</td><td align="center" class="Rrule">2 (1.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">13 (16)</td><td align="center" class="Rrule">9 (40.9)</td><td align="center" class="Rrule">34 (39.5)</td><td align="center" class="Rrule">49 (30.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Vomiting</td><td align="center" class="Rrule">4 (4.9)</td><td align="center" class="Rrule">5 (22.7)</td><td align="center" class="Rrule">5 (5.8)</td><td align="center" class="Rrule">13 (8.0)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">General Disorders And Administration Site Conditions</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pyrexia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (4.5)</td><td align="center" class="Rrule">3 (3.5)</td><td align="center" class="Rrule">3 (1.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Investigations</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Increased Heart rate</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3 (3.5)</td><td align="center" class="Rrule">3 (1.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Metabolism and Nutrition Disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypokalemia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (2.3)</td><td align="center" class="Rrule">2 (1.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hyponatremia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (2.3)</td><td align="center" class="Rrule">2 (1.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Musculoskeletal And Connective Tissue Disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Back pain</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (2.3)</td><td align="center" class="Rrule">3 (1.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Muscle Spasms</td><td align="center" class="Rrule">2 (2.5)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">11 (12.8)</td><td align="center" class="Rrule">10 (6.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nervous System Disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dizziness</td><td align="center" class="Rrule">2 (2.5)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">4 (4.7)</td><td align="center" class="Rrule">4 (2.5)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">8 (9.9)</td><td align="center" class="Rrule">1 (4.5)</td><td align="center" class="Rrule">13 (15.1)</td><td align="center" class="Rrule">6 (3.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypoaesthesia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">9 (12.7)</td><td align="center" class="Rrule">2 (2.1)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Peroneal Nerve Palsy</td><td align="center" class="Rrule">3 (3.7)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Psychiatric Disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Disorientation</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (2.3)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Insomnia</td><td align="center" class="Rrule">2 (2.5)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">5 (5.8)</td><td align="center" class="Rrule">14 (8.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Respiratory, Thoracic And Mediastinal Disorders </td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypoxia</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">4 (4.7)</td><td align="center" class="Rrule">4 (2.5)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Oropharyngeal Pain</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (2.3)</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Skin And Subcutaneous Tissue Disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Pruritus</td><td align="center" class="Rrule">6 (7.4)</td><td align="center" class="Rrule">1 (4.5)</td><td align="center" class="Rrule">6 (7.0)</td><td align="center" class="Rrule">9 (5.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Rash</td><td align="center" class="Rrule">4 (4.9)</td><td align="center" class="Rrule">1 (4.5)</td><td align="center" class="Rrule">1 (1.2)</td><td align="center" class="Rrule">1 (0.6)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Vascular Disorders</td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Hypertension</td><td align="center" class="Rrule">3 (3.7)</td><td align="center" class="Rrule">1 (4.5)</td><td align="center" class="Rrule">5 (5.8)</td><td align="center" class="Rrule">7 (4.3)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Hypotension</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3 (3.5)</td><td align="center" class="Rrule">9 (5.6)</td> </tr> </tbody> </table></div>

Notable Adverse Reactions from Active-Controlled Studies in Unapproved Populations

The safety of EXPAREL was evaluated in a multicenter, randomized, double-blind, active-controlled trial in 119 patients undergoing foot and ankle procedures (Study 9) [see Clinical Studies (14.3)]. Patients were administered a dose of either 266 mg EXPAREL, 266 mg EXPAREL admixed with 50 mg bupivacaine HCl, or 100 mg bupivacaine HCl. The following adverse reactions were observed following administration of EXPAREL or EXPAREL admixed with bupivacaine in Study 9 that either were not observed in Studies 4 and 5, or were observed at a higher frequency than was observed in Studies 4 and 5. These include:

Because adverse reactions reported during postmarketing are 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.

These adverse reactions are consistent with those observed in clinical studies and most commonly involve the following system organ classes: Injury, Poisoning, and Procedural Complications (e.g., drug-drug interaction, procedural pain), Nervous System Disorders (e.g., palsy, seizure), General Disorders And Administration Site Conditions (e.g., lack of efficacy, pain), Skin And Subcutaneous Tissue Disorders (e.g., erythema, rash), and Cardiac Disorders (e.g., bradycardia, cardiac arrest).

Bupivacaine

Bupivacaine HCl administered together with EXPAREL may impact the pharmacokinetic and/or physicochemical properties of EXPAREL, and this effect is concentration dependent. Therefore, bupivacaine HCl and EXPAREL may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before EXPAREL as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2.

Non-Bupivacaine Local Anesthetics

EXPAREL should not be admixed with local anesthetics other than bupivacaine. Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. There are no data to support administration of other local anesthetics prior to administration of EXPAREL.

Other than bupivacaine as noted above, EXPAREL should not be admixed with other drugs prior to administration.

Water and Hypotonic Agents

Do not dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of the liposomal particles.

Risk Summary

There are no studies conducted with EXPAREL in pregnant women. In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Clinical Considerations

Labor or Delivery

Bupivacaine is contraindicated for obstetrical paracervical block anesthesia. While EXPAREL has not been studied with this technique, the use of bupivacaine for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death.

Bupivacaine can rapidly cross the placenta, and when used for epidural, caudal, or pudendal 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.

Data

Animal Data

Bupivacaine hydrochloride was administered subcutaneously to rats and rabbits during the period of organogenesis (implantation to closure of the hard plate). Rat doses were 4.4, 13.3, and 40 mg/kg/day (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) and rabbit doses were 1.3, 5.8, and 22.2 mg/kg/day (equivalent to 0.1, 0.4 and 1.6 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight). No embryo-fetal effects were observed in rats at the doses tested with the high dose causing increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity.

Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and post-natal development study when pregnant animals were administered subcutaneous doses of 4.4, 13.3, and 40 mg/kg/day bupivacaine hydrochloride (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) from implantation through weaning (during pregnancy and lactation).

Risk Summary

Limited published literature reports that bupivacaine and its metabolite, pipecoloxylidide, are present in human milk at low levels. There is no available information on effects of the drug in the breastfed infant or effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EXPAREL and any potential adverse effects on the breastfed infant from EXPAREL or from the underlying maternal condition.

The safety and effectiveness of EXPAREL to produce postsurgical local analgesia via infiltration have been established in pediatric patients aged 6 years and older. Use of EXPAREL for this indication is supported by evidence from adequate and well-controlled studies in adults, and pharmacokinetic (PK) and safety data in pediatric patients aged 6 years and older from Studies Peds-1 and Peds-2 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].

The safety and effectiveness of EXPAREL have not been established to produce postsurgical:

Of the total number of patients in the EXPAREL local infiltration clinical studies (N=823), 171 patients were greater than or equal to 65 years of age and 47 patients were greater than or equal to 75 years of age. Of the total number of patients in the EXPAREL nerve block clinical studies (N= 1046), 312 patients were greater than or equal to 65 years of age and 70 patients were greater than or equal to 75 years of age. No overall differences in safety or effectiveness of EXPAREL have been observed between patients 65 years of age and older and younger adult patients.

In clinical studies, differences in various pharmacokinetic parameters have been observed between patients 65 years of age and older and younger adult patients. Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to bupivacaine may be greater in patients with renal impairment than in patients with normal renal function. Because patients 65 years of age and older are more likely to have renal impairment, increase monitoring for EXPAREL-associated adverse reactions [see Adverse Reactions (6)].

Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity [see Clinical Pharmacology (12.3)]. Therefore, consider increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic disease.

Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to EXPAREL may be greater in patients with renal impairment than in patients with normal renal function. Therefore, in patients with renal impairment, increase monitoring for EXPAREL-associated adverse reactions [see Adverse Reactions (6)].

Clinical Presentation

Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution [See Warnings and Precautions (5) and Adverse Reactions (6)].

Signs and symptoms of overdose include CNS symptoms (perioral paresthesia, dizziness, dysarthria, confusion, mental obtundation, sensory and visual disturbances, and eventually convulsions) and cardiovascular effects (that range from hypertension and tachycardia to myocardial depression, hypotension, bradycardia, and asystole).

Plasma levels of bupivacaine associated with toxicity can vary. Although concentrations of 2,500 to 4,000 ng/mL have been reported to elicit early subjective CNS symptoms of bupivacaine toxicity, symptoms of toxicity have been reported at levels as low as 800 ng/mL.

Management of Local Anesthetic Overdose

At the first sign of change, oxygen should be administered.

The first step in the management of convulsions, as well as underventilation or apnea, 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 the use of anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force).

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.

Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.

Active Ingredient

Bupivacaine is related chemically and pharmacologically to the amide-type local anesthetics. It is a homologue of mepivacaine and is related chemically to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. Chemically, bupivacaine is 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide with a molecular weight of 288.4. Bupivacaine has the following structural formula:

EXPAREL

The median diameter of the liposome particles in EXPAREL ranges from 24 to 31 μm. The liposomes are suspended in a 0.9% Sodium Chloride Injection. Each vial contains bupivacaine at a nominal concentration of 13.3 mg/mL. Inactive ingredients and their nominal concentrations are: cholesterol, 4.7 mg/mL; 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) sodium salt (DPPG), 0.9 mg/mL; tricaprylin, 2.0 mg/mL; 1, 2-dierucoylphosphatidylcholine (DEPC), 8.2 mg/mL; phosphoric acid to adjust pH; and sodium chloride to adjust tonicity. The pH of EXPAREL is in the range of 5.8 to 7.4.

Bupivacaine in EXPAREL has different functional properties relative to those of the unencapsulated or nonlipid-associated bupivacaine products. Bupivacaine that is released from EXPAREL has a different pharmacokinetic and systemic profile relative to other bupivacaine products. In addition, the nominal weight percent concentration of bupivacaine in EXPAREL is based on bupivacaine free base rather than bupivacaine HCl (100 mg of bupivacaine HCl contains 88.6 mg of bupivacaine free base) [see Dosage and Administration (2.1)].

Local anesthetics block 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.

Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. 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 conductivity 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. Clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after accidental intravascular injection of bupivacaine.

Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state.

After administration of EXPAREL, the systemic plasma levels of bupivacaine were observed for 96 hours after local infiltration, 120 hours after interscalene brachial plexus nerve block, 168 hours after sciatic nerve block in the popliteal fossa, and 168 hours after adductor canal block [see Warnings and Precautions (5.2)]. In general, peripheral nerve blocks have shown systemic plasma levels of bupivacaine for extended duration when compared to local infiltration. Systemic plasma levels of bupivacaine following administration of EXPAREL are not correlated with local efficacy.

Absorption

The rate of systemic absorption of bupivacaine is dependent upon the total dose of EXPAREL administered, the route of administration, and the vascularity of the administration site.

