PRODUCT MONOGRAPH

NAME OF DRUG

MARCAINE (

bupivacaine hydrochloride injection USP

bupivacaine and epinephrine injection USP bupivacaine in dextrose injection USP)

ACTION

Marcaine (bupivacaine hydrochloride) stabilizes the neuronal membrane and prevents both the generation and the conduction of nerve impulses, thereby exerting a local anesthetic action. The onset of action is rapid, and anesthesia is long lasting. The advantage of bupivacaine over other local anesthetics is in the prolonged duration of effective anesthesia. It is to be noted however, that the duration of action of a local anesthetic is dependent on a number of factors including site of injection, route of administration, concentration and volume. 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. When administered in recommended doses and concentrations, Marcaine does not ordinarily produce irritation or tissue damage, and does not cause methemoglobinemia.

Pharmacokinetics

Following injection of Marcaine for caudal, epidural, or peripheral nerve block in man, peak levels of Marcaine in the blood are reached in 30 to 45 minutes, followed by a gradual decline to insignificant levels during the next three to six hours. The plasma elimination half-life of Marcaine in adults is 2.7 hours (range 1.2 to 4.6 hours). In infants, the half-life ranges from 6 to 22 hours, thus it is significantly longer than in adults. Half-life is also prolonged in the elderly. Local anesthetics are bound to plasma proteins in varying degrees. The highly lipophilic agents, such as bupivacaine, are far more highly protein-bound than the more hydrophilic compounds. Marcaine is approximately 95% protein-bound in normal adults. If plasma protein concentrations are decreased, more of the free drug will be available to exert activity. Because of its amide structure, Marcaine is metabolized primarily in the liver. The major metabolite of Marcaine is pipecoloxylidine, a dealkylated derivative. Patients with hepatic disease may be more susceptible to the potential toxicities of the amide-type local anesthetics. The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by renal perfusion and factors affecting urinary pH. 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. Marcaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4).

CONTRAINDICATIONS

Marcaine (bupivacaine hydrochloride) is contraindicated in persons with known hypersensitivity to local anesthetics of the amide type, or to other components of Marcaine solutions (see AVAILABILITY). Marcaine is contraindicated in severe shock and in heart block and when there is inflammation and/or sepsis near the site of the proposed injection. Marcaine is contraindicated for intravenous regional anesthesia (Bier Block).

Spinal Use

With the exception of serious diseases of the central nervous system or of the lumbar vertebral column, most anesthesiologists consider the following conditions to be only relative contraindications to spinal anesthesia. The decision as to whether or not spinal anesthesia should be used for an individual case depends on the physician's appraisal of the advantages, as opposed to the risks, and on his ability to cope with the complications that may arise.

1. Disease of the cerebrospinal system, such as meningitis, spinal fluid block, cranial or spinal hemorrhage, increased intracranial pressure, tumors and syphilis.

2. Shock. This should be treated before any anesthetic is administered. However, in emergency operations, spinal anesthesia may at times be considered the method of choice.

3. Profound anemia, cachexia and when death is imminent.

4. Sepsis with positive blood cultures.

5. High Blood Pressure. Spinal anesthesia should be well tolerated if particular care is taken to prevent a sudden or appreciable fall in blood pressure.

6. Low Blood Pressure. The use of suitable pressor agents and methods of controlling the diffusion of the anesthetic should remove the principal objection to spinal anesthesia in patients with low blood pressure.

7. Highly nervous and sensitive persons. Pre-operative medication should overcome this difficulty.

8. Visceral preforation, bowel strangulation, acute peritonitis. Some surgeons object to contraction of the gastrointestinal musculature; others, however, consider the associated arrest of peristalsis an advantage. With gastrointestinal hemorrhage, spinal anesthesia should be used with caution or may even be contraindicated.

9. Cardiac decompensation, massive pleural effusion and increased intra-abdominal pressure (e.g. full-term pregnancy, massive ascites, large tumor). High spinal anesthesia should not be used in patients with these conditions unless the Trendelenburg position can be omitted or the intra-abdominal pressure released slowly.

