Bupivacaine Hydrochloride

5 WARNINGS AND PRECAUTIONS 5.1 Use of Spinal Anesthetics During Uterine Contractions Spinal anesthetics including Bupivacaine Hydrochloride in Dextrose Injection, USP 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. 5.2 Patients with Hypertension 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, USP. 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, USP. 5.3 Dose-Related Toxicity The safety and effectiveness of Bupivacaine Hydrochloride in Dextrose Injection, USP 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, USP 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, USP that results in effective anesthesia to avoid serious adverse reactions. Avoid rapid injection of a large volume of Bupivacaine Hydrochloride in Dextrose Injection, USP. Injection of repeated doses of Bupivacaine Hydrochloride in Dextrose Injection, USP 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. 5.4 Risk of Systemic Toxicities with Unintended Intravascular Injection Unintended intravascular injection of Bupivacaine Hydrochloride in Dextrose Injection, USP 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, USP, 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, USP-filled syringe will result in an identifiable swirl in the solution. A negative aspiration for blood does not ensure against an intravascular injection. 5.5 Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose 6 phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition [ see Drug Interactions (7.2) ]. 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, USP 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. 5.6 Risk of Cardiac Arrest with Use of Epidural Bupivacaine in Obstetrical Anesthesia There have been reports of cardiac arrest with difficult resuscitation or death during use of Bupivacaine Hydrochloride Injection, USP for epidural anesthesia in obstetrical patients. In most cases, this has followed use of Bupivacaine Hydrochloride Injection, USP 0.75%, not Bupivacaine Hydrochloride in Dextrose Injection, USP. The package insert for Bupivacaine Hydrochloride Injection, USP 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, USP is recommended for spinal anesthesia in obstetrical patients. 5.7 Chondrolysis with Intra-Articular Infusion 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 2 nd month after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. 5.8 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 Bupivacaine Hydrochloride in Dextrose Injection, USP in this procedure is lacking. Therefore, Bupivacaine Hydrochloride in Dextrose Injection, USP is contraindicated for use with this technique [ see Contraindications (4) ]. 5.9 Patients with Severe Disturbances of Cardiac Rhythm, Shock, or Heart Block Consider alternate anesthetic techniques in patients with severe disturbances of cardiac rhythm, shock, or heart block [ see Contraindications (4) ]. 5.10 Risk of Toxicity in Patients with Hepatic Impairment 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, USP [ 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. 5.11 Risk of Use in Patients with Impaired Cardiovascular Function Bupivacaine Hydrochloride in Dextrose Injection, USP 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, USP and the prolongation of AV conduction produced by the drug. Monitor patients closely for blood pressure, heart rate, and ECG changes.

6 ADVERSE REACTIONS The following clinically significant adverse reactions have been reported and described in other sections of the labeling: Allergic-Type Reactions [ see Contraindications (4) ] Dose-Related Toxicity [ see Warnings and Precautions (5.3) ] Systemic Toxicities with Unintended Intravascular Injection [ see Warnings and Precautions (5.4) ] Methemoglobinemia [ see Warnings and Precautions (5.5) ] Cardiac Arrest in Obstetrical Anesthesia [ see Warnings and Precautions (5.6) ] Chondrolysis with Intra-Articular Infusion [ see Warnings and Precautions (5.7) ] Cardiac Arrest with Intravenous Regional Anesthesia Use [ see Contraindications (4) , Warnings and Precautions (5.8) ] 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, USP are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to Bupivacaine Hydrochloride in Dextrose Injection, USP 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. 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. 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) ]. 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. 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. 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. 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.