Pharmacokinetic parameters of EXPAREL after local infiltration, and following an interscalene brachial plexus nerve block, sciatic nerve block in the popliteal fossa, and adductor canal block were evaluated following surgical procedures. Descriptive statistics of pharmacokinetic parameters of representative EXPAREL doses in each study are provided in Table 5 for adult patients after administration of single doses of EXPAREL via local infiltration; Table 6 for adult patients after administration of single doses of EXPAREL via nerve block; and in Table 7 for pediatric patients aged 6 to less than 17 years old after administration of single doses of EXPAREL via local infiltration.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 5: Summary of Pharmacokinetic Parameters for Bupivacaine after Administration of Single Doses of EXPAREL via Local Infiltration in Adult Patients </span> </caption> <col align="left" valign="top" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule">Parameters<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></th><th align="center" class="Botrule Rrule" valign="top">Bunionectomy<a class="Sup" href="#footnote-7" name="footnote-reference-7">†</a> <br/>106 mg <br/>(8 mL)</th><th align="center" class="Botrule Rrule" valign="top">Hemorrhoidectomy<a class="Sup" href="#footnote-8" name="footnote-reference-8">‡</a> <br/>266 mg <br/>(20 mL)</th><th align="center" class="Botrule Rrule" valign="top">Spine Surgery<a class="Sup" href="#footnote-9" name="footnote-reference-9">§</a> <br/>266 mg <br/>(20 mL)</th><th align="center" class="Botrule Rrule" valign="top">Cardiothoracic Surgery<a class="Sup" href="#footnote-10" name="footnote-reference-10">¶</a> <br/>266 mg <br/>(20 mL)</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">(N=26)</th><th align="center" class="Rrule">(N=25)</th><th align="center" class="Rrule">(N=11)</th><th align="center" class="Rrule">(N=5)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">NE: Not evaluated </td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>Arithmetic mean (standard deviation) except T<span class="Sub">max</span> where it is median (minimum, maximum). </dd> <dt> <a href="#footnote-reference-7" name="footnote-7">†</a> </dt> <dd>Patients undergoing bunionectomy (Study 1)</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">‡</a> </dt> <dd>Patients undergoing hemorrhoidectomy (Study 2)</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">§</a> </dt> <dd>Patients undergoing open posterior spinal fusion or reconstructive surgery </dd> <dt> <a href="#footnote-reference-10" name="footnote-10">¶</a> </dt> <dd>Patients undergoing posterolateral thoracotomy </dd> <dt> <a href="#footnote-reference-11" name="footnote-11">#</a> </dt> <dd>AUC<span class="Sub">0-last</span>, 0-72h;</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">Þ</a> </dt> <dd>AUC<span class="Sub">0-last</span>, 0-96h</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">C<span class="Sub">max</span> (ng/mL)</td><td align="center" class="Rrule">166 (93)</td><td align="center" class="Rrule">867 (353)</td><td align="center" class="Rrule">513 (268)</td><td align="center" class="Rrule">445 (120)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">T<span class="Sub">max</span> (h)</td><td align="center" class="Rrule">2 (0.5, 24)</td><td align="center" class="Rrule">0.5 (0.25, 36)</td><td align="center" class="Rrule">0.6 (0.2, 37)</td><td align="center" class="Rrule">0.6 (0.6, 36)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">0-40h</span> <br/>(h × ng/mL)</td><td align="center" class="Rrule">NE</td><td align="center" class="Rrule">NE</td><td align="center" class="Rrule">13035 (8782)</td><td align="center" class="Rrule">9867 (1332)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">(0-last)</span> <br/>(h × ng/mL)</td><td align="center" class="Rrule">5864 (2038) <a class="Sup" href="#footnote-11" name="footnote-reference-11">#</a></td><td align="center" class="Rrule">16867 (7868) <a class="Sup" href="#footnote-11">#</a></td><td align="center" class="Rrule">17214 (11621) <a class="Sup" href="#footnote-12" name="footnote-reference-12">Þ</a></td><td align="center" class="Rrule">14277 (3449) <a class="Sup" href="#footnote-12">Þ</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">(inf)</span> <br/>(h × ng/mL)</td><td align="center" class="Rrule">7105 (2283)</td><td align="center" class="Rrule">18289 (7569)</td><td align="center" class="Rrule">17917 (12187)</td><td align="center" class="Rrule">15768 (4530)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">t<span class="Sub">½</span> (h)</td><td align="center" class="Rrule">34 (17)</td><td align="center" class="Rrule">24 (39)</td><td align="center" class="Rrule">9 (2)</td><td align="center" class="Rrule">14 (6)</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 6: Summary of Pharmacokinetic Parameters for Bupivacaine after Administration of Single Doses of EXPAREL via Nerve Block in Adult Patients (Studies 3, 4 and 5)</span> </caption> <col align="left" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" rowspan="3">Parameters<a class="Sup" href="#footnote-13" name="footnote-reference-13">*</a></th><th align="center" class="Rrule">Interscalene Brachial Plexus Nerve Block<a class="Sup" href="#footnote-14" name="footnote-reference-14">†</a></th><th align="center" class="Rrule" valign="top">Sciatic Nerve Block in the Popliteal Fossa<a class="Sup" href="#footnote-15" name="footnote-reference-15">‡</a></th><th align="center" class="Rrule" valign="bottom">Adductor Canal Block<a class="Sup" href="#footnote-16" name="footnote-reference-16">§</a></th> </tr> <tr class="Botrule"> <th align="center" class="Lrule Rrule">EXPAREL<br/>133 mg (10 mL)</th><th align="center" class="Rrule">EXPAREL<br/>133 mg (10 mL) + BUP as Mayo field block (100 mg<a class="Sup" href="#footnote-17" name="footnote-reference-17">¶</a>)<br/>(Total dose: 221.6 mg bupivacaine)</th><th align="center" class="Rrule">EXPAREL<br/>133 mg (10 mL) + BUP 50 mg + BUP as IPACK (37.5 mg) + BUP (up to 15 mg) as spinal anesthesia<br/>(Total dose: 224 mg bupivacaine)</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">(N = 12)</th><th align="center" class="Rrule">(N = 21)</th><th align="center" class="Rrule">(N = 24)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4">BUP: Bupivacaine HCl. <br/>IPACK: Infiltration between the popliteal artery and capsule of the knee<br/>NE: Not evaluated </td> </tr> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-13" name="footnote-13">*</a> </dt> <dd>Arithmetic mean (standard deviation) except T<span class="Sub">max</span> where it is median (minimum, maximum). </dd> <dt> <a href="#footnote-reference-14" name="footnote-14">†</a> </dt> <dd>Patients undergoing total shoulder arthroplasty (Study 3)</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">‡</a> </dt> <dd>Patients undergoing bunionectomy (Study 4)</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">§</a> </dt> <dd>Patients undergoing total knee arthroplasty (Study 5)</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">¶</a> </dt> <dd>100 mg bupivacaine HCl contains 88.6 mg of bupivacaine free base.</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">#</a> </dt> <dd>AUC<span class="Sub">0-last</span>, 0-120h ; </dd> <dt> <a href="#footnote-reference-19" name="footnote-19">Þ</a> </dt> <dd>AUC<span class="Sub">0-last</span>, 0-168h</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">C<span class="Sub">max</span> (ng/mL)</td><td align="center" class="Rrule">207 (137) </td><td align="center" class="Rrule">382 (241)</td><td align="center" class="Rrule">495 (165)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">T<span class="Sub">max</span> (h)</td><td align="center" class="Rrule">48 (3, 74)</td><td align="center" class="Rrule">8.1 (1.7, 12)</td><td align="center" class="Rrule">0.7 (0.4, 72)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">(0-last)</span> (h × ng/mL)</td><td align="center" class="Rrule">11484 (8615)<a class="Sup" href="#footnote-18" name="footnote-reference-18">#</a></td><td align="center" class="Rrule">16005 (6740) <a class="Sup" href="#footnote-19" name="footnote-reference-19">Þ</a></td><td align="center" class="Rrule">25039 (11921) <a class="Sup" href="#footnote-19">Þ</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">(inf)</span> (h × ng/mL) </td><td align="center" class="Rrule">11590 (8603)</td><td align="center" class="Rrule">17004 (7206)</td><td align="center" class="Rrule">25109 (11918)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">t<span class="Sub">½</span> (h)</td><td align="center" class="Rrule">11 (5)</td><td align="center" class="Rrule">28 (14)</td><td align="center" class="Rrule">11 (3)</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 7: Summary of Pharmacokinetic Parameters for Bupivacaine after Administration of Single Doses of EXPAREL via Local Infiltration in Pediatric Patients Aged 6 to Less Than 17 Years Old (Studies Peds-1 and Peds-2)</span> </caption> <col align="left" valign="middle" width="34%"/> <col align="center" valign="middle" width="33%"/> <col align="center" valign="middle" width="33%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule" rowspan="3">Parameters<a class="Sup" href="#footnote-20" name="footnote-reference-20">*</a></th><th align="center" class="Botrule Rrule">Spine Surgery</th><th align="center" class="Botrule Rrule">Cardiac Surgery</th> </tr> <tr class="Botrule"> <th align="center" class="Lrule Rrule">EXPAREL<br/>4 mg/kg<br/>(Maximum 266 mg)</th><th align="center" class="Lrule Rrule">EXPAREL<br/>4 mg/kg<br/>(Maximum 266 mg)</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">6 to &lt;17 years <br/>(N = 17)</th><th align="center" class="Lrule Rrule">6 to &lt;12 years<br/>(N = 21)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">NR<span class="Sup">1</span> = Not reported, since the last sampling time point varies among different patients. <br/>NR<span class="Sup">2</span>= Not reported, since the terminal elimination phase was not adequately characterized in sufficient number of patients.</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-20" name="footnote-20">*</a> </dt> <dd>Arithmetic mean (standard deviation) except T<span class="Sub">max</span> where it is median (minimum, maximum). </dd> <dt> <a href="#footnote-reference-21" name="footnote-21">†</a> </dt> <dd>AUC<span class="Sub">0-last</span>, 0-72h </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">C<span class="Sub">max</span> (ng/mL)</td><td align="center" class="Rrule">353 (125)</td><td align="center" class="Rrule">447 (243)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">T<span class="Sub">max</span> (h)</td><td align="center" class="Rrule">1.2 (0.3-26)</td><td align="center" class="Rrule">23 (0.2, 55)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">(0- 40 h)</span> (h × ng/mL) </td><td align="center" class="Rrule">8782 (2834)</td><td align="center" class="Rrule">11286 (4791)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">(0-last)</span> (h × ng/mL)</td><td align="center" class="Rrule">NR<span class="Sup">1</span></td><td align="center" class="Rrule">16776 (7936)<a class="Sup" href="#footnote-21" name="footnote-reference-21">†</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">AUC<span class="Sub">(inf)</span> (h × ng/mL)</td><td align="center" class="Rrule">NR<span class="Sup">2</span></td><td align="center" class="Rrule">NR<span class="Sup">2</span></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">t<span class="Sub">½</span> (h)</td><td align="center" class="Rrule">NR<span class="Sup">2</span></td><td align="center" class="Rrule">NR<span class="Sup">2</span></td> </tr> </tbody> </table></div>

Distribution

After bupivacaine has been released from EXPAREL and is absorbed systemically, bupivacaine distribution is expected to be the same as for any bupivacaine HCl solution formulation.

Local anesthetics including bupivacaine are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

Local anesthetics including bupivacaine appear 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 local anesthetics 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, non-ionized drugs such as bupivacaine readily enter the fetal blood from the maternal circulation.

Elimination

Metabolism

Amide-type local anesthetics, such as bupivacaine, are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecoloxylidide (PPX) is the major metabolite of bupivacaine; approximately 5% of bupivacaine is converted to PPX. Elimination of drug depends largely upon the availability of plasma protein binding sites in the circulation to carry it to the liver where it is metabolized.

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.

Excretion

After bupivacaine has been released from EXPAREL and is absorbed systemically, bupivacaine excretion is expected to be the same as for other bupivacaine formulations.

The kidney is the main excretory organ for most local anesthetics and their metabolites. Only 6% of bupivacaine is excreted unchanged in the urine.

Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Acidifying the urine hastens the renal elimination of local anesthetics. 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.

Specific Populations

Hepatic Impairment

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, the effects of decreased hepatic function on bupivacaine pharmacokinetics following administration of EXPAREL were studied in patients with moderate hepatic impairment. Consistent with the hepatic clearance of bupivacaine, mean plasma concentrations were higher in patients with moderate hepatic impairment than in the healthy control volunteers with approximately 1.5- and 1.6-fold increases in the mean values for Cmax and the area under the curve (AUC), respectively. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine have not been conducted.

Mutagenesis

The mutagenic potential of bupivacaine has not been determined.

Impairment of Fertility

The effect of bupivacaine on fertility has not been determined.

In five multicenter, randomized, double-blinded, placebo-controlled clinical studies in adults, the efficacy of EXPAREL was established to produce postsurgical:

Four additional studies (Studies 6, 7, 8, and 9) [see Clinical Studies (14.4)] did not provide sufficient efficacy and/or safety data to support an indication for the following nerve blocks: femoral block in patients undergoing total knee arthroplasty, intercostal nerve block in patients undergoing posterolateral thoracotomy, and combined sciatic (in popliteal fossa) and saphenous (in adductor canal) nerve block [see Indications and Usage (1)].

