PRECAUTIONS SECTION.

Precautions. General: The safety and effectiveness of local anesthetics depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. (See WARNINGS, ADVERSE REACTIONS, and OVERDOSAGE.) During major regional nerve blocks, the patient should have intravenous fluids running via an indwelling catheter to assure functioning intravenous pathway. The lowest dosage of local anesthetic that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. The rapid injection of large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible. Epidural Anesthesia: During epidural administration of Bupivacaine Hydrochloride, 0.5% and 0.75% solutions should be administered in incremental doses of mL to mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Injections should be made slowly, with frequent aspirations before and during the injection to avoid intravascular injection. Syringe aspirations should also be performed before and during each supplemental injection in continuous (intermittent) catheter techniques. An intravascular injection is still possible even if aspirations for blood are negative.During the administration of epidural anesthesia, it is recommended that test dose be administered initially and the effects monitored before the full dose is given. When using continuous catheter technique, test doses should be given prior to both the original and all reinforcing doses, because plastic tubing in the epidural space can migrate into blood vessel or through the dura. When clinical conditions permit, the test dose should contain epinephrine (10 mcg to 15 mcg has been suggested) to serve as warning of unintended intravascular injection. If injected into blood vessel, this amount of epinephrine is likely to produce 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 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 heart rate increase. Patients on beta-blockers may not manifest changes in heart rate, but blood pressure monitoring can detect transient rise in systolic blood pressure. The test dose should also contain 10 mg to 15 mg of Bupivacaine Hydrochloride or an equivalent amount of another local anesthetic to detect an unintended intrathecal administration. This will be evidenced within 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 formulation of Bupivacaine Hydrochloride contains 15 mg of bupivacaine and 15 mcg of epinephrine in volume of mL. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects.Injection of repeated doses of local anesthetics 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. Local anesthetics should also be used with caution in patients with hypotension or heartblock.Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patients state of consciousness should be performed after each local anesthetic injection. It should be kept in mind at such times that 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 CNS toxicity.Local anesthetic solutions containing vasoconstrictor should be used cautiously and 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.Because amide-local anesthetics such as Bupivacaine Hydrochloride are metabolized by the liver, these drugs, especially repeat doses, 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 greater risk of developing toxic plasma concentrations. Local anesthetics 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.Serious dose-related cardiac arrhythmias may occur if preparations containing vasoconstrictor such as epinephrine are employed in patients during or following the administration of potent inhalation anesthetics. In deciding whether to use these products concurrently 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.Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Because it is not known whether amide-type local anesthetics may trigger this reaction and because the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that standard protocol for management should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure, and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and prompt institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene. (Consult dantrolene sodium intravenous package insert before using.)Use in Head and Neck Area: Small doses of local anesthetics 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. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded. (See DOSAGE AND ADMINISTRATION.)Use in Ophthalmic Surgery: Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block, as with all other regional procedures, the immediate availability of equipment, drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be assured (see also WARNINGS and Use In Head and Neck Area, above). 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 and PRECAUTIONS, General). Mixing Bupivacaine Hydrochloride with other local anesthetics is not recommended because of insufficient data on the clinical use of such mixtures.When Bupivacaine Hydrochloride 0.75% 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.Use in Dentistry: Because of the long duration of anesthesia, when Bupivacaine Hydrochloride 0.5% with epinephrine is used for dental injections, patients should be cautioned about the possibility of inadvertent trauma to tongue, lips, and buccal mucosa and advised not to chew solid foods or test the anesthetized area by biting or probing.Information for Patients: 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. Also, when appropriate, the physician should discuss other information including adverse reactions in the package insert of Bupivacaine Hydrochloride.Patients receiving dental injections of Bupivacaine Hydrochloride should be cautioned not to chew solid foods or test the anesthetized area by biting or probing until anesthesia has worn off (up to hours).Inform patients that use of local anesthetics may cause methemoglobinemia 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.Clinically Significant Drug Interactions: The administration of local anesthetic solutions containing epinephrine or norepinephrine 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 patient monitoring is essential.Concurrent administration of vasopressor drugs and of ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine.Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals of most local anesthetics including bupivacaine to evaluate the carcinogenic potentia of bupivacaine hydrochloride have not been conducted. The mutagenic potential and the effect on fertility of bupivacine hydrochloride have not been determined.Pregnancy: There are no adequate and well-controlled studies in pregnant women. Bupivacaine Hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses. This does not exclude the use of Bupivacaine at term for obstetrical anesthesia or analgesia. (See Labor and Delivery.)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 maximum recommended human dose (MRHD) of 400 mg/day on mg/m2 body surface area (BSA) basis. No embryo-fetal effects were obseerved in rats at the high dose which caused increased maternal lethality. An increase in embryo-fetal deaths were observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 1/5th the MRHD on BSA basis.In rat pre-and post-natal development study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, 40 mg/kg/day, decreased pup survival was observed at the high dose. The high dose is comparable to the daily MRHD of 400 mg/day on BSA basis.Labor and Delivery: SEE BOXED WARNING REGARDING OBSTETRlCAL USE OF 0.75% BUPIVACAINE HYDROCHLORIDE.Bupivacaine Hydrochloride is contraindicated for obstetrical paracervical block anesthesia.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, Pharmacokinetics.) 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.Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patients legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable.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 parturients 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 administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left.Nursing Mothers: Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, decision should be made whether to discontinue nursing or not administer bupivacaine, taking into account the importance of the drug to the mother.Pediatric Use: Until further experience is gained in pediatric patients younger than 12 years, administration of Bupivacaine Hydrochloride in this age group is not recommended. Continuous infusions of bupivacaine in children have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities. (See WARNINGS, PRECAUTIONS, and OVERDOSAGE.)Geriatric Use: Patients over 65 years, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride. (See ADVERSE REACTIONS.)Elderly patients may require lower doses of Bupivacaine Hydrochloride. (See PRECAUTIONS, Epidural Anesthesia and DOSAGE AND ADMINISTRATION.) In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. (See CLINICAL PHARMACOLOGY.)This product is known to be substantially excreted by the kidney, and the risk of toxic 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. (See CLINICAL PHARMACOLOGY.). Image3.jpg.