WARNINGS

RESUSCITATIVE EQUIPMENT, OXYGEN AND DRUGS SHOULD BE IMMEDIATELY AVAILABLE WHENEVER ANY LOCAL ANESTHETIC DRUG IS USED. THE HIGHEST (0.75%) CONCENTRATION OF ISOTONIC MARCAINE (BUPIVACAINE HYDROCHLORIDE) INJECTION IS NOT RECOMMENDED FOR OBSTETRICAL ANESTHESIA. THERE HAVE BEEN REPORTS OF CARDIAC ARREST WITH DIFFICULT RESUSCITATION OR DEATH FOLLOWING ITS USE FOR EPIDURAL ANESTHESIA IN OBSTETRICAL PATIENTS. RESUSCITATION HAS BEEN DIFFICULT OR IMPOSSIBLE DESPITE APPARENTLY ADEQUATE PREPARATION AND APPROPRIATE MANAGEMENT. CARDIAC ARREST HAS OCCURRED AFTER CONVULSIONS RESULTING FROM SYSTEMIC TOXICITY, PROBABLY FOLLOWING UNINTENTIONAL INTRAVASCULAR INJECTION. Marcaine should not be used in obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. Marcaine with epinephrine 1:200,000 or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs because severe persistent hypertension may occur. Marcaine with epinephrine 1:200,000 or other vasopressors should be used with extreme caution in patients receiving monoamine oxidase inhibitors (MAOI) or antidepressants of the imipramine type because severe hypertension may occur. Epinephrine-containing solutions should not be injected into tissues supplied by end arteries, for example, fingers and toes, ears, the nose, and the penis. It is essential that aspiration for blood or cerebrospinal fluid be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. During the performance of spinal anesthesia, a free flow of cerebrospinal fluid is indicative of entry into the subarachnoid space. However, aspiration should be performed before the anesthetic solution is injected to confirm entry into the subarachnoid space and to avoid intravascular injection. Mixing or the prior or intercurrent use of any other local anesthetic with Marcaine is not recommended because of insufficient data regarding the interaction and safety of such mixtures. Marcaine 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.

PRECAUTIONS

General

The safety and effectiveness of local anesthetics depend upon proper dosage, correct technique, adequate precautions and readiness for emergencies. Resuscitative equipment, oxygen and resuscitative drugs should be available for immediate use. During major nerve blocks, the patient should have a functioning i.v. line in place, providing ready access to the circulation for the administration of emergency drugs, should an adverse reaction occur. The lowest dosage that gives effective anesthesia should be used, to avoid high plasma levels and serious systemic side effects. The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible. The following precautions apply to all local anesthetics: Select needles of proper length and bevel for the technique employed. Inject slowly with frequent aspirations and, if blood is aspirated, relocate the needle. Inadvertent intravascular injection may cause serious complications. Absorption is more rapid when injections are made into highly vascular tissues. In caudal or epidural anesthesia, abandon the method if the subarachnoid space has been entered, as shown by aspiration of spinal fluid. However, a negative aspiraiton is not 100% reliable. Injection of repeated doses of Marcaine (bupivacaine hydrochloride) may cause a significant increase in blood levels due to accumulation of the drug or its metabolites or slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly and acutely ill patients may require reduced doses commensurate with age and physical condition. The decision to use a local anesthetic containing a vascoconstrictor in patients with peripheral vascular disease, will depend on the physician's appraisal of the relative advantages and risks. Dose-related cardiac arrhythmias may occur if preparations containing epinephrine are employed in patients during or immediately following the administraiton of halothane, cyclopropane, trichloroethylene or other related agents. In deciding whether to use these products concurrently in the same patient, the combined action of both agents upon the myocardium, the concentraiton and volume of vascoconstrictor used, and the time since injection, when applicable, should be taken into account. Because amide-type local anesthetics, such as bupivacaine, are metabolized in the liver, these drugs should be used cautiously in patients with hepatic disease. 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 A to V conduction produced by these drugs. Local anesthetics which contain preservatives, i.e., those supplied in multiple dose vials, should not be used for caudal or epidural anesthesia.

Spinal Use

In addition to the above noted precautions, when administering bupivacaine hyperbaric solution for spinal anesthesia, the patient's blood pressure should be carefully monitored. Spinal anesthesia is usually associated with a fall in arterial blood pressure due to sympathetic blockade.