Study 1: Infiltration for Bunionectomy in Adults

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (NCT00890682) (Study 1) evaluated the safety and efficacy of 106 mg (8 mL) EXPAREL in 193 adult patients undergoing bunionectomy. The mean age was 43 years (range 18 to 72).

Study medication was administered directly into the site at the conclusion of the surgery, prior to closure. There was an infiltration of placebo or 7 mL of EXPAREL into the tissues surrounding the osteotomy and 1 mL into the subcutaneous tissue.

Pain intensity was rated by the patients on a 0 to 10 numeric rating scale (NRS) out to 72 hours. Postoperatively, patients were allowed rescue medication (5 mg oxycodone/325 mg acetaminophen orally every 4 to 6 hours as needed) or, if that was insufficient within the first 24 hours, ketorolac (15 to 30 mg IV). The primary outcome measure was the area under the curve (AUC) of the NRS pain intensity scores (cumulative pain scores) collected over the first 24-hour period. There was a significant treatment effect for EXPAREL compared to placebo. EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. There was no significant difference in the amount of morphine equivalents used through 72 hours post-surgery, 43 mg versus 42 mg for placebo and EXPAREL, respectively. In addition, there was not a significant difference in the percentage of patients that used ketorolac, 43% versus 31% for placebo and EXPAREL, respectively.

Study 2: Infiltration for Hemorrhoidectomy in Adults

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (NCT00890721) (Study 2) evaluated the safety and efficacy of 266 mg (20 mL) EXPAREL in 189 adult patients undergoing hemorrhoidectomy. The mean age was 48 years (range 18 to 86).

EXPAREL or placebo were administered directly into the site (greater than or equal to 3 cm) at the conclusion of the surgery. Dilution of 20 mL of EXPAREL with 10 mL of saline, for a total of 30 mL, was divided into six 5-mL aliquots. A field block was performed by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers.

Pain intensity was rated by the patients on a 0 to 10 NRS at multiple time points up to 72 hours. Postoperatively, patients were allowed rescue medication (morphine sulfate 10 mg intramuscular every 4 hours as needed).

The primary outcome measure was the AUC of the NRS pain intensity scores (cumulative pain scores) collected over the first 72-hour period.

There was a significant treatment effect for EXPAREL compared to placebo. See Figure 1 for the mean pain intensity over time for the EXPAREL and placebo treatment groups for the 72-hour efficacy period.

There were statistically significant, but small differences in the amount of opioid rescue analgesia used across the treatment groups, the clinical benefit of which has not been established. The median time to rescue analgesic use was 15 hours for patients treated with EXPAREL and one hour for patients treated with placebo. Twenty-eight percent of patients treated with EXPAREL required no rescue medication at 72 hours compared to 10% treated with placebo. For those patients who did require rescue medication, the mean amount of morphine sulfate intramuscular injections used over 72 hours was 22 mg for patients treated with EXPAREL and 29 mg for patients treated with placebo.

Study 3: Interscalene Brachial Plexus Nerve Block for Total Shoulder Arthroplasty or Rotator Cuff Repair in Adults

A multicenter, randomized, double-blind, placebo-controlled study (NCT02713230) (Study 3) was conducted in 156 adult patients undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair with general anesthesia. The mean age was 61 years (range 33 to 80). Prior to the surgical procedure, patients received 133 mg (10 mL) of EXPAREL expanded with normal saline to 20 mL or placebo as a brachial plexus nerve block (perineural use) via interscalene or supraclavicular approach with ultrasound guidance. Only two patients received nerve block with EXPAREL by supraclavicular approach. Postsurgically, patients were administered acetaminophen/paracetamol up to 1,000 mg orally or intravenously every 8 hours unless contraindicated. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5-10 mg every 4 hours or as needed). If a patient could not tolerate oral medication, intravenous morphine (2.5-5 mg) or hydromorphone (0.5-1 mg) could be administered every 4 hours or as needed.

In Study 3, there was a statistically significant treatment effect for EXPAREL compared to placebo in cumulative pain scores through 48 hours as measured by the AUC of the visual analog scale (VAS) pain intensity scores. There were statistically significant, but small differences in the amount of opioid consumption through 48 hours, the clinical benefit of which has not been demonstrated. For those patients who required rescue medication, the mean amount of morphine-equivalent opioid rescue used over 48 hours was 12 mg for EXPAREL-treated patients and 54 mg for placebo-treated patients and 23 mg with EXPAREL-treated patients vs. 70 mg for placebo-treated patients over 72 hours.

Although at 48 hours, 9 patients (13%) in the EXPAREL group remained opioid-free compared to 1 patient (1%) in the placebo group, a difference which was statistically significant, at 72 hours, there were 4 (6%) patients in the EXPAREL group who remained opioid-free compared to 1 (1%) patient in the placebo group, a difference that is not statistically significant.

Study 4: Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy in Adults

A multicenter, randomized, double-blind, active controlled study (NCT05157841) (Study 4) was conducted in 185 adult patients undergoing bunionectomy. The mean age was 49 years (range 18 to 76).

Prior to the surgical procedure, patients received 133 mg of EXPAREL mixed with 20 mL saline OR 50 mg (20 mL) of 0.25% bupivacaine HCl mixed with 10 mL saline via sciatic nerve block (perineural use) in the popliteal fossa. All patients received 100 mg (20 mL) of 0.5% immediate-release bupivacaine HCl as a Mayo field block after study drug administration (i.e., in the operating room immediately prior to surgical incision). All patients also received a dose of 1,000 mg of intravenous (IV) acetaminophen at the time of surgical incision. IV fentanyl was allowed for intraoperative pain control (not exceeding 1 mcg/kg unless deemed medically necessary).

Postsurgically, all patients received one post-operative dose of 1,000 mg IV acetaminophen, administered approximately 8 hours after the first dose (approximately 8 hours after incision). Patients were administered pain medications on an as needed basis; opioids were not given on a pre-determined schedule. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5 mg and increasing the dose to 10 mg if initial opioid dose was insufficient). If a patient could not tolerate oral medication or the oral oxycodone pain relief was insufficient, IV morphine (initiated at 2 mg) or hydromorphone (initiated at 0.2 mg) could be administered. No NSAIDs or other opioids including tramadol were allowed for the breakthrough pain management and no acetaminophen (other than the scheduled IV acetaminophen) was used for breakthrough pain.

In Study 4, there was a statistically significant treatment effect for EXPAREL (with 0.5% immediate-release bupivacaine HCl as a Mayo field block) compared to bupivacaine HCl (with 0.5% immediate-release bupivacaine HCl as a Mayo field block) in cumulative pain scores through 96 hours as measured by AUC of the NRS pain intensity scores. There were statistically significant differences in the total amount of postsurgical opioid medication used through 96 hours, the clinical benefit of which has not been demonstrated. For those patients who required postsurgical opioid medication, the mean amount of morphine-equivalent opioid rescue used over 96 hours was 18 mg for patients treated with EXPAREL + Mayo field block and 45 mg for patients treated with bupivacaine HCl + Mayo field block. There was also a statistically significant difference in the percentage of opioid-free patients through 96 hours compared with bupivacaine HCl (24% in the EXPAREL + Mayo field block vs. 6% in the bupivacaine HCl + Mayo field block).

See Figure 2 for the LS mean pain intensity scores after administration of either 133 mg of EXPAREL or 50 mg of 0.25% bupivacaine HCl.

Figure 2. NRS Pain Intensity After Administration of Study Drug by Sciatic Nerve Block in the Popliteal Fossa.

Study 5: Adductor Canal Block for Total Knee Arthroplasty in Adults

A multicenter, randomized, double-blind, active controlled study (NCT05139030) (Study 5) was conducted in 166 adult patients undergoing primary unilateral total knee arthroplasty. The mean age was 62 years (range 37 to 83).

Prior to the surgical procedure, patients received (via adductor canal block) (perineural use):

All patients also received 37.5 mg (15 mL) of 0.25% immediate-release bupivacaine HCl as an infiltration between the popliteal artery and capsule of the knee (IPACK) block immediately following study drug administration. All patients received spinal anesthesia immediately prior to surgery with 0.5% bupivacaine HCl (up to 15 mg). All patients also received a dose of 1,000 mg of intravenous (IV) acetaminophen at the time of surgical incision. IV fentanyl was allowed for intraoperative pain control (not exceeding 1 ug/kg unless deemed medically necessary).

Postsurgically, all patients received one post-operative dose of 1,000 mg IV acetaminophen, administered approximately 8 hours after the first dose (approximately 8 hours after incision). Patients were administered pain medications on an as needed basis for breakthrough pain; opioids were not given on a pre-determined schedule. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5 mg and increasing the dose to 10 mg if initial opioid dose was insufficient). If a patient could not tolerate oral medication or the oral oxycodone pain relief was insufficient, IV morphine (initiated at 2 mg) or hydromorphone (initiated at 0.2 mg) could be administered. No NSAIDs or other opioids including tramadol were allowed for the breakthrough pain management and no acetaminophen (other than the scheduled IV acetaminophen) was used for breakthrough pain.

In Study 5, there was a statistically significant treatment effect for EXPAREL + IPACK block compared to bupivacaine HCl + IPACK in cumulative pain scores through 96 hours as measured by AUC of the NRS pain intensity scores. There were statistically significant differences in the total amount of postsurgical opioid medication used through 96 hours, the clinical benefit of which has not been demonstrated. For those patients who required postsurgical opioid medication, the mean amount of morphine-equivalent opioid rescue used over 96 hours was 102 mg for patients treated with EXPAREL + IPACK and 133 mg for patients treated with bupivacaine HCl+ IPACK. The median time to first postsurgical use was 4.2 hours for patients treated with EXPAREL + IPACK and 3.6 hours for patients treated with bupivacaine HCl + IPACK.

See Figure 3 for LS mean pain intensity scores after administration of either 133 mg of 1.3% EXPAREL admixed with 50 mg) of 0.5% bupivacaine HCl or 50 mg of 0.5% bupivacaine HCl.

Figure 3. NRS Pain Intensity After Administration of Study Drug by Adductor Canal Block

Studies 6 and 7: Inadequate Demonstration of Efficacy and Safety in Femoral Nerve Block in Total Knee Arthroplasty

EXPAREL was administered via a femoral nerve block in two placebo-controlled studies in adults (Studies 6 and 7). The results of these studies did not support a femoral nerve block indication due to inadequate safety data (Study 6) and/or due to inadequate efficacy findings (Study 7). In addition, patient falls were reported only in the EXPAREL treatment groups, and none was reported in placebo groups.

Study 6

Study 6, a multicenter, randomized, double-blind, parallel-group, placebo-controlled study (NCT01683071), was conducted in 196 adult patients undergoing primary unilateral total knee arthroplasty (TKA) under general or spinal anesthesia. The mean age was 65 years (range 42 to 88). Prior to the surgical procedure, 266 mg (20 mL) of EXPAREL or placebo was administered as a femoral nerve block with ultrasound guidance. Postsurgically, patients were allowed opioid rescue medication administered initially by intravenous injection of hydromorphone and subsequently by a patient-controlled analgesia (PCA) pump containing morphine or hydromorphone only. Once patients were tolerating oral medication, oral immediate-release oxycodone was administered on an as-needed basis (but not more than 10 mg every 4 hours) or, if that was insufficient, a third rescue of 1.25 mg/mL of 0.125% bupivacaine HCl was administered at a rate of 8 mL per hour via the previously placed femoral nerve catheter.

In this study, there was a statistically significant treatment effect for EXPAREL compared to placebo in cumulative pain scores through 72 hours as measured by the AUC of the NRS pain (at rest) intensity scores.

There was a statistically significant, although small decrease in opioid consumption for the EXPAREL treatment group compared to the placebo group, the clinical benefit of which has not been established. All patients in both the EXPAREL and placebo treatment groups required opioid rescue medication during the first 72 hours. The mean amount of opioid rescue used over 72 hours was 76 mg for patients treated with EXPAREL and 103 mg for patients treated with placebo.