WARNINGS SECTION.

Warnings. THE 0.75% CONCENTRATION OF BUPIVACAINE HYDROCHLORIDE IS NOT RECOMMENDED FOR 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% 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% CONCENTRATION SHOULD BE RESERVED FOR SURGICAL PROCEDURES WHERE HIGH DEGREE OF MUSCLE RELAXATION AND PROLONGED EFFECT ARE NECESSARY.LOCAL ANESTHETICS SHOULD ONLY BE EMPLOYED BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES WHICH MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED, AND THEN ONLY AFTER INSURING THE IMMEDIATE AVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY RESUSCITATIVE EQUIPMENT, AND THE PERSONNEL RESOURCES NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES. (See also ADVERSE REACTIONS, PRECAUTIONS, and OVERDOSAGE.) 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.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 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 cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels mays 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 and any other oxidizing agents. Depending in the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy hydration. more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.Local anesthetic solutions containing antimicrobial preservatives, i.e., those supplied in multiple-dose vials, should not be used for epidural or caudal anesthesia because safety has not been established with regard to intrathecal injection, either intentionally or unintentionally, of such preservatives.Intra-articular infusions of local anesthetics 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 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 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.It is essential that aspiration for blood or cerebrospinal fluid (where applicable) be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, negative aspiration does not ensure against an intravascular or subarachnoid injection.Bupivacaine Hydrochloride with epinephrine 1:200,000 or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs, because severe persistent hypertension may occur. Likewise, solutions of Bupivacaine Hydrochloride containing vasoconstrictor, such as epinephrine, should be used with extreme caution in patients receiving monoamineoxidase inhibitors (MAOI) or antidepressants of the triptyline or imipramine types, because severe prolonged hypertension may result.Until further experience is gained in pediatric patients younger than 12 years, administration of Bupivacaine Hydrochloride in this age group is not recommended.Mixing or the prior or intercurrent use of any other local anesthetic with Bupivacaine Hydrochloride cannot be recommendedbecause of insufficient data on the clinical use of such mixtures. There have been reports of cardiac arrest and death during the use of Bupivacaine Hydrochloride for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of Bupivacaine Hydrochloride in this procedure is lacking. Therefore, Bupivacaine Hydrochloride is not recommended for use in this technique.Bupivacaine Hydrochloride with epinephrine 1:200,000 contains sodium metabisulfite, 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. Single-use ampuls and single-dose vials of Bupivacaine Hydrochloride without epinephrine do not contain sodium metabisulfite.