Epidural Use

It is recommended that a test dose be administered initially and the effects monitored before the full dose is given. However, the optimal formulation and the usefulness of the test dose in obstetrics are being debated. Generally, 2 to 3 ML of 0.50% bupivacaine containing 1:200,000 epinephrine should be administered to check that the spinal canal or a blood vessel has not been entered while locating the epidural needle or catheter. In the event of spinal injection, clinical signs of spinal block would become evident in a few minutes. In the event of intravascular injection, a transient increase in pulse rate and/or systolic blood pressure is usually detectable with a monitor. The other symptoms and signs of "epinephrine response" are less dependable. Concomitantly administered medications may modify these responses. When reinforcing doses are required, the test dose should be used again to check the catheter location. However, an intravascular or subarachnoid injection is still possible even if results of the test dose are negative.

Use in Head and Neck Area

Relatively small doses of local anesthetics injected into the head and neck area, including retrobulbar 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 stumulation 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.

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. 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. When Marcaine 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 Pregnancy

Decreased pup survival in rats and an embryocidal effect in rabbits have been observed when bupivacaine hydrochloride was administered to these species in doses comparable, respectively, to nine and five times the maximal recommended daily human dose (400 mg). There are no adequate and well-controlled studies in pregnant women of the effect of bupivacaine on the developing fetus. Bupivacaine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use in Labor and Delivery

The highest (0.75%) isotonic concentration is not recommended for obstetrical anesthesia (see WARNINGS). This, however, does not exclude the use of isotonic Marcaine 0.25% or 0.50% or the spinal use of the hyperbaric Marcaine 0.75% in dextrose at term for obstetrical anesthesia or analgesia. Marcaine is contraindicated for obstetrical paracervical block anesthesia (see WARNINGS). 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. However, the fetal/maternal ratio for Marcaine is relatively low (see Pharmacokinetics).

Nursing Mother

It is not known whether local anesthetic drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when local anesthetics are administered to a nursing woman. Bupivacaine has been reported to be excreted in human milk suggesting that the nursing infant could be theoretically exposed to a dose of the drug. Because of the potential for serious adverse reactions in nursing infants from bupivacaine, a 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

The 0.25% and 0.50% solutions of bupivacaine, with or without epinephrine, are recommended in children older than 2 years. For the appropriate concentration and dosage, see DOSAGE AND ADMINISTRATION section. Until further experience is gained, the following restrictions apply to the use of Marcaine: (a) isotonic bupivacaine solutions with or without epinephrine are not recommended for spinal use; (b) the 0.75% isotonic solution of bupivacaine with or without epinephrine is not recommended in patients younger than 12 years; (c) Marcaine spinal (bupivacaine hydrochloride 0.75% hyperbaric solution in dextrose) is not recommended for spinal use in patients younger than 18 years.

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. Administration of H2 blockers prior to epidural anesthesia is inadvisable since toxic levels of local anesthetic may result.

Dosage and administration

As with all local anesthetics, the dosage of Marcaine (bupivacaine hydrochloride) varies and depends upon 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, individual tolerance, the technique of anesthesia and the physical condition of the patient. The lowest dosage and concentration needed to provide effective anesthesia should be administered. In recommended doses, bupivacine produces complete sensory block, but the effect on motor function differs among the three concentrations. C 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 0.50% or 0.75% solutions. C 0.50% provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential. C 0.75% produces complete motor block. This concentration is recommended only for epidural block (single dose) in abdominal operations requiring complete muscle relaxation without the aid of other medicaiton, and for retrobulbar anesthesia. It is not recommended for epidural block in obstetrical patients. The duration of anesthesia with bupivacaine is such that, for most procedures, 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 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. The maximum doses of bupivacaine are considered to apply to a healthy 70 kilogram, young male. However, it is not recommended that they be exceeded in heavier persons. At present, there is insufficient clinical evidence with multiple dosage or intermittent dose techniques to permit precise recommendations for such procedures to be given. However, limited clinical experience in this area of use indicates that bupivacaine may be repeated in 3 to 6 hours; total daily doses have been up to 400 mg. The duration of anesthetic effect may be prolonged by the addition of a vasco-constricting substance, e.g. epinephrine. The 0.75% concentration of isotonic Marcaine (bupivacaine hydrochloride) is not recommended for obstetrical anesthesia or analgesia (see WARNINGS). The 0.50% and 0.25% concentrations of isotonic Marcaine and the 0.75% hyperbaric solution of Marcaine in dextrose are recommended at term for obstetrical anesthesia and analgesia. The following table is presented as a guide to the use of bupivacaine in adults. The doses shown have generally proved satisfactory for the average patient. They may require reduction in relation to age and the physical condition of the patient.