The study was inadequate to fully characterize the safety of EXPAREL when used for femoral nerve block due to patient falls, which occurred only in the EXPAREL-treated patients and not in the placebo-treated patients.

Study 7

Study 7, a multicenter, randomized, double-blind, parallel-group, placebo-controlled study (NCT02713178), was conducted in 230 adult patients undergoing primary unilateral total knee arthroplasty (TKA) under general or spinal anesthesia. The mean age was 65 years (range 39 to 89). Prior to the surgical procedure, either 266 mg (20 mL) of EXPAREL or 133 mg (10 mL) of EXPAREL plus 10 mL of normal saline or placebo was administered as a femoral nerve block with ultrasound guidance. In addition to study drug, 8 mL of 0.5% bupivacaine HCl diluted with 8 mL of normal saline was administered by the surgeon as a periarticular infiltration to the posterior capsule (8 mL each behind the medial and lateral condyles) before placement of the prosthesis. Postsurgically, patients were allowed opioid rescue medication consisting of oral immediate-release oxycodone (initiated at 5 to 10 mg every 4 hours or as needed). If a patient could not tolerate oral medication, IV morphine (2.5 to 5 mg) or hydromorphone (0.5 to 1 mg) was permitted every 4 hours or as needed. Patient-controlled analgesia was not permitted. No other analgesic agents, including NSAIDs, were permitted through 108 hours. However, to reflect the current standard of care of postsurgical multimodal therapy, all patients received cyclobenzaprine (a single dose of 10 mg orally or as needed) and acetaminophen/paracetamol (up to 1,000 mg orally or IV every 8 hours for a maximum total daily dose of 3000 mg) postsurgically.

In this study there were no statistically significant treatment effects for the EXPAREL group compared to the placebo group in cumulative pain intensity scores or total opioid consumption. All patients in the EXPAREL and placebo treatment groups required opioid rescue medication over 72 hours. The median Tmax of bupivacaine observed in this study was 72 hours with a range of 2.5 to 108 hours. Similar to Study 6, patient falls only occurred in the EXPAREL-treated patients and not the placebo-treated patients.

Study 8: Lack of Efficacy in Intercostal Nerve Block for Posterolateral Thoracotomy

A multicenter, randomized, double-blind, placebo-controlled study was conducted in 191 adult patients undergoing posterolateral thoracotomy under general anesthesia (NCT01802411) (Study 8). The mean age was 58 years (range 18 to 82).

After the surgical procedure was completed but prior to the surgical site closure, 266 mg (20 mL) of EXPAREL was administered by the surgeon as an intercostal nerve block divided into three equal doses in three syringes of approximately 88 mg in 6.6 mL volume per nerve, and administered to each of three nerve segments (index nerve, nerve above, and nerve below). Postsurgically, patients were allowed opioid rescue medication administered initially by intravenous fentanyl 100 mcg, which was to be administered once via bolus only. For the US sites, the second rescue medication was to be PCA-administered morphine or hydromorphone. For the European sites, the second rescue medication was to be intramuscular administered morphine up to 10 mg every 4 hours. At all sites, once a patient was tolerating oral medication, oral immediate-release oxycodone was administered (but not more than 10 mg every 4 hours). Patients who did not achieve adequate pain relief with this regimen were to be withdrawn from the study and followed for safety only.

In this study there were no statistically significant treatment effects for EXPAREL 266 mg compared to placebo in cumulative pain intensity scores or total opioid consumption. Four percent of patients treated with EXPAREL required no rescue medication at 72 hours compared to 1% treated with placebo. For those patients who did require rescue medication, the mean amount of opioid rescue used over 72 hours was 71 mg for patients treated with EXPAREL and 71 mg for patients treated with placebo. The median Tmax of bupivacaine observed in this study was 1 hour with a range of 0.5 hours to 50 hours.

Study 9: Lack of Efficacy in Combined Sciatic (in popliteal fossa) and Saphenous (in adductor canal) Nerve Block Study in Lower Extremity Surgeries

A multicenter, randomized, double-blind, active-controlled trial (NCT04518462) (Study 9) was conducted in 119 adult patients who underwent foot and ankle procedures (bunionectomy, first metatarsophalangeal fusion, forefoot & hindfoot fusion, total ankle arthroplasty). The mean age was 48 years (range 20 to 72). Prior to the surgical procedure, patients received one of the following three treatments under ultrasound guidance as a sciatic nerve block in the popliteal fossa and a saphenous nerve block in the adductor canal:

The total volume (40 mL) was divided evenly between the two blocks. All patients received general anesthesia or nonopioid sedation (except fentanyl); were allowed medication for intraoperative nausea/vomiting prevention; and were allowed medication for breakthrough pain postsurgery which followed a step-wise approach starting with acetaminophen or a nonsteroidal anti-inflammatory drug (not exceeding the maximum dose), and, if needed escalating to an initial 5 mg dose of oxycodone, then to a 10 mg dose of oxycodone, and finally to intravenous morphine (initiated at 2 mg) or intravenous hydromorphone (initiated at 0.2 mg).

In Study 9 there was no significant difference in the primary endpoint [least square mean (LSM) area under the curve (AUC) numerical rating scale (NRS) pain score from 0 to 96 hours after surgery] between EXPAREL + NS and the 0.25% bupivacaine HCl treatment groups. Cumulative opioid consumption differences between groups were nonsignificant 0-96 hours after surgery. The LSM amount of opioids received over 96 hours was 21 mg in EXPAREL group and 20 mg in bupivacaine HCl group.

Storage

Store EXPAREL vials refrigerated between 2°C to 8°C (36°F to 46°F). EXPAREL may be held at a controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 30 days in sealed, intact (unopened) vials. Do not re-refrigerate vials.

Do not freeze or expose EXPAREL to high temperatures (greater than 40°C or 104°F) for an extended period. Do not administer EXPAREL if it is suspected of having been frozen or exposed to high temperatures. Do not use the vial if the stopper is bulging.

Handling

See Dosage and Administration (2.1, 2.4) for important preparation instructions.

Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

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Inform patients in advance that EXPAREL can cause temporary loss of sensation or motor activity that may last for up to 5 days.

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Manufactured for Pacira Pharmaceuticals, Inc., a wholly owned subsidiary of Pacira BioSciences, Inc. San Diego, CA 92121 USA

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Trademark of Pacira Pharmaceuticals, Inc.

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©2023 Pacira Pharmaceuticals, Inc. All rights reserved.

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For additional information call 1-855-RX-EXPAREL (1-855-793-9727) or visit www.EXPAREL.com

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NDC 65250-133-10

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EXPAREL® (bupivacaine liposome injectable suspension)

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STERILE1.3%Rx Only

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133 mg / 10 mL (13.3 mg/mL)

{ "type": "p", "children": [], "text": "133 mg / 10 mL (13.3 mg/mL)" }

For infiltration, interscalene brachial plexusnerve block, sciatic nerve block in thepopliteal fossa, and adductor canal block

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10 mL vial

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NDC 65250-133-09Contains 1010 mL Vials

{ "type": "p", "children": [], "text": "NDC 65250-133-09Contains 1010 mL Vials" }

EXPAREL® (bupivacaine liposome injectable suspension)

{ "type": "p", "children": [], "text": "EXPAREL®\n(bupivacaine liposome injectable suspension)" }

1.3%133 mg/10 mL (13.3 mg/mL)

{ "type": "p", "children": [], "text": "1.3%133 mg/10 mL (13.3 mg/mL)" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

For infiltration, interscalene brachial plexus nerve block, sciatic nerve blockin the popliteal fossa, and adductor canal block

{ "type": "p", "children": [], "text": "For infiltration, interscalene brachial plexus nerve block, sciatic nerve blockin the popliteal fossa, and adductor canal block" }

Contents: Each 10 mL vial contains 133 mg of bupivacaine free base.

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Usual Dosage: see Prescribing Information. Do not substitute for or with otherformulations containing bupivacaine or bupivacaine HCl. Single dose vial;discard any unused portion.

{ "type": "p", "children": [], "text": "Usual Dosage: see Prescribing Information. Do not substitute for or with otherformulations containing bupivacaine or bupivacaine HCl. Single dose vial;discard any unused portion." }

Do not freeze. Do not use the vial if the stopper is bulging.

{ "type": "p", "children": [], "text": "Do not freeze. Do not use the vial if the stopper is bulging." }

NDC 65250-133-04Contains 410 mL Vials

{ "type": "p", "children": [], "text": "NDC 65250-133-04Contains 410 mL Vials" }

EXPAREL® (bupivacaine liposome injectable suspension)

{ "type": "p", "children": [], "text": "EXPAREL®\n(bupivacaine liposome injectable suspension)" }

1.3%133 mg/10 mL (13.3 mg/mL)

{ "type": "p", "children": [], "text": "1.3%133 mg/10 mL (13.3 mg/mL)" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

For infiltration, interscalene brachial plexus nerve block, sciatic nerve blockin the popliteal fossa, and adductor canal block

{ "type": "p", "children": [], "text": "For infiltration, interscalene brachial plexus nerve block, sciatic nerve blockin the popliteal fossa, and adductor canal block" }

Contents: Each 10 mL vial contains 133 mg of bupivacaine free base.

{ "type": "p", "children": [], "text": "Contents: Each 10 mL vial contains 133 mg of bupivacaine free base." }

Usual Dosage: see Prescribing Information. Do not substitute for or with otherformulations containing bupivacaine or bupivacaine HCl. Single dose vial;discard any unused portion.

{ "type": "p", "children": [], "text": "Usual Dosage: see Prescribing Information. Do not substitute for or with otherformulations containing bupivacaine or bupivacaine HCl. Single dose vial;discard any unused portion." }

Do not freeze. Do not use the vial if the stopper is bulging.

{ "type": "p", "children": [], "text": "Do not freeze. Do not use the vial if the stopper is bulging." }

NDC 65250-266-20

{ "type": "p", "children": [], "text": "NDC 65250-266-20" }

EXPAREL® (bupivacaine liposome injectable suspension)

{ "type": "p", "children": [], "text": "EXPAREL®\n(bupivacaine liposome injectable suspension)" }

STERILE1.3%Rx Only

{ "type": "p", "children": [], "text": "STERILE1.3%Rx Only" }

266 mg/20 mL (13.3 mg/mL)

{ "type": "p", "children": [], "text": "266 mg/20 mL (13.3 mg/mL)" }

For infiltration, interscalene brachial plexusnerve block, sciatic nerve block in thepopliteal fossa, and adductor canal block

{ "type": "p", "children": [], "text": "For infiltration, interscalene brachial plexusnerve block, sciatic nerve block in thepopliteal fossa, and adductor canal block" }

20 mL Vial

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NDC 65250-266-09Contains 1020 mL Vials

{ "type": "p", "children": [], "text": "NDC 65250-266-09Contains 1020 mL Vials" }

EXPAREL® (bupivacaine liposome injectable suspension)

{ "type": "p", "children": [], "text": "EXPAREL®\n(bupivacaine liposome injectable suspension)" }

1.3%266 mg/20 mL (13.3 mg/mL)

{ "type": "p", "children": [], "text": "1.3%266 mg/20 mL (13.3 mg/mL)" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

For infiltration, interscalene brachial plexus nerve block, sciatic nerve blockin the popliteal fossa, and adductor canal block

{ "type": "p", "children": [], "text": "For infiltration, interscalene brachial plexus nerve block, sciatic nerve blockin the popliteal fossa, and adductor canal block" }

Contents: Each 20 mL vial contains 266 mg of bupivacaine free base.

{ "type": "p", "children": [], "text": "Contents: Each 20 mL vial contains 266 mg of bupivacaine free base." }

Usual Dosage: see Prescribing Information. Do not substitute for or with otherformulations containing bupivacaine or bupivacaine HCl. Single dose vial;discard any unused portion.

{ "type": "p", "children": [], "text": "Usual Dosage: see Prescribing Information. Do not substitute for or with otherformulations containing bupivacaine or bupivacaine HCl. Single dose vial;discard any unused portion." }

Do not freeze. Do not use the vial if the stopper is bulging.