ADVERSE REACTIONS SECTION.

Adverse Reactions. Reactions to Bupivacaine Hydrochloride are characteristic of those associated with other amide-type local anesthetics. 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 experiences which demand immediate counter-measures are related to the CNS and the cardiovascular system. These adverse experiences are generally dose related and due to high plasma levels which may result 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 subarachnoid 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) may result 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 may occur. This may lead to secondary cardiac arrest if untreated. Patients over 65 years, particularly those with hypertension, may be at increased risk for experiencing the hypotensive effects of Bupivacaine Hydrochloride. Factors influencing plasma protein binding, such as acidosis, systemic diseases which alter protein production, or competition of other drugs for protein binding sites, may diminish individual tolerance.CNS Reactions: These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, exctextent 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. In survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations.Cardiovascular System Reactions: High doses or unintentional intravascular injection may lead 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, PRECAUTIONS, and OVERDOSAGE.)Allergic: Allergic-type reactions are rare and may occur as result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials or sulfites in epinephrinecontaining solutions. 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 symptomatology (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 definitely established.Neurologic: 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 contribution from the drug.In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur. Subsequent adverse effects may depend partially on the amount of drug administered intrathecally and the physiological and physical effects of dural puncture. high spinal is characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia.Neurologic effects following epidural or caudal anesthesia may include 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 may have 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 may include persistent anesthesia, paresthesia, weakness, paralysis, all of which may have slow, incomplete, or no recovery.

DOSAGE & ADMINISTRATION SECTION.

Dosage and Administration. The dose of any local anesthetic 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. The smallest dose and concentration required to produce the desired result should be administered. Dosages of Bupivacaine Hydrochloride should be reduced for elderly and/or debilitated patients and patients with cardiac and/or liver disease. The rapid injection of large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.For specific techniques and procedures, refer to standard textbooks. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Bupivacaine Hydrochloride is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).In recommended doses, Bupivacaine Hydrochloride produces complete sensory block, but the effect on motor function differs among the three concentrations. 0.25% when used for caudal, epidural, or peripheral nerve block, produces incomplete motor block. Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently. Onset of action may be slower than with the 0.5% or 0.75% solutions. 0.5% provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential. 0.75% produces complete motor block. Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical anesthesia.The duration of anesthesia with Bupivacaine Hydrochloride is such that for most indications, single dose is sufficient.Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from particular injection site. Most experience to date is with single doses of Bupivacaine Hydrochloride up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization of each case.These doses may be repeated up to once every three hours. In clinical studies to date, total daily doses have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine.The dosages in Table have generally proved satisfactory and are recommended as guide for use in the average adult. These dosages should be reduced for elderly or debilitated patients. Until further experience is gained, Bupivacaine Hydrochloride is not recommended for pediatric patients younger than 12 years. Bupivacaine Hydrochloride is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (Bier Block).Use in Epidural Anesthesia: During epidural administration of Bupivacaine Hydrochloride, 0.5% and 0.75% solutions should be administered in incremental doses of mL to mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of mL to mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended. Repeat doses should be preceded by test dose containing epinephrine if not contraindicated. Use only the single-dose ampuls and single-dose vials for caudal or epidural anesthesia; the multiple-dose vials contain preservative and therefore should not be used for these procedures.Test Dose for Caudal and Lumbar Epidural Blocks: The Test Dose of Bupivacaine Hydrochloride (0.5% bupivacaine with 1:200,000 epinephrine in 3 mL ampul) is recommended for use as test dose when clinical conditions permit prior to caudal and lumbar epidural blocks. This may serve as warning of unintended intravascular or subarachnoid injection. (See PRECAUTIONS.) The pulse rate and other signs should be monitored carefully immediately following each test dose administration to detect possible intravascular injection, and adequate time for onset of spinal block should be allotted to detect possible intrathecal injection. An intravascular or subarachnoid injection is still possible even if results of the test dose are negative. The test dose itself may produce systemic toxic reaction, high spinal or cardiovascular effects from the epinephrine. (See WARNINGS and OVERDOSAGE.)Use in Dentistry: the 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibulare area when longer duration of local anesthetic action is desired, such as for oral surgical 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 making allowance for to 10 minutes onset time. (See CLINICAL PHARMACOLOGY.) The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over single dental sitting, should not ordinarily exceed 90 mg for healthy adult patient (ten 1.8 mL injections of 0.5% Bupivacaine Hydrochloride with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, Bupivacaine in dentistry is not recommended for pediatric patients younger than 12 years.Unused portions of solution not containing preservatives, i.e., those supplied in single-dose ampuls and single-dose vials, should be discarded following initial use.This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered.Table 1.Recommended Concentrations and Doses of Bupivacaine Hydrochloride(1) With continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% may produce complete motor block. Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery.(2) For single-dose use, not for intermittent epidural technique. Not for obstetrical anesthesia.(3) See PRECAUTIONS.(4) Solutions with or without epinephrine.. Image4.jpg.