1. With continuous (intermittent) techniques in caudal and epidural block, using 0.25% and 0.50% solutions, repeat doses increase the degree of motor block. For intermittent epidural anesthesia, use maximum increments of 3 to 5 mL of 0.50% Marcaine with sufficient time between doses to detect any toxic effects. The first dose of 0.50% may produce complete motor block. In most intercostal nerve blocks for intra-abdominal surgery, the 0.25% concentration has produced satisfactory motor blockade.

2. For single dose use: Not for intermittent technique. Not for obstetrical anesthesia.

3. Use of an appropriate test dose is recommended prior to injecting the full epidural dose (see "PRECAUTIONS").

Pediatric Dosage

Until further experience is gained, the following restrictions apply to the use of Marcaine (bupivacaine hydrochloride): (a) isotonic bupivacaine solutions with or without epinephrine are not recommended for spinal use; (b) the 0.75% isotonic solution of bupivacaine with or without epinephrine is not recommended in patients younger than 12 years; (c) Marcaine spinal (bupivacaine hydrochloride 0.75% hyperbaric solution in dextrose) is not recommended for spinal use in patients younger than 18 years. The 0.25% and 0.50% solutions of bupivacaine, with or without epinephrine, are recommended in children older than 2 years. For the appropriate suggested concentrations and dosage, see the following table:

Spinal Use

Bupivacaine for spinal anesthesia is available as a 0.75% hyperbaric solution. The smallest dose required to produce the desired result should be administered and the dosage should be reduced for elderly and debilitated patients and patients with cardiac and/or liver disease. The use of the hyperbaric solution should permit improved control of the extent of anesthesia since the solution will have a higher specific gravity than spinal fluid. Bupivacaine in dextrose (0.75% hyperbaric solution) is not recommended in patients younger than 18 years of age.

The extent and degree of spinal anesthesia depend on: the dose of anesthetic (see table), the specific gravity of the anesthetic solution, the volume of solution administered, the force of injection, the level of puncture and the position of the patient during and immediately after injection. The lateral recumbent position is the customary one for injection; however, when both perineal and abdominal anesthesia are required, the sitting position may be preferred. After preliminary antiseptic preparation of the back, the spinal interspace to be punctured is marked and anesthetized with 1 to 2 mL of 0.25% bupivacaine HCl solution. Ephedrine (25 mg) may be administered if needed to maintain blood pressure. After the spinal anesthetic has been administered, the specific gravity of the solution injected determines which position the patient should be placed in, at least for the first 15 to 20 minutes. Continuous sensory tests should be made by gentle strokes with a sharp instrument or by pinching the skin, comparing the sensitivity to that of the inside of the forearm. Since hypalgesia always precedes anesthesia, it is necessary to determine the line of demarcation between hypalgesia and normal sensation, to avoid extension of anesthesia above the desired segment. After injection of a 0.75% hyperbaric solution for spinal anesthesia, the patient is immediately placed on his back and the table tilted to a 10 to 20 degree Trendelenburg position in order to allow the solution to flow cephalad. Under no circumstances should a patient be left in a head-down position longer than one minute from the start of injection without testing the height of anesthesia. The neck is sharply flexed by supporting the head on a double pillow. When hypalgesia is extended to the desired height, the table is promptly brought to the horizontal position and time (about 10 to 20 minutes) allowed for the anesthetic agent to become fixed.

AVAILABILITY

Isotonic Solutions

These solutions are not for spinal anesthesia. MARCAINE HYDROCHLORIDE Solutions of MARCAINE (bupivacaine hydrochloride) that do not contain epinephrine may be autoclaved. Autoclave at 15-pound pressure, 121/C (250/F) for 15 minutes. Do not use if solution is discolored or contains a precipitate. C 0.25% - Contains 2.5 mg bupivacaine hydrochloride per mL Single-dose vials of 10 mL (without preservative) box of 5 Single-dose vials of 20 mL (without preservative) box of 5 Multiple-dose vials of 50 mL (with methylparaben as preservative) box of 1 C 0.50% - Contains 5 mg bupivacaine hydrochloride per mL Single-dose vials of 10 mL (without preservative) box of 5 Single-dose vials of 20 mL (without preservative) box of 5 Multiple-dose vials of 50 mL (with methylparaben as preservative) box of 1 C 075% - Contains 7.5 mg bupivacaine hydrochloride per mL Single-dose vials of 20 mL (without preservative) box of 5