{ "type": "p", "children": [], "text": "Do not freeze. Do not use the vial if the stopper is bulging." }

NDC 65250-266-04Contains 420 mL Vials

{ "type": "p", "children": [], "text": "NDC 65250-266-04Contains 420 mL Vials" }

EXPAREL® (bupivacaine liposome injectable suspension)

{ "type": "p", "children": [], "text": "EXPAREL®\n(bupivacaine liposome injectable suspension)" }

1.3%266 mg/20 mL (13.3 mg/mL)

{ "type": "p", "children": [], "text": "1.3%266 mg/20 mL (13.3 mg/mL)" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

For infiltration, interscalene brachial plexus nerve block, sciatic nerve blockin the popliteal fossa, and adductor canal block

{ "type": "p", "children": [], "text": "For infiltration, interscalene brachial plexus nerve block, sciatic nerve blockin the popliteal fossa, and adductor canal block" }

Contents: Each 20 mL vial contains 266 mg of bupivacaine free base.

{ "type": "p", "children": [], "text": "Contents: Each 20 mL vial contains 266 mg of bupivacaine free base." }

Usual Dosage: see Prescribing Information. Do not substitute for or with otherformulations containing bupivacaine or bupivacaine HCl. Single dose vial;discard any unused portion.

{ "type": "p", "children": [], "text": "Usual Dosage: see Prescribing Information. Do not substitute for or with otherformulations containing bupivacaine or bupivacaine HCl. Single dose vial;discard any unused portion." }

Do not freeze. Do not use the vial if the stopper is bulging.

{ "type": "p", "children": [], "text": "Do not freeze. Do not use the vial if the stopper is bulging." }

These highlights do not include all the information needed to use MARCAINE™ and MARCAINE™ WITH EPINEPHRINE safely and effectively. See full prescribing information for MARCAINE™ and MARCAINE™ WITH EPINEPHRINE.

{ "type": "p", "children": [], "text": "These highlights do not include all the information needed to use MARCAINE™ and MARCAINE™ WITH EPINEPHRINE safely and effectively. See full prescribing information for MARCAINE™ and MARCAINE™ WITH EPINEPHRINE." }

MARCAINE™ (bupivacaine hydrochloride) injection, for infiltration, perineural, caudal, epidural, or retrobulbar useMARCAINE™ WITH EPINEPHRINE (bupivacaine hydrochloride and epinephrine) injection, for infiltration, perineural, caudal, or epidural useInitial U.S. Approval: 1972

{ "type": "p", "children": [], "text": "MARCAINE™ (bupivacaine hydrochloride) injection, for infiltration, perineural, caudal, epidural, or retrobulbar useMARCAINE™ WITH EPINEPHRINE (bupivacaine hydrochloride and epinephrine) injection, for infiltration, perineural, caudal, or epidural useInitial U.S. Approval: 1972" }

WARNING: RISK OF CARDIAC ARREST WITH USE OF MARCAINE IN OBSTETRICAL ANESTHESIASEE 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).

{ "type": "p", "children": [], "text": "WARNING: RISK OF CARDIAC ARREST WITH USE OF MARCAINE IN OBSTETRICAL ANESTHESIASEE 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)." }

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)].

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "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)].

{ "type": "p", "children": [], "text": "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)]." }

2.1 Important Dosage and Administration Information

{ "type": "p", "children": [], "text": "2.1 Important Dosage and Administration Information" }

{ "type": "ul", "children": [ "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." ], "text": "" }

Administration Precautions

{ "type": "p", "children": [], "text": "Administration Precautions" }

{ "type": "ul", "children": [ "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)]." ], "text": "" }

2.2 Recommended Concentrations and Dosages of MARCAINE / MARCAINE WITH EPINEPHRINEThe 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.

{ "type": "p", "children": [], "text": "2.2 Recommended Concentrations and Dosages of MARCAINE / MARCAINE WITH EPINEPHRINEThe 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.

{ "type": "p", "children": [], "text": "The types of block and recommended MARCAINE / MARCAINE WITH EPINEPHRINE concentrations are shown in Table 1." }

Table 1. Types of Block and Recommended MARCAINE / MARCAINE WITH EPINEPHRINE Concentrations

{ "type": "p", "children": [], "text": "Table 1. Types of Block and Recommended MARCAINE / MARCAINE WITH EPINEPHRINE Concentrations" }

✓= indicated use [see WARNINGS AND PRECAUTIONS (5.1)].

{ "type": "p", "children": [], "text": "\n✓= indicated use [see WARNINGS AND PRECAUTIONS (5.1)].\n" }

*MARCAINE 0.75% (7.5 mg/mL) is not recommended for nonobstetrical surgical procedures in pregnant patients.†Avoid use of multiple-dose vials of MARCAINE and MARCAINE WITH EPINEPHRINE for caudal or epidural anesthesia [see WARNINGS AND PRECAUTIONS (5.4)].

{ "type": "p", "children": [], "text": "*MARCAINE 0.75% (7.5 mg/mL) is not recommended for nonobstetrical surgical procedures in pregnant patients.†Avoid use of multiple-dose vials of MARCAINE and MARCAINE WITH EPINEPHRINE for caudal or epidural anesthesia [see WARNINGS AND PRECAUTIONS (5.4)]." }

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.

{ "type": "p", "children": [], "text": "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." }

Table 2. MARCAINE / MARCAINE WITH EPINEPHRINE Concentration vs. Motor Function

{ "type": "p", "children": [], "text": "Table 2. MARCAINE / MARCAINE WITH EPINEPHRINE Concentration vs. Motor Function" }

*These products include MARCAINE and MARCAINE WITH EPINEPHRINE [the epinephrine concentration (1:200,000) is not included in the table].

{ "type": "p", "children": [], "text": "*These products include MARCAINE and MARCAINE WITH EPINEPHRINE [the epinephrine concentration (1:200,000) is not included in the table]." }

†These are only MARCAINE products [there is no 0.75% (7.5 mg/mL) concentration for MARCAINE WITH EPINEPHRINE].

{ "type": "p", "children": [], "text": "†These are only MARCAINE products [there is no 0.75% (7.5 mg/mL) concentration for MARCAINE WITH EPINEPHRINE]." }

The duration of anesthesia with MARCAINE / MARCAINE WITH EPINEPHRINE is such that for most indications, a single-dose is sufficient.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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." }

Table 3. Recommended Concentrations and Doses of MARCAINE / MARCAINE WITH EPINEPHRINE in Adults

{ "type": "p", "children": [], "text": "Table 3. Recommended Concentrations and Doses of MARCAINE / MARCAINE WITH EPINEPHRINE in Adults" }

a. With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% (5 mg/mL) may produce complete motor block. Intercostal nerve block with 0.25% (2.5 mg/mL) also may produce complete motor block for intra-thoracic and upper intra-abdominal surgery.

{ "type": "p", "children": [], "text": "a. With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% (5 mg/mL) may produce complete motor block. Intercostal nerve block with 0.25% (2.5 mg/mL) also may produce complete motor block for intra-thoracic and upper intra-abdominal surgery." }

b. Solutions with or without epinephrine (i.e., applies to MARCAINE and MARCAINE WITH EPINEPHRINE). The MARCAINE WITH EPINEPHRINE products include epinephrine (1:200,000).

{ "type": "p", "children": [], "text": "b. Solutions with or without epinephrine (i.e., applies to MARCAINE and MARCAINE WITH EPINEPHRINE). The MARCAINE WITH EPINEPHRINE products include epinephrine (1:200,000)." }

c. For single-dose use; not for intermittent epidural technique. Not for obstetrical anesthesia.

{ "type": "p", "children": [], "text": "c. For single-dose use; not for intermittent epidural technique. Not for obstetrical anesthesia." }

2.3 Use in Epidural AnesthesiaDuring 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)].

{ "type": "p", "children": [], "text": "2.3 Use in Epidural AnesthesiaDuring 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)].

{ "type": "p", "children": [], "text": "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 BlocksThree 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)].

{ "type": "p", "children": [], "text": "2.4 Test Dose for Caudal and Lumbar Epidural BlocksThree 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 DentistryMARCAINE 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)]. Use the lowest effective dose and allow time between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, not exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% (5 mg/mL) MARCAINE WITH EPINEPHRINE). Inject slowly and with frequent aspirations.

{ "type": "p", "children": [], "text": "2.5 Use in DentistryMARCAINE 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)]. Use the lowest effective dose and allow time between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, not exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% (5 mg/mL) MARCAINE WITH EPINEPHRINE). Inject slowly and with frequent aspirations." }

2.6 Use in Ophthalmic SurgeryWhen MARCAINE 0.75% (7.5 mg/mL) is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone should determine readiness of the patient for surgery [see WARNINGS AND PRECAUTIONS (5.15)].

{ "type": "p", "children": [], "text": "2.6 Use in Ophthalmic SurgeryWhen MARCAINE 0.75% (7.5 mg/mL) is used for retrobulbar block, complete corneal anesthesia usually precedes onset of clinically acceptable external ocular muscle akinesia. Therefore, presence of akinesia rather than anesthesia alone should determine readiness of the patient for surgery [see WARNINGS AND PRECAUTIONS (5.15)]." }

MARCAINE (bupivacaine hydrochloride) injection is a clear, colorless solution available as:

{ "type": "p", "children": [], "text": "MARCAINE (bupivacaine hydrochloride) injection is a clear, colorless solution available as:" }

{ "type": "ul", "children": [ "0.25% (25 mg/10 mL) (2.5 mg/mL) in single-dose vials.", "0.25% (75 mg/30 mL) (2.5 mg/mL) in single-dose vials.", "0.25% (125 mg/50 mL) (2.5 mg/mL) in multiple-dose vials.", "0.5% (50 mg/10 mL) (5 mg/mL) in single-dose vials.", "0.5% (150 mg/30 mL) (5 mg/mL) in single-dose vials.", "0.5% (250 mg/50 mL) (5 mg/mL) in multiple-dose vials.", "0.75% (75 mg/10 mL) (7.5 mg/mL) in single-dose vials.", "0.75% (225 mg/30 mL) (7.5 mg/mL) in single-dose vials." ], "text": "" }

MARCAINE with 1:200,000 epinephrine (bupivacaine hydrochloride and epinephrine) injection is a clear, colorless solution available as:

{ "type": "p", "children": [], "text": "MARCAINE with 1:200,000 epinephrine (bupivacaine hydrochloride and epinephrine) injection is a clear, colorless solution available as:" }

{ "type": "ul", "children": [ "0.25% (25 mg/10 mL) (2.5 mg/mL) in single-dose vials.", "0.25% (75 mg/30 mL) (2.5 mg/mL) in single-dose vials.", "0.25% (125 mg/50 mL) (2.5 mg/mL) in multiple-dose vials.", "0.5% (50 mg/10mL) (5 mg/mL) in single-dose vials.", "0.5% (150 mg/30 mL) (5 mg/mL) in single-dose vials.", "0.5% (250 mg/50 mL) (5 mg/mL) in multiple-dose vials." ], "text": "" }

MARCAINE / MARCAINE WITH EPINEPHRINE is contraindicated in:

{ "type": "p", "children": [], "text": "MARCAINE / MARCAINE WITH EPINEPHRINE is contraindicated in:" }

{ "type": "ul", "children": [ "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." ], "text": "" }

5.1 Risk of Cardiac Arrest with Use of MARCAINE in Obstetrical AnesthesiaThere 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.

{ "type": "p", "children": [], "text": "5.1 Risk of Cardiac Arrest with Use of MARCAINE in Obstetrical AnesthesiaThere 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 ToxicityThe 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.

{ "type": "p", "children": [], "text": "5.2 Dose-Related ToxicityThe 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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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 MethemoglobinemiaCases 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.

{ "type": "p", "children": [], "text": "5.3 MethemoglobinemiaCases 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.

{ "type": "p", "children": [], "text": "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 VialsAvoid 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.