CLINICAL PHARMACOLOGY SECTION.

12 Clinical Pharmacology. 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 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)].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 primary depressant effect on the medulla and on higher centers. The depressed stage may occur without prior excited state.The duration of local anesthesia after administration of Bupivacaine Hydrochloride Injection 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 to 10 minutes and may last up to 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 Bupivacaine Hydrochloride Injection do not correlate with local efficacy.AbsorptionThe 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. 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 Bupivacaine Hydrochloride Injection for caudal, epidural, or peripheral nerve block, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by decline to insignificant levels during the next three to six hours.DistributionBupivacaine 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 high protein binding capacity (95%) has low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.Depending upon the route of administration, bupivacaine is distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.Pharmacokinetic studies on the plasma profile of bupivacaine after direct intravenous injection (Bupivacaine Hydrochloride Injection is not approved for intravenous use) suggest 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.EliminationThe half-life of bupivacaine in adults is 2.7 hours.MetabolismAmide-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.ExcretionThe 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 PopulationsGeriatric PatientsElderly patients exhibited higher peak plasma concentrations than younger patients following administration of Bupivacaine Hydrochloride Injection. The total plasma clearance was decreased in these patients [see USE IN SPECIFIC POPULATIONS (8.5)].Patients with Hepatic ImpairmentVarious 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 ImpairmentVarious 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)].

DRUG INTERACTIONS SECTION.

7 Drug Interactions. 7.1 Local AnestheticsThe toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine 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 (5.2)].7.2 Monoamine Oxidase Inhibitors and Tricyclic AntidepressantsThe administration Bupivacaine Hydrochloride and Epinephrine Injection 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 patients hemodynamic status is essential [see WARNINGS AND PRECAUTIONS (5.6)].7.3 Ergot-Type Oxytocic DrugsConcurrent administration of Bupivacaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of Bupivacaine Hydrochloride and Epinephrine concomitantly with ergot-type oxytocic drugs [see WARNINGS AND PRECAUTIONS (5.6)].7.4 Nonselective Beta-Adrenergic AntagonistsAdministration of Bupivacaine Hydrochloride and Epinephrine Injection (containing 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 patients blood pressure and heart rate is essential [see WARNINGS AND PRECAUTIONS (5.6)].7.5 Drugs Associated with MethemoglobinemiaPatients who are administered Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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)].7.6 Potent Inhalation AnestheticsSerious dose-related cardiac arrhythmias may occur if preparations containing vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) 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 Bupivacaine Hydrochloride and Epinephrine Injection and these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.. Local Anesthetics: The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. (7.1)Monoamine Oxidase Inhibitors and Tricyclic Antidepressants: Administration of Bupivacaine Hydrochloride and Epinephrine Injection to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. (5.6, 7.2)Ergot-Type Oxytocic Drugs: Concurrent administration of Bupivacaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. (5.6, 7.3)Nonselective Beta-Adrenergic Antagonists: Administration of Bupivacaine Hydrochloride and Epinephrine Injection (containing vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. (5.6, 7.4)Drugs Associated with Methemoglobinemia: Patients are at increased risk of developing methemoglobinemia when concurrently exposed to nitrates, nitrites, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other drugs. (7.5)Potent Inhalation Anesthetics: Serious dose-related cardiac arrhythmias may occur if preparations containing vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics. (5.13, 7.6). Local Anesthetics: The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. (7.1). Monoamine Oxidase Inhibitors and Tricyclic Antidepressants: Administration of Bupivacaine Hydrochloride and Epinephrine Injection to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. (5.6, 7.2). Ergot-Type Oxytocic Drugs: Concurrent administration of Bupivacaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. (5.6, 7.3). Nonselective Beta-Adrenergic Antagonists: Administration of Bupivacaine Hydrochloride and Epinephrine Injection (containing vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. (5.6, 7.4). Drugs Associated with Methemoglobinemia: Patients are at increased risk of developing methemoglobinemia when concurrently exposed to nitrates, nitrites, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other drugs. (7.5). Potent Inhalation Anesthetics: Serious dose-related cardiac arrhythmias may occur if preparations containing vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics. (5.13, 7.6). Image3.jpg. Image4.jpg.

