Bupivacaine Hydrochloride

1 INDICATIONS AND USAGE Bupivacaine hydrochloride injection 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 bupivacaine hydrochloride injection is recommended for each type of block indicated to produce local or regional anesthesia or analgesia [ see Dosage and Administration ( 2.2 ) ]. Limitations of Use Not all blocks are indicated for use with bupivacaine hydrochloride injection 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 ) ]. Bupivacaine hydrochloride injection contains bupivacaine, an amide local anesthetic. Bupivacaine hydrochloride injection is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. For each type of block indicated to produce local or regional anesthesia or analgesia, specific concentrations and presentations are recommended. ( 1 , 2.2 ) Limitations of Use Not all blocks are indicated for use with bupivacaine hydrochloride injection given clinically significant risks associated with use. ( 1 , 2.2 , 4 , 5.1 , 5.4 , 5.5 , 5.7 , 5.9 )

2 DOSAGE AND ADMINISTRATION Not for intrathecal use. ( 2.1 ) Avoid use of solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia. ( 2.1 , 5.4 ) See full prescribing information for: Recommended concentrations and dosages of bupivacaine hydrochloride injection according to type of block. ( 2.2 ) Additional dosage and administration information pertaining to use in epidural anesthesia and use, in ophthalmic surgery. ( 2.3 , 2.6 ) 2.1 Important Dosage and Administration Information Bupivacaine hydrochloride injection is not for intrathecal use. Avoid use of bupivacaine hydrochloride injection 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. Bupivacaine hydrochloride injection is a 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 bupivacaine hydrochloride injection is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions Bupivacaine hydrochloride injection 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 bupivacaine hydrochloride injection 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 bupivacaine hydrochloride injection [ see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 ),Overdosage ( 10 ) ]. Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting bupivacaine hydrochloride injection, 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 bupivacaine hydrochloride injection 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 bupivacaine hydrochloride injection 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. 2.2 Recommended Concentrations and Dosages of Bupivacaine Hydrochloride Injection The dosage of bupivacaine hydrochloride injection 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 re…

5 WARNINGS AND PRECAUTIONS Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patient's state of consciousness after injection of bupivacaine hydrochloride. ( 5.2 ) Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. See full prescribing information for more detail on managing these risks. ( 5.3 ) Chondrolysis with Intra-Articular Infusion: Intra-articular infusions of local anesthetics including bupivacaine hydrochloride following arthroscopic and other surgical procedures is an unapproved use, andthere have been post-marketing reports of chondrolysis in patients receiving such infusions. ( 5.5 ) 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). ( 5.7 ) Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection: Unintended intravascular or intrathecal injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Aspirate for blood or cerebrospinal fluid (where applicable) prior to each dose. ( 5.9 ) 5.1 Risk of Cardiac Arrest with Use of Bupivacaine Hydrochloride Injection in Obstetrical Anesthesia 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 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% (7.5mg/mL) concentration of bupivacaine hydrochloride is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary. 5.2 Dose-Related Toxicity The safety and effectiveness of bupivacaine hydrochloride 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 bupivacaine hydrochloride solutions. Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, light headedness, 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, under ventilation 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 bupivacaine hydrochloride that results in effective anesthesia to avoid high plasma levels and serious adverse effects. Avoid rapid injection of a large volume of bupivacaine hydrochloride solution and administer fractional(incremental) doses when feasible. Injection of repeated doses of bupivacaine hydrochloride may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status. 5.3 Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use.…

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

7 DRUG INTERACTIONS Local Anesthetics: The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. ( 7.1 ) Drugs Associated with Methemoglobinemia: Patients are at increased risk of developing methemoglobinemia when concurrently exposed to nitrates, nitrites, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other drugs. ( 7.5 ) Potent Inhalation Anesthetics: Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics. ( 7.6 ) 7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If co administration of other local anesthetics with bupivacaine hydrochloride 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 ) ]. 7.5 Drugs Associated with Methemoglobinemia Patients who are administered bupivacaine hydrochloride are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [ see Warnings and Precautions ( 5.3 ) ]. Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, isofamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine 7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics.

6 ADVERSE REACTIONS The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling: Cardiac Arrest in Obstetrical Anesthesia [ see Warnings and Precautions ( 5.1 ) ] Dose-Related Toxicity [ see Warnings and Precautions ( 5.2 ) ] Methemoglobinemia [ see Warnings and Precautions ( 5.3 ) ] Chondrolysis with Intra-Articular Infusion [ see Warnings and Precautions ( 5.5 ) ] Cardiac Arrest with Intravenous Regional Anesthesia Use [ see Contraindications ( 4 ), Warnings and Precautions ( 5.7 ) ] Systemic Toxicities with Unintended Intravascular or Intrathecal Injection [ see Warnings and Precautions ( 5.9 ) ] Respiratory Arrest Following Retrobulbar Block [ see Warnings and Precautions ( 5.15 ) ] The following adverse reactions from voluntary reports or clinical studies have been reported with bupivacaine or bupivacaine and epinephrine. Because many of the sereactions 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 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 tocephalad extension of the motor level of anesthesia have occurred. This has led to secondary cardiac arrest when untreated. Nervous System Disorders: Adverse reactions were characterized by excitation and/or depression of the central nervous system and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, respiratory arrest, nausea, vomiting, chills, pupillary constriction. In the practice of caudal or lumbar epidural block, unintentional penetration of the subarachnoid space by the catheter or needle has occurred. Subsequent adverse effects may have depended partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia. Neurologic effects following epidural or caudal anesthesia have included spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control, all of which had slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Neurologic effects following other procedures or routes of administration have included persistent anesthesia, paresthesia, weakness, paralysis, all with slow, incomplete, or no recovery. Convulsions…