{ "type": "p", "children": [], "text": "5.4 Antimicrobial Preservatives in Multiple-Dose VialsAvoid 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 InfusionIntra-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 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

{ "type": "p", "children": [], "text": "5.5 Chondrolysis with Intra-Articular InfusionIntra-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 2nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement." }

5.6 Risk of Adverse Reactions Due to Drug Interactions with MARCAINE WITH EPINEPHRINERisk of Severe, Persistent Hypertension Due to Drug Interactions Between MARCAINE WITH EPINEPHRINE and Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

{ "type": "p", "children": [], "text": "5.6 Risk of Adverse Reactions Due to Drug Interactions with MARCAINE WITH EPINEPHRINERisk 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)].

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "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. Avoid use of MARCAINE WITH EPINEPHRINE concomitantly with ergot-type oxytocic drugs [see DRUG INTERACTIONS (7.3)].

{ "type": "p", "children": [], "text": "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 DRUG INTERACTIONS (7.3)]." }

Risk of Hypertension and Bradycardia Due to Drug Interactions Between MARCAINE WITH EPINEPHRINE and Nonselective Beta-Adrenergic Antagonists

{ "type": "p", "children": [], "text": "Risk of Hypertension and Bradycardia Due to Drug Interactions Between MARCAINE WITH EPINEPHRINE and 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 DRUG INTERACTIONS (7.4)].

{ "type": "p", "children": [], "text": "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 DRUG INTERACTIONS (7.4)]." }

5.7 Risk of Cardiac Arrest with Intravenous Regional Anesthesia Use (Bier Block)There have been reports of cardiac arrest and death during the use of bupivacaine for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of MARCAINE in this procedure is lacking. Therefore, MARCAINE / MARCAINE WITH EPINEPHRINE is contraindicated for use with this technique [see CONTRAINDICATIONS (4)].

{ "type": "p", "children": [], "text": "5.7 Risk of Cardiac Arrest with Intravenous Regional Anesthesia Use (Bier Block)There have been reports of cardiac arrest and death during the use of bupivacaine for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of MARCAINE in this procedure is lacking. Therefore, MARCAINE / MARCAINE WITH EPINEPHRINE is contraindicated for use with this technique [see CONTRAINDICATIONS (4)]." }

5.8 Allergic-Type Reactions to Sulfites in MARCAINE WITH EPINEPHRINEMARCAINE WITH EPINEPHRINE contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. MARCAINE without epinephrine does not contain sodium metabisulfite.

{ "type": "p", "children": [], "text": "5.8 Allergic-Type Reactions to Sulfites in MARCAINE WITH EPINEPHRINEMARCAINE WITH EPINEPHRINE contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. MARCAINE without epinephrine does not contain sodium metabisulfite." }

5.9 Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal InjectionUnintended intravascular or intrathecal injection of MARCAINE / MARCAINE WITH EPINEPHRINE may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Unintentional intrathecal injection during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column has resulted in underventilation or apnea ("Total or High Spinal"). A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia [see ADVERSE REACTIONS (6)].

{ "type": "p", "children": [], "text": "5.9 Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal InjectionUnintended intravascular or intrathecal injection of MARCAINE / MARCAINE WITH EPINEPHRINE may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Unintentional intrathecal injection during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column has resulted in underventilation or apnea (\"Total or High Spinal\"). A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia [see ADVERSE REACTIONS (6)]." }

Aspirate for blood or cerebrospinal fluid (where applicable) before injecting 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.

{ "type": "p", "children": [], "text": "Aspirate for blood or cerebrospinal fluid (where applicable) before 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." }

Use of Test Dose with Epidural Anesthesia

{ "type": "p", "children": [], "text": "Use of Test Dose with Epidural Anesthesia" }

To serve as a warning of unintended intravascular or intrathecal injection, 3 mL of MARCAINE WITH EPINEPHRINE without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) may be used as a test dose prior to administration of the full dose in caudal and lumbar epidural blocks [see DOSAGE AND ADMINISTRATION (2.4)]. Three mL of MARCAINE WITH EPINEPHRINE without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) contains 15 mg bupivacaine and 15 mcg epinephrine. An intravascular or intrathecal injection is still possible even if results of the test dose are negative.

{ "type": "p", "children": [], "text": "To serve as a warning of unintended intravascular or intrathecal injection, 3 mL of MARCAINE WITH EPINEPHRINE without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) may be used as a test dose prior to administration of the full dose in caudal and lumbar epidural blocks [see DOSAGE AND ADMINISTRATION (2.4)]. Three mL of MARCAINE WITH EPINEPHRINE without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) contains 15 mg bupivacaine and 15 mcg epinephrine. An intravascular or intrathecal injection is still possible even if results of the test dose are negative." }

Signs/symptoms of unintended intravascular or intrathecal injection of the test dose of MARCAINE WITH EPINEPHRINE and monitoring recommendations are described below.

{ "type": "p", "children": [], "text": "Signs/symptoms of unintended intravascular or intrathecal injection of the test dose of MARCAINE WITH EPINEPHRINE and monitoring recommendations are described below." }

Unintended intravascular injection: Likely to produce a transient "epinephrine response" within 45 seconds, consisting of an increase in heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for increases. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure.Unintended intrathecal injection: Evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk).The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects [see OVERDOSAGE (10)].

{ "type": "p", "children": [], "text": "Unintended intravascular injection: Likely to produce a transient \"epinephrine response\" within 45 seconds, consisting of an increase in heart rate and/or systolic blood pressure, circumoral pallor, palpitations, and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Therefore, following the test dose, the heart rate should be monitored for increases. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect a transient rise in systolic blood pressure.Unintended intrathecal injection: Evidenced within a few minutes by signs of spinal block (e.g., decreased sensation of the buttocks, paresis of the legs, or, in the sedated patient, absent knee jerk).The test dose itself may produce a systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects [see OVERDOSAGE (10)]." }

5.10 Risk of Toxicity in Patients with Hepatic ImpairmentBecause amide local anesthetics such as bupivacaine are metabolized by the liver, consider reduced dosing and increased monitoring for bupivacaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with MARCAINE / MARCAINE WITH EPINEPHRINE, especially with repeat doses [see USE IN SPECIFIC POPULATIONS (8.6)].

{ "type": "p", "children": [], "text": "5.10 Risk of Toxicity in Patients with Hepatic ImpairmentBecause amide local anesthetics such as bupivacaine are metabolized by the liver, consider reduced dosing and increased monitoring for bupivacaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with MARCAINE / MARCAINE WITH EPINEPHRINE, especially with repeat doses [see USE IN SPECIFIC POPULATIONS (8.6)]." }

5.11 Risk of Use in Patients with Impaired Cardiovascular FunctionMARCAINE / MARCAINE WITH EPINEPHRINE should be given in reduced doses in patients with impaired cardiovascular function (e.g., hypotension, heartblock) because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by MARCAINE / MARCAINE WITH EPINEPHRINE. Monitor patients closely for blood pressure, heart rate, and ECG changes.

{ "type": "p", "children": [], "text": "5.11 Risk of Use in Patients with Impaired Cardiovascular FunctionMARCAINE / MARCAINE WITH EPINEPHRINE should be given in reduced doses in patients with impaired cardiovascular function (e.g., hypotension, heartblock) because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by MARCAINE / MARCAINE WITH EPINEPHRINE. Monitor patients closely for blood pressure, heart rate, and ECG changes." }

5.12 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood SupplyUse 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. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result.

{ "type": "p", "children": [], "text": "5.12 Risk of Ischemic Injury or Necrosis in Body Areas with Limited Blood SupplyUse 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. Patients with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result." }

5.13 Risk of Cardiac Arrhythmias with Concomitant Use of Potent Inhalation AnestheticsSerious 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 DRUG INTERACTIONS (7.6)]. In deciding whether to concurrently use MARCAINE WITH EPINEPHRINE with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account.

{ "type": "p", "children": [], "text": "5.13 Risk of Cardiac Arrhythmias with Concomitant Use of Potent Inhalation AnestheticsSerious 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 DRUG INTERACTIONS (7.6)]. In deciding whether to concurrently use MARCAINE WITH EPINEPHRINE with potent inhalation anesthetics in the same patient, the combined action of both agents upon the myocardium, the concentration and volume of vasoconstrictor used, and the time since injection, when applicable, should be taken into account." }

5.14 Risk of Adverse Reactions with Use in Head and Neck AreaSmall doses of local anesthetics (e.g., MARCAINE) injected into the head and neck area, including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Monitor circulation and respiration and constantly observe patients receiving MARCAINE / MARCAINE WITH EPINEPHRINE blocks. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see DOSAGE AND ADMINISTRATION (2.2)].

{ "type": "p", "children": [], "text": "5.14 Risk of Adverse Reactions with Use in Head and Neck AreaSmall doses of local anesthetics (e.g., MARCAINE) injected into the head and neck area, including retrobulbar, dental, and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. The injection procedures require the utmost care. Confusion, convulsions, respiratory depression, and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. They may also be due to puncture of the dural sheath of the optic nerve during retrobulbar block with diffusion of any local anesthetic along the subdural space to the midbrain. Monitor circulation and respiration and constantly observe patients receiving MARCAINE / MARCAINE WITH EPINEPHRINE blocks. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see DOSAGE AND ADMINISTRATION (2.2)]." }

5.15 Risk of Respiratory Arrest with Use in Ophthalmic SurgeryClinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block (e.g., with MARCAINE / MARCAINE WITH EPINEPHRINE), as with all other regional procedures, resuscitative equipment and drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be immediately available [see WARNINGS AND PRECAUTIONS (5.14)]. As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses.

{ "type": "p", "children": [], "text": "5.15 Risk of Respiratory Arrest with Use in Ophthalmic SurgeryClinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block (e.g., with MARCAINE / MARCAINE WITH EPINEPHRINE), as with all other regional procedures, resuscitative equipment and drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be immediately available [see WARNINGS AND PRECAUTIONS (5.14)]. As with other anesthetic procedures, patients should be constantly monitored following ophthalmic blocks for signs of these adverse reactions, which may occur following relatively low total doses." }

A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local infiltration, including the conjunctiva [see INDICATIONS AND USAGE (1)].

{ "type": "p", "children": [], "text": "A concentration of 0.75% bupivacaine is indicated for retrobulbar block; however, this concentration is not indicated for any other peripheral nerve block, including the facial nerve, and not indicated for local infiltration, including the conjunctiva [see INDICATIONS AND USAGE (1)]." }

5.16 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa in Dental ApplicationsBecause of the long duration of anesthesia, when MARCAINE WITH EPINEPHRINE [0.5% (5 mg/mL) of bupivacaine] is used for dental injections, warn patients about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns [see PATIENT COUNSELING INFORMATION (17)].

{ "type": "p", "children": [], "text": "5.16 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa in Dental ApplicationsBecause of the long duration of anesthesia, when MARCAINE WITH EPINEPHRINE [0.5% (5 mg/mL) of bupivacaine] is used for dental injections, warn patients about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advise them not to chew solid foods until sensation returns [see PATIENT COUNSELING INFORMATION (17)]." }

The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling:

{ "type": "p", "children": [], "text": "The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling:" }

{ "type": "ul", "children": [ "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)]" ], "text": "" }

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.

{ "type": "p", "children": [], "text": "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 EPINEPRHINE 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.

{ "type": "p", "children": [], "text": "Adverse reactions to MARCAINE / MARCAINE WITH EPINEPRHINE 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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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)].

{ "type": "p", "children": [], "text": "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)].

{ "type": "p", "children": [], "text": "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)]." }

7.1 Local AnestheticsThe 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)].

{ "type": "p", "children": [], "text": "7.1 Local AnestheticsThe 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 AntidepressantsThe 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)].

{ "type": "p", "children": [], "text": "7.2 Monoamine Oxidase Inhibitors and Tricyclic AntidepressantsThe 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 DrugsConcurrent 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)].

{ "type": "p", "children": [], "text": "7.3 Ergot-Type Oxytocic DrugsConcurrent 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 AntagonistsAdministration 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)].