USE IN SPECIFIC POPULATIONS SECTION.

8 Use In Specific Populations. Risk SummaryBupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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 Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pregnant women to inform 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 rat pre- and post-natal developmental study (dosing from implantation through weaning) at dose level comparable to the daily maximum recommended human dose (MRHD) on body surface area (BSA) basis. Based on animal data, advise pregnant women of the potential risks to 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 ConsiderationsMaternal Adverse ReactionsMaternal 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 patients 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 DeliveryEpidural, 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 parturients 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 administration of regional block to parturients. To do this, the patient must be maintained in the left lateral decubitus position or blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left.DataAnimal DataBupivacaine 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 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 BSA basis.In 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 BSA basis.8.2 LactationRisk SummaryLactation 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 dose of the drug. Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection should be administered to lactating women only if clearly indicated. Studies assessing the effects of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in breastfed children have not been performed. Studies to assess the effect of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection on milk production or excretion have not been performed. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for bupivacaine and any potential adverse effects on the breastfed child from bupivacaine or from the underlying maternal condition.8.4 Pediatric UseBupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is approved for use in adults. Administration of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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.8.5 Geriatric UsePatients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.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)].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 Injection/Bupivacaine Hydrochloride and Epinephrine Injection.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 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 Injection/Bupivacaine Hydrochloride and Epinephrine Injection, 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 Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection dosage [see USE IN SPECIFIC POPULATIONS (8.5)].. Pediatric Use: Administration of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pediatric patients younger than 12 years is not recommended. (8.4)Geriatric Use: Patients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection. (8.5)Moderate to Severe Hepatic Impairment: Consider increased monitoring for bupivacaine systemic toxicity. (8.6)See 17 for PATIENT COUNSELING INFORMATION.Revised: 3/2021.

WARNINGS AND PRECAUTIONS SECTION.

