e, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. if local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious cns and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. discontinue bupivacaine hydrochloride 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. 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, a 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 a severe persistent hypertension may occur. likewise, solutions of bupivacaine hydrochloride containing a 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 recommended because 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, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. the overall prevalence of sulfite sensitivity in the general population is unknown and probably low. sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. single-use ampuls and single-dose vials of bupivacaine hydrochloride without epinephrine do not contain sodium metabisulfite. boxed warning

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, a 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 a 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 1 have generally proved satisfactory and are recommended as a 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 3 ml to 5 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 3 ml to 5 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 a test dose containing epinephrine if not contraindicated. use only the single-use ampuls and single-dose vials for caudal or epidural anesthesia; the multiple-use vials contain a 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 a 3 ml ampul) is recommended for use as a test dose when clinical conditions permit prior to caudal and lumbar epidural blocks. this may serve as a 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 a 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 mandibular area when a 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 2 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 a single dental sitting, should not ordinarily exceed 90 mg for a 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-use 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-use, not for intermittent epidural technique. not for obstetrical anesthesia. 3 see precautions . 4 solutions with or without epinephrine. dosage and administration

tilation 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, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. this may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. other cns 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 a 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 a result of sensitivity to the local anesthetic or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-use vials or sulfites in epinephrine-containing 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 a 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 a dural puncture. a 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.

icular 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. recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine. therefore, incremental dosing is necessary. following systemic absorption, local anesthetics can produce cns stimulation, depression, or both. apparent central stimulation is manifested as restlessness, tremors and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. however, the local anesthetics have a primary depressant effect on the medulla and on higher centers. the depressed stage may occur without a prior excited state. pharmacokinetics: the rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. a dilute concentration of epinephrine (1:200,000 or 5 mcg/ml) usually reduces the rate of absorption and peak plasma concentration of bupivacaine hydrochloride, permitting the use of moderately larger total doses and sometimes prolonging the duration of action. the onset of action with bupivacaine hydrochloride is rapid and anesthesia is long lasting. the duration of anesthesia is significantly longer with bupivacaine hydrochloride than with any other commonly used local anesthetic. it has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesics is reduced. the onset of action following dental injections is usually 2 to 10 minutes and anesthesia may last two or three times longer than lidocaine and mepivacaine for dental use, in many patients up to 7 hours. the duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000. local anesthetics are bound to plasma proteins in varying degrees. generally, the lower the plasma concentration of drug the higher the percentage of drug bound to plasma proteins. local anesthetics appear to cross the placenta by passive diffusion. the rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. bupivacaine hydrochloride with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). the extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. pharmacokinetic studies on the plasma profile of bupivacaine hydrochloride after direct intravenous injection suggest a three-compartment open model. the first compartment is represented by the rapid intravascular distribution of the drug. the second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. the third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. the elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized. after injection of bupivacaine hydrochloride for caudal, epidural, or peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours. various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary ph, renal blood flow, the route of drug administration, and the age of the patient. the half-life of bupivacaine hydrochloride in adults is 2.7 hours and in neonates 8.1 hours. in clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger patients. elderly patients also exhibited higher peak plasma concentrations following administration of this product. the total plasma clearance was decreased in these patients. amide-type local anesthetics such as bupivacaine hydrochloride are metabolized primarily in the liver via conjugation with glucuronic acid. patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. pipecoloxylidine is the major metabolite of bupivacaine hydrochloride. the kidney is the main excretory organ for most local anesthetics and their metabolites. urinary excretion is affected by urinary perfusion and factors affecting urinary ph. only 6% of bupivacaine is excreted unchanged in the urine. when administered in recommended doses and concentrations, bupivacaine hydrochloride does not ordinarily produce irritation or tissue damage.

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