{ "type": "p", "children": [], "text": "7.4 Nonselective Beta-Adrenergic AntagonistsAdministration 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 MethemoglobinemiaPatients who are administered MARCAINE / MARCAINE WITH EPINEPHRINE are at increased risk of developing methemoglobinemia when concurrently exposed to following drugs, which could include other local anesthetics [see WARNINGS AND PRECAUTIONS (5.3)].

{ "type": "p", "children": [], "text": "7.5 Drugs Associated with MethemoglobinemiaPatients who are administered MARCAINE / MARCAINE WITH EPINEPHRINE are at increased risk of developing methemoglobinemia when concurrently exposed to following drugs, which could include other local anesthetics [see WARNINGS AND PRECAUTIONS (5.3)]." }

Examples of Drugs Associated with Methemoglobinemia:

{ "type": "p", "children": [], "text": "Examples of Drugs Associated with Methemoglobinemia:" }

7.6 Potent Inhalation AnestheticsSerious 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)].

{ "type": "p", "children": [], "text": "7.6 Potent Inhalation AnestheticsSerious 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 ButyrophenonesPhenothiazines 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.

{ "type": "p", "children": [], "text": "7.7 Phenothiazines and ButyrophenonesPhenothiazines 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." }

8.1 PregnancyRisk Summary

{ "type": "p", "children": [], "text": "8.1 PregnancyRisk Summary" }

MARCAINE / MARCAINE WITH EPINEPHRINE is contraindicated for obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1)].

{ "type": "p", "children": [], "text": "MARCAINE / MARCAINE WITH EPINEPHRINE is contraindicated for obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.1)]." }

There are no available data on use of MARCAINE / MARCAINE WITH EPINEPHRINE in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

{ "type": "p", "children": [], "text": "There are no available data on use of MARCAINE / MARCAINE WITH EPINEPHRINE in pregnant women to inform a drug-associated risk of adverse developmental outcomes." }

In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at clinically relevant doses. Decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning) at a dose level comparable to the daily maximum recommended human dose (MRHD) on a body surface area (BSA) basis. Based on animal data, advise pregnant women of the potential risks to a fetus (see DATA).

{ "type": "p", "children": [], "text": "In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at clinically relevant doses. Decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning) at a dose level comparable to the daily maximum recommended human dose (MRHD) on a body surface area (BSA) basis. Based on animal data, advise pregnant women of the potential risks to a fetus (see DATA)." }

Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal 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 CNS, peripheral vascular tone, and cardiac function.

{ "type": "p", "children": [], "text": "Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal 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 CNS, peripheral vascular tone, and cardiac function." }

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

{ "type": "p", "children": [], "text": "If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively." }

Clinical Considerations

{ "type": "p", "children": [], "text": "Clinical Considerations" }

Maternal Adverse Reactions

{ "type": "p", "children": [], "text": "Maternal Adverse Reactions" }

Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. 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.

{ "type": "p", "children": [], "text": "Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. 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

{ "type": "p", "children": [], "text": "Labor or Delivery" }

Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Epidural anesthesia has 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.

{ "type": "p", "children": [], "text": "Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Epidural anesthesia has 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. This has not been reported with bupivacaine.

{ "type": "p", "children": [], "text": "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. This has not been reported with bupivacaine." }

It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left.

{ "type": "p", "children": [], "text": "It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left." }

Data

{ "type": "p", "children": [], "text": "Data" }

Animal Data

{ "type": "p", "children": [], "text": "Animal Data" }

Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses.

{ "type": "p", "children": [], "text": "Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses." }

Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are comparable to the daily MRHD of 400 mg/day on a mg/m2 BSA basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 0.3 times the MRHD on a BSA basis.

{ "type": "p", "children": [], "text": "Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate). The high doses are comparable to the daily MRHD of 400 mg/day on a mg/m2 BSA basis. No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 0.3 times the MRHD on a BSA basis." }

In a rat pre- and post-natal developmental study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg, decreased pup survival was observed at the high dose. The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis.

{ "type": "p", "children": [], "text": "In a rat pre- and post-natal developmental study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg, decreased pup survival was observed at the high dose. The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis." }

8.2 LactationRisk Summary

{ "type": "p", "children": [], "text": "8.2 LactationRisk Summary" }

Lactation studies have not been conducted with bupivacaine. Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. MARCAINE / MARCAINE WITH EPINEPHRINE should be administered to lactating women only if clearly indicated. Studies assessing the effects of MARCAINE / MARCAINE WITH EPINEPHRINE in breastfed children have not been performed. Studies to assess the effect of MARCAINE / MARCAINE WITH EPINEPHRINE on milk production or excretion have not been performed. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for bupivacaine and any potential adverse effects on the breastfed child from bupivacaine or from the underlying maternal condition.

{ "type": "p", "children": [], "text": "Lactation studies have not been conducted with bupivacaine. Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. MARCAINE / MARCAINE WITH EPINEPHRINE should be administered to lactating women only if clearly indicated. Studies assessing the effects of MARCAINE / MARCAINE WITH EPINEPHRINE in breastfed children have not been performed. Studies to assess the effect of MARCAINE / MARCAINE WITH EPINEPHRINE on milk production or excretion have not been performed. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for bupivacaine and any potential adverse effects on the breastfed child from bupivacaine or from the underlying maternal condition." }

8.4 Pediatric UseMARCAINE / MARCAINE WITH EPINEPHRINE is approved for use in adults. Administration of MARCAINE / MARCAINE WITH EPINEPHRINE in pediatric patients younger than 12 years is not recommended.

{ "type": "p", "children": [], "text": "8.4 Pediatric UseMARCAINE / MARCAINE WITH EPINEPHRINE is approved for use in adults. Administration of MARCAINE / MARCAINE WITH EPINEPHRINE in pediatric patients younger than 12 years is not recommended." }

Continuous infusions of bupivacaine in pediatric patients have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities.

{ "type": "p", "children": [], "text": "Continuous infusions of bupivacaine in pediatric patients have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities." }

8.5 Geriatric UsePatients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with MARCAINE / MARCAINE WITH EPINEPHRINE.

{ "type": "p", "children": [], "text": "8.5 Geriatric UsePatients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with MARCAINE / MARCAINE WITH EPINEPHRINE." }

In clinical studies of bupivacaine, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger adult patients.

{ "type": "p", "children": [], "text": "In clinical studies of bupivacaine, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger adult patients." }

Differences in various pharmacokinetic parameters have been observed between elderly and younger adult patients [see CLINICAL PHARMACOLOGY (12.3)].

{ "type": "p", "children": [], "text": "Differences in various pharmacokinetic parameters have been observed between elderly and younger adult patients [see CLINICAL PHARMACOLOGY (12.3)]." }

This product is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients may require lower doses of MARCAINE / MARCAINE WITH EPINEPHRINE.

{ "type": "p", "children": [], "text": "This product is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Elderly patients may require lower doses of MARCAINE / MARCAINE WITH EPINEPHRINE." }

8.6 Hepatic ImpairmentAmide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment treated with MARCAINE / MARCAINE WITH EPINEPHRINE, especially with repeat doses [see WARNINGS AND PRECAUTIONS (5.10)].

{ "type": "p", "children": [], "text": "8.6 Hepatic ImpairmentAmide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity. Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment treated with MARCAINE / MARCAINE WITH EPINEPHRINE, especially with repeat doses [see WARNINGS AND PRECAUTIONS (5.10)]." }

8.7 Renal ImpairmentBupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. This should be considered when selecting the MARCAINE / MARCAINE WITH EPINEPHRINE dosage [see USE IN SPECIFIC POPULATIONS (8.5)].

{ "type": "p", "children": [], "text": "8.7 Renal ImpairmentBupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. This should be considered when selecting the MARCAINE / MARCAINE WITH EPINEPHRINE dosage [see USE IN SPECIFIC POPULATIONS (8.5)]." }

Clinical Presentation

{ "type": "p", "children": [], "text": "Clinical Presentation" }

Acute emergencies from use of MARCAINE / MARCAINE WITH EPINEPHRINE are generally related to high plasma levels encountered during therapeutic use or to unintended intrathecal injection [see WARNINGS AND PRECAUTIONS (5.2, 5.9), ADVERSE REACTIONS (6)].

{ "type": "p", "children": [], "text": "Acute emergencies from use of MARCAINE / MARCAINE WITH EPINEPHRINE are generally related to high plasma levels encountered during therapeutic use or to unintended intrathecal injection [see WARNINGS AND PRECAUTIONS (5.2, 5.9), ADVERSE REACTIONS (6)]." }

If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of bupivacaine may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Hypoventilation or apnea due to unintentional intrathecal injection of MARCAINE / MARCAINE WITH EPINEPHRINE may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts.

{ "type": "p", "children": [], "text": "If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of bupivacaine may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest. Respiratory abnormalities, including apnea, may occur. Hypoventilation or apnea due to unintentional intrathecal injection of MARCAINE / MARCAINE WITH EPINEPHRINE may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts." }

Management

{ "type": "p", "children": [], "text": "Management" }

The first step in the management of systemic toxic reactions, as well as hypoventilation or apnea due to unintentional intrathecal injection of MARCAINE / MARCAINE WITH EPINEPHRINE, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated.

{ "type": "p", "children": [], "text": "The first step in the management of systemic toxic reactions, as well as hypoventilation or apnea due to unintentional intrathecal injection of MARCAINE / MARCAINE WITH EPINEPHRINE, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated." }

If necessary, use drugs to manage the convulsions. A bolus intravenous dose of a benzodiazepine will counteract CNS stimulation related to MARCAINE. Immediately after the institution of ventilatory measures, evaluate the adequacy of the circulation. Supportive treatment of circulatory depression may require Advance Cardiac Life Support measures.

{ "type": "p", "children": [], "text": "If necessary, use drugs to manage the convulsions. A bolus intravenous dose of a benzodiazepine will counteract CNS stimulation related to MARCAINE. Immediately after the institution of ventilatory measures, evaluate the adequacy of the circulation. Supportive treatment of circulatory depression may require Advance Cardiac Life Support measures." }

MARCAINE / MARCAINE WITH EPINEPHRINE contains bupivacaine hydrochloride, an amide local anesthetic, as the active pharmaceutical ingredient. The route of administration for MARCAINE (without epinephrine) is by injection, for infiltration, perineural, caudal, epidural, or retrobulbar use. The route of administration for MARCAINE WITH EPINEPHRINE is by injection, for infiltration, perineural, caudal, or epidural use. Multiple-dose vials contain methylparaben [see WARNINGS AND PRECAUTIONS (5.4)].

{ "type": "p", "children": [], "text": "MARCAINE / MARCAINE WITH EPINEPHRINE contains bupivacaine hydrochloride, an amide local anesthetic, as the active pharmaceutical ingredient. The route of administration for MARCAINE (without epinephrine) is by injection, for infiltration, perineural, caudal, epidural, or retrobulbar use. The route of administration for MARCAINE WITH EPINEPHRINE is by injection, for infiltration, perineural, caudal, or epidural use. Multiple-dose vials contain methylparaben [see WARNINGS AND PRECAUTIONS (5.4)]." }

Bupivacaine hydrochloride is 2-piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate. It is a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula:

{ "type": "p", "children": [], "text": "Bupivacaine hydrochloride is 2-piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride, monohydrate. It is a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone. It has the following structural formula:" }

MARCAINE with 1:200,000 epinephrine, contains bupivacaine hydrochloride and epinephrine bitartrate (an alpha and beta-adrenergic agonist) as active pharmaceutical ingredients. This product is for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. Multiple dose vials contain methylparaben and they should not be used for caudal and lumbar epidural blocks.