5 Warnings And Precautions. 5.1 Risk of Cardiac Arrest with Use of Bupivacaine Hydrochloride Injection in Obstetrical AnesthesiaThere have been reports of cardiac arrest with difficult resuscitation or death during use of Bupivacaine Hydrochloride Injection 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 Bupivacaine Hydrochloride Injection is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where high degree of muscle relaxation and prolonged effect are necessary.5.2 Dose-Related ToxicityThe safety and effectiveness of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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 patients state of consciousness should be performed after injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine 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, 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 Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection that results in effective anesthesia to avoid high plasma levels and serious adverse effects. Avoid rapid injection of large volume of Bupivacaine. Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection solution and administer fractional (incremental) doses when feasible.Injection of repeated doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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 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 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 Injection/Bupivacaine Hydrochloride and Epinephrine 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. 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 Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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 Bupivacaine Hydrochloride Injection 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 Bupivacaine Hydrochloride and Epinephrine InjectionRisk of Severe, Persistent Hypertension Due to Drug Interactions Between Bupivacaine Hydrochloride and Epinephrine Injection and Monoamine Oxidase Inhibitors and Tricyclic AntidepressantsAdministration of Bupivacaine Hydrochloride and Epinephrine Injection (containing 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 patients hemodynamic status is essential [see DRUG INTERACTIONS (7.2)].Risk of Severe, Persistent Hypertension or Cerebrovascular Accidents Due to Drug Interactions Between Bupivacaine Hydrochloride and Epinephrine Injection and Ergot-Type Oxytocic DrugsConcurrent administration of Bupivacaine Hydrochloride and Epinephrine Injection and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of Bupivacaine Hydrochloride and Epinephrine Injection concomitantly with ergot-type oxytocic drugs [see DRUG INTERACTIONS (7.3)].Risk of Hypertension and Bradycardia Due to Drug Interactions Between Bupivacaine Hydrochloride and Epinephrine Injection and Nonselective Beta-Adrenergic AntagonistsAdministration of Bupivacaine Hydrochloride and Epinephrine Injection (containing 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 patients 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 Bupivacaine Hydrochloride Injection in this procedure is lacking. Therefore, Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is contraindicated for use with this technique [see CONTRAINDICATIONS (4)].5.8 Allergic-Type Reactions to Sulfites in Bupivacaine Hydrochloride and Epinephrine InjectionBupivacaine Hydrochloride and Epinephrine Injection contains sodium metabisulfite, 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. Bupivacaine Hydrochloride Injection without epinephrine does not contain sodium metabisulfite.5.9 Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal InjectionUnintended intravascular or intrathecal injection of. Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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). 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 Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection.Use of Test Dose with Epidural AnesthesiaTo serve as warning of unintended intravascular or intrathecal injection, mL of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) may be used as test dose prior to administration of the full dose in caudal and lumbar epidural blocks [see DOSAGE AND ADMINISTRATION (2.4)]. Three mL of Bupivacaine Hydrochloride and Epinephrine Injection 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 Bupivacaine Hydrochloride and Epinephrine Injection and monitoring recommendations are described below.Unintended intravascular injection: Likely to produce 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 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 transient rise in systolic blood pressure.Unintended intrathecal injection: Evidenced within 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 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 Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, especially with repeat doses [see USE IN SPECIFIC POPULATIONS (8.6)].5.11 Risk of Use in Patients with Impaired Cardiovascular FunctionBupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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 Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection. 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 Bupivacaine Hydrochloride and Epinephrine Injection 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 vasoconstrictor such as epinephrine (e.g., Bupivacaine Hydrochloride and Epinephrine Injection) are used in patients during or following the administration of potent inhalation anesthetics [see DRUG INTERACTIONS (7.6)]. In deciding whether to concurrently use Bupivacaine Hydrochloride and Epinephrine Injection 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., Bupivacaine Hydrochloride Injection) 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 Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection 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 Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection), 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)].5.16 Risk of Inadvertent Trauma to Tongue, Lips, and Buccal Mucosa in Dental ApplicationsBecause of the long duration of anesthesia, when Bupivacaine Hydrochloride and Epinephrine Injection [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)].. Unintended intravascular injection: Likely to produce 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 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 transient rise in systolic blood pressure.. Unintended intrathecal injection: Evidenced within 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 systemic toxic reaction, high spinal or epinephrine-induced cardiovascular effects [see OVERDOSAGE (10)].. Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patients state of consciousness after injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection. (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 Injection following arthroscopic and other surgical procedures is an unapproved use, and there 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)Allergic-Type Reactions to Sulfites in Bupivacaine Hydrochloride and Epinephrine Injection: Bupivacaine Hydrochloride and Epinephrine Injection contains sodium metabisulfite, sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. (5.8)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 and consider using test dose of Bupivacaine Hydrochloride and Epinephrine Injection. (5.9). Dose-Related Toxicity: Monitor cardiovascular and respiratory vital signs and patients state of consciousness after injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection. (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 Injection following arthroscopic and other surgical procedures is an unapproved use, and there 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). Allergic-Type Reactions to Sulfites in Bupivacaine Hydrochloride and Epinephrine Injection: Bupivacaine Hydrochloride and Epinephrine Injection contains sodium metabisulfite, sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. (5.8). 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 and consider using test dose of Bupivacaine Hydrochloride and Epinephrine Injection. (5.9).