MARCAINE HYDROCHLORIDE WITH EPINEPHRINE 1:200,000 (as bitartrate)

Solutions of MARCAINE that contain epinephrine should not be autoclaved and should be protected from light. Do not use if solution is pinkish or darker than slightly yellow or contains a precipitate. C 0.25% - with epinephrine 1:200,000 Contains 2.5 mg bupivacaine hydrochloride per mL Single-dose vials of 20 mL (without preservative) box of 5 C 0.50% - with epinephrine 1:200,000 Contains 5 mg bupivacaine hydrochloride per mL Single-dose ampuls of 3 mL (without preservative) box of 10 Single-dose vials of 20 mL (without preservative) box of 5 These solutions are made isotonic with NaC1 and the pH is adjusted with NaOH or HCl. The pH range for solutions without epinephrine is 4.0 to 6.5 and, for solutions with epinephrine, is 3.4 to 4.5. Each mL of solution with epinephrine contains 0.0091 mg epinephrine bitartrate and, as non- medicinal ingredients, 0.5 mg sodium metabisulfite, 1.25 mg monothioglycerol, and 2 mg ascorbic acid as antioxidants, 1.33 mg sodium lactate buffer and 0.1 mg edetate calcium disodium as stabilizer.

% - hyperbaric solution for spinal use only

MARCAINE

spinal solution is supplied in 2 mL single dose ampuls (boxes of 10) containing 0.75% hyperbaric solution.

Each mL of solution contains 7.5 mg bupivacaine hydrochloride and 82.5 mg dextrose in Water for Injection. The pH is adjusted between 4.0 and 6.5 with NaOH or HCl. The solution may be autoclaved once at 15-pound pressure, 121/C (250/F) for 15 minutes. Do not administer any solution which is discolored or contains particulate matter.

PHARMACOLOGY

Bupivacaine is chemically and pharmacologically related to the amino-acyl local anesthetics with the chemical name 2-Piperidinecarboxamide, 1-butyl-N-(2,6-dimethylphenyl)-, monohydrochloride. It is a white, crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone, and has the following structural formula: Molecular Formula: C18H29C1N20 Molecular Weight: 324.89 Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. After injection of bupivacaine for caudal, epidural or peripheral nerve block in man, peak blood levels were reached in 30 to 45 minutes, followed by a decline to insignificant levels in the next 3 to 6 hours. In metabolic studies in the rat, subcutaneous doses of C14 - labelled bupivacaine were rapidly absorbed. The gastrointestinal tract, liver, spleen and kidney showed relatively high concentrations. Radioactivity in adipose tissue was high immediately after drug administraion but decreased rapidly and was not detected at 24 hours. The principal route of biotransformation in the rat is by conjugation with glucuronic acid. Because of its amide structure, bupivacaine is not detoxified by plasma esterases.

TOXICOLOGY

Acute LD50 determinations in the mouse and rat were as follows:

At high intravenous doses in mice and rats, symptoms of toxicity included CNS stimulation followed by convulsions. Central stimulation is followed by depression and death is usually due to respiratory depression. Dogs tolerated single intramuscular doses of up to 10 mg/kg, with and without epinephrine. Bupivacaine produced seizures in rhesus monkeys when serum levels reached the 4.5 to 5.5 ag/mL range. No significant pathologic changes were observed following sub-lethal doses of bupivacaine in the rat, rabbit, dog and monkey, except for dose-related inflammatory reactions in the muscle tissue at the injection sites. In irritation studies in the rabbit, healing of the intramuscular lesions was well advanced or complete within seven days after the injection. Libelius and others reported denervation-like changes in the skeletal muscle of rats following repeated intramuscular injection into the same site. They commented, however, that the conditions under which these changes occurred are not likely to be encountered in the clinical use of the drug. No immediate or delayed allergic responses were observed in the guinea pig after sensitivity testing. No evidence of drug-induced teratogenic effects was observed in rats and rabbits given subcutaneous injections of bupivacaine. Decreased pup survival in rats and an embryocidal effect in rabbits have been observed when bupivacaine hydrochloride was administered to these species in doses comparable to nine and five times, respectively the maximal recommended daily human dose (400 mg).

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BIBLIOGRAPHY (cont'd)

BIBLIOGRAPHY (cont'd)