{ "type": "p", "children": [], "text": "\nMARCAINE with 1:200,000 epinephrine, contains bupivacaine hydrochloride and epinephrine bitartrate (an alpha and beta-adrenergic agonist) as active pharmaceutical ingredients. This product is for injection via local infiltration, peripheral nerve block, and caudal and lumbar epidural blocks. Multiple dose vials contain methylparaben and they should not be used for caudal and lumbar epidural blocks.\n" }

Epinephrine bitartrate is (–) - 3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol (+)-tartrate (1:1) salt. Epinephrine is a vasoconstrictor. It has the following structural formula:

{ "type": "p", "children": [], "text": "Epinephrine bitartrate is (–) - 3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol (+)-tartrate (1:1) salt. Epinephrine is a vasoconstrictor. It has the following structural formula:" }

MARCAINE (bupivacaine hydrochloride) is a clear and colorless sterile isotonic solution. Each mL of single-dose vial contains 2.5 mg, 5 mg or 7.5 mg of bupivacaine hydrochloride (equivalent to 2.22 mg, 4.44 mg or 6.66 mg of bupivacaine, respectively), sodium chloride for isotonicity, sodium hydroxide or hydrochloric acid to adjust the pH between 4 and 6.5, in water for injection.

{ "type": "p", "children": [], "text": "\nMARCAINE (bupivacaine hydrochloride) is a clear and colorless sterile isotonic solution. Each mL of single-dose vial contains 2.5 mg, 5 mg or 7.5 mg of bupivacaine hydrochloride (equivalent to 2.22 mg, 4.44 mg or 6.66 mg of bupivacaine, respectively), sodium chloride for isotonicity, sodium hydroxide or hydrochloric acid to adjust the pH between 4 and 6.5, in water for injection.\n" }

For the Multiple-dose vials, each mL also contains 1 mg methylparaben as preservative.

{ "type": "p", "children": [], "text": "For the Multiple-dose vials, each mL also contains 1 mg methylparaben as preservative." }

MARCAINE with epinephrine 1:200,000 (as bitartrate) is a clear and colorless sterile isotonic solution. Each mL contains 2.5 mg or 5 mg bupivacaine hydrochloride (equivalent to 2.22 mg or 4.44 mg of bupivacaine, respectively), and 0.0091 mg epinephrine bitartrate (equivalent to 0.005 mg of epinephrine), with sodium chloride for isotonicity, 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, and 0.1 mg edetate calcium disodium as stabilizer. The pH of these solutions is adjusted to between 3.4 and 4.5 with sodium hydroxide or hydrochloric acid.

{ "type": "p", "children": [], "text": "MARCAINE with epinephrine 1:200,000 (as bitartrate) is a clear and colorless sterile isotonic solution. Each mL contains 2.5 mg or 5 mg bupivacaine hydrochloride (equivalent to 2.22 mg or 4.44 mg of bupivacaine, respectively), and 0.0091 mg epinephrine bitartrate (equivalent to 0.005 mg of epinephrine), with sodium chloride for isotonicity, 0.5 mg sodium metabisulfite, 0.001 mL monothioglycerol, and 2 mg ascorbic acid as antioxidants, 0.0017 mL 60% sodium lactate buffer, and 0.1 mg edetate calcium disodium as stabilizer. The pH of these solutions is adjusted to between 3.4 and 4.5 with sodium hydroxide or hydrochloric acid." }

For the Multiple-dose vials, each mL also contains 1 mg methylparaben as preservative.

{ "type": "p", "children": [], "text": "For the Multiple-dose vials, each mL also contains 1 mg methylparaben as preservative." }

The specific gravity of MARCAINE 0.5% with epinephrine 1:200,000 (as bitartrate) at 25°C is 1.008 and at 37°C is 1.008.

{ "type": "p", "children": [], "text": "The specific gravity of MARCAINE 0.5% with epinephrine 1:200,000 (as bitartrate) at 25°C is 1.008 and at 37°C is 1.008." }

12.1 Mechanism of ActionBupivacaine 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.

{ "type": "p", "children": [], "text": "12.1 Mechanism of ActionBupivacaine 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.

{ "type": "p", "children": [], "text": "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 PharmacodynamicsSystemic 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)].

{ "type": "p", "children": [], "text": "12.2 PharmacodynamicsSystemic 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.

{ "type": "p", "children": [], "text": "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 period of analgesia that persists after the resolution of the block and return of sensation.

{ "type": "p", "children": [], "text": "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 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.

{ "type": "p", "children": [], "text": "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 PharmacokineticsSystemic plasma levels of bupivacaine following administration of MARCAINE do not correlate with local efficacy.

{ "type": "p", "children": [], "text": "12.3 PharmacokineticsSystemic plasma levels of bupivacaine following administration of MARCAINE do not correlate with local efficacy." }

Absorption

{ "type": "p", "children": [], "text": "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)].

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "Elimination" }

The half-life of bupivacaine in adults is 2.7 hours.

{ "type": "p", "children": [], "text": "The half-life of bupivacaine in adults is 2.7 hours." }

Metabolism

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "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.

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "Specific Populations" }

Geriatric Patients

{ "type": "p", "children": [], "text": "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)].

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "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)].

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "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)].

{ "type": "p", "children": [], "text": "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)]." }

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis

{ "type": "p", "children": [], "text": "13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis" }

Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted.

{ "type": "p", "children": [], "text": "Long-term studies in animals to evaluate the carcinogenic potential of bupivacaine hydrochloride have not been conducted." }

Mutagenesis

{ "type": "p", "children": [], "text": "Mutagenesis" }

The mutagenic potential of bupivacaine hydrochloride has not been determined.

{ "type": "p", "children": [], "text": "The mutagenic potential of bupivacaine hydrochloride has not been determined." }

Impairment of Fertility

{ "type": "p", "children": [], "text": "Impairment of Fertility" }

The effect of bupivacaine on fertility has not been determined.

{ "type": "p", "children": [], "text": "The effect of bupivacaine on fertility has not been determined." }

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F). [See USP Controlled Room Temperature.]" }

MARCAINESolutions of MARCAINE that do not contain epinephrine may be autoclaved. Autoclave at 15-pound pressure, 121 °C (250 °F) for 15 minutes. Protect from light. This product is clear and colorless. Do not use the solution if it is discolored or if it contains a precipitate.

{ "type": "p", "children": [], "text": "MARCAINESolutions of MARCAINE that do not contain epinephrine may be autoclaved. Autoclave at 15-pound pressure, 121 °C (250 °F) for 15 minutes. Protect from light. This product is clear and colorless. Do not use the solution if it is discolored or if it contains a precipitate." }

For single-dose vials: Discard unused portion.

{ "type": "p", "children": [], "text": "\nFor single-dose vials: Discard unused portion.\n" }

MARCAINE with epinephrine 1:200,000 (as bitartrate)Do not autoclave solutions of MARCAINE that contain epinephrine and protect from light. This product is clear and colorless. Do not use the solution if it is discolored or if it contains a precipitate.

{ "type": "p", "children": [], "text": "MARCAINE with epinephrine 1:200,000 (as bitartrate)Do not autoclave solutions of MARCAINE that contain epinephrine and protect from light. This product is clear and colorless. Do not use the solution if it is discolored or if it contains a precipitate." }

For single-dose vials: Discard unused portion.

{ "type": "p", "children": [], "text": "\nFor single-dose vials: Discard unused portion.\n" }

<div class="scrollingtable"><table width="100%"> <caption> <span>Product repackaged by: Henry Schein, Inc., Bastian, VA 24314</span> </caption> <tbody class="Headless"> <tr class="First"> <td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit</td> </tr> <tr> <td>NDC 0409-1559-10<br/>Tray of 10</td><td>NDC 0404-9906-10<br/>1 single-dose vial in a bag<br/>(Vial bears NDC 0409-1559-18)</td><td>0.25% Contains 2.5 mg bupivacaine hydrochloride per mL<br/>25 mg/10 mL<br/>(2.5 mg/mL)</td> </tr> <tr> <td>NDC 0409-1560-10<br/>Tray of 10</td><td>NDC 0404-9907-10<br/>1 single-dose vial in a bag<br/>(Vial bears NDC 0409-1560-18)</td><td>0.5% Contains 5 mg bupivacaine hydrochloride per mL<br/>50 mg/10 mL<br/>(5 mg/mL)</td> </tr> <tr> <td>NDC 0409-1560-29<br/>Carton of 10</td><td>NDC 0404-9907-30<br/>1 single-dose vial in a bag<br/>(Vial bears NDC 0409-1560-19)</td><td>0.5% Contains 5 mg bupivacaine hydrochloride per mL<br/>150 mg/30 mL<br/>(5 mg/mL)</td> </tr> <tr class="Last"> <td>NDC 0409-1746-30<br/>Carton of 10</td><td>NDC 0404-9908-30<br/>1 single-dose vial in a bag<br/>(Vial bears NDC 0409-1746-71)</td><td>0.25% with epinephrine 1:200,000-Contains 2.5 mg bupivacaine hydrochloride per mL<br/>75 mg/30 mL mg/mL)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Product repackaged by: Henry Schein, Inc., Bastian, VA 24314</span>\n</caption>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit</td>\n</tr>\n<tr>\n<td>NDC 0409-1559-10<br/>Tray of 10</td><td>NDC 0404-9906-10<br/>1 single-dose vial in a bag<br/>(Vial bears NDC 0409-1559-18)</td><td>0.25% Contains 2.5 mg bupivacaine hydrochloride per mL<br/>25 mg/10 mL<br/>(2.5 mg/mL)</td>\n</tr>\n<tr>\n<td>NDC 0409-1560-10<br/>Tray of 10</td><td>NDC 0404-9907-10<br/>1 single-dose vial in a bag<br/>(Vial bears NDC 0409-1560-18)</td><td>0.5% Contains 5 mg bupivacaine hydrochloride per mL<br/>50 mg/10 mL<br/>(5 mg/mL)</td>\n</tr>\n<tr>\n<td>NDC 0409-1560-29<br/>Carton of 10</td><td>NDC 0404-9907-30<br/>1 single-dose vial in a bag<br/>(Vial bears NDC 0409-1560-19)</td><td>0.5% Contains 5 mg bupivacaine hydrochloride per mL<br/>150 mg/30 mL<br/>(5 mg/mL)</td>\n</tr>\n<tr class=\"Last\">\n<td>NDC 0409-1746-30<br/>Carton of 10</td><td>NDC 0404-9908-30<br/>1 single-dose vial in a bag<br/>(Vial bears NDC 0409-1746-71)</td><td>0.25% with epinephrine 1:200,000-Contains 2.5 mg bupivacaine hydrochloride per mL<br/>75 mg/30 mL mg/mL)</td>\n</tr>\n</tbody>\n</table></div>" }

Allergic-Type Reactions

{ "type": "p", "children": [], "text": "Allergic-Type Reactions" }

Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.8), ADVERSE REACTIONS (6)].

{ "type": "p", "children": [], "text": "Assess if the patient has had allergic-type reactions to amide-type local anesthetics or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrine-containing solutions [see CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.8), ADVERSE REACTIONS (6)]." }

Temporary Loss of Sensation and Motor Activity After Caudal or Epidural Anesthesia

{ "type": "p", "children": [], "text": "Temporary Loss of Sensation and Motor Activity After Caudal or Epidural Anesthesia" }

When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia.

{ "type": "p", "children": [], "text": "When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of caudal or epidural anesthesia." }

Instructions After Dental Injection of MARCAINE

{ "type": "p", "children": [], "text": "Instructions After Dental Injection of MARCAINE" }

Advise patients receiving dental injections of MARCAINE not to chew solid foods or to test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours) [see WARNINGS AND PRECAUTIONS (5.16)].

{ "type": "p", "children": [], "text": "Advise patients receiving dental injections of MARCAINE not to chew solid foods or to test the anesthetized area by biting or probing until anesthesia has worn off (up to 7 hours) [see WARNINGS AND PRECAUTIONS (5.16)]." }

Methemoglobinemia

{ "type": "p", "children": [], "text": "Methemoglobinemia" }

Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see WARNINGS AND PRECAUTIONS (5.3)].

{ "type": "p", "children": [], "text": "Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue [see WARNINGS AND PRECAUTIONS (5.3)]." }

This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

{ "type": "p", "children": [], "text": "This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com." }

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

{ "type": "p", "children": [], "text": "Distributed by Hospira, Inc., Lake Forest, IL 60045 USA" }

LAB-1178-5.0

{ "type": "p", "children": [], "text": "LAB-1178-5.0" }