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MARCAINEŽ
Sanofi
Bupivacaine HCl
Local Anesthetic
 
Action And Clinical Pharmacology: Bupivacaine stabilizes the neuronal membrane and prevents both the generation and the conduction of nerve impulses, thereby exerting 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, bupivacaine does not ordinarily produce irritation or tissue damage, and does not cause methemoglobinemia.

Following injection of bupivacaine 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 gradual decline to insignificant levels during the next 3 to 6 hours.

The plasma elimination half-life of bupivacaine 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. Bupivacaine 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, bupivacaine is metabolized primarily in the liver. The major metabolite of bupivacaine 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 the degree of plasma protein binding, the degree of ionization, and 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 with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4).

Indications And Clinical Uses: For the production of local or regional anesthesia and analgesia in infiltration procedures, peripheral nerve blocks, retrobulbar block, and caudal, epidural and subarachnoid (spinal) blocks.

Contra-Indications: Known hypersensitivity to local anesthetics of the amide type or to other components of bupivacaine solutions (see Supplied); the presence of inflammation and/or sepsis near the proposed injection site; severe shock; heart block.

Bupivacaine is contraindicated for i.v. regional anesthesia (Bier Block).

Spinal Use: With the exception of certain 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 individual physician's appraisal of the advantages as opposed to the risks and on his ability to cope with the complications that may arise. Disease of the cerebrospinal system, such as meningitis, spinal fluid block, cranial or spinal hemorrhage, increased intracranial pressure, tumors and syphilis. 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. Profound anemia, cachexia and when death is imminent. Sepsis with positive blood cultures. High Blood Pressure. Spinal anesthesia should be well tolerated if particular care is taken to prevent a sudden or appreciable fall in blood pressure. 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. Highly nervous and sensitive persons. Preoperative medication should overcome this difficulty. Visceral perforation, 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. Cardiac decompensation, massive pleural effusion, and increased intra-abdominal pressure (e.g., fullterm 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.

Manufacturers' Warnings In Clinical States: Resuscitative equipment and drugs should be readily available when any local anesthetic is used. The highest (0.75%) isotonic concentration 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.

Bupivacaine should not be used in obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death.

Bupivacaine with epinephrine 1:200 000 or other vasopressors should not be used concomitantly with ergot-type oxytocic drugs because severe persistent hypertension may occur.

Bupivacaine with epinephrine 1:200 000 or other vasopressors should be used with extreme caution in patients receiving MAO inhibitors 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 bupivacaine is not recommended because of insufficient data regarding the interaction and safety of such mixtures.

Bupivacaine 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: 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 aspiration is not 100% reliable.

Injection of repeated doses of bupivacaine may cause a significant increase in blood concentrations 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 vasoconstrictor 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 administration 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 concentration and volume of vasoconstrictor 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 AV 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 a full dose is given. However, the optimal formulation and usefulness of the test dose in obstetrics are being debated. Generally 2 to 3 mL of 0.5% bupivacaine containing 1:200 000 epinephrine 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.

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 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.

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 bupivacaine 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.

Pregnancy: Decreased pup survival in rats and an embryocidal effect in rabbits have been observed when bupivacaine was administered to these species in doses comparable, respectively, to 9 and 5 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Obstetrics: The highest (0.75%) isotonic concentration is not recommended for obstetrical anesthesia (see Warnings). This, however does not exclude the use of isotonic bupivacaine 0.25% or 0.50% or the spinal use of the hyperbaric bupivacaine 0.75% in dextrose at term for obstetrical anesthesia or analgesia.

Bupivacaine 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 bupivacaine is relatively low.

Lactation: It is not known whether local anesthetics are excreted in human milk. However, because many drugs are excreted in human milk, caution should be exercised when bupivacaine is 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.

Children: The 0.25 and 0.5% solutions of bupivacaine, with or without epinephrine, are recommended in children older than 2 years. For the appropriate concentration and dosage see Dosage section.

Until further experience is gained, the following restrictions apply to the use of bupivacaine: isotonic bupivacaine solutions with or without epinephrine are not recommended for spinal use; the 0.75% isotonic solution of bupivacaine with or without epinephrine is not recommended in patients younger than 12 years.

Bupivacaine spinal (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 MAO 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 anesthestic may result.

Adverse Reactions: Reactions to bupivacaine are characteristic of those associated with amide type local anesthetics. A major cause of adverse reactions to this group of drugs is excessive plasma levels, which may be due to overdosage, inadvertent intravascular injection, or slow metabolic degradation.

The most commonly encountered adverse reactions which demand immediate countermeasures involve the CNS and the cardiovascular system. The adverse reactions are usually 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. Factors influencing plasma protein binding, e.g., diseases which alter protein synthesis or competition of other drugs for protein binding, may diminish individual tolerance.

The CNS effects are characterized by excitation or depression. The first manifestation may be anxiety, nervousness, dizziness, blurred vision, or tremors, followed by drowsiness, convulsions, unconsciousness, and possibly respiratory arrest. Since excitement may be transient or absent, the first manifestation may be drowsiness, sometimes merging into unconsciousness and respiratory arrest. Other CNS effects may be nausea, vomiting, chills, constriction of the pupils or tinnitus. The cardiovascular manifestations of excessive plasma levels may include depression of the myocardium, blood pressure changes (usually hypotension), decreased cardiac output, heart block, bradycardia, ventricular arrhythmias including ventricular tachycardia and ventricular fibrillation, and cardiac arrest.

Allergic reactions are characterized by cutaneous lesions (e.g., urticaria, edema), and other manifestations of allergy.

Neurologic reactions following epidural or caudal anesthesia may include: high or total spinal block, urinary retention; fecal and urinary incontinence, loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, and paralysis of the lower extremities; headache and backache; and slowing of labor and increased incidence of forceps delivery.

Reactions due to systemic absorption may be slow or rapid in onset. Those of rapid onset include respiratory depression, cardiovascular collapse and cardiac arrest. This type of reaction necessitates a high degree of preparedness since it can occur with little warning.

In some subjects, bupivacaine may produce marked peripheral vasoconstriction in unanesthetized areas which may last for several hours.

Spinal use: The most commonly encountered adverse reactions which demand immediate countermeasures are hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalid extension of the motor level of anesthesia. These may lead to cardiac arrest if untreated. In addition, one or several of the following complications or side effects may be observed during or after spinal anesthesia. 1. Meningitis. With the employment of an aseptic technique, septic meningitis should be practically nonexistent. Some instances of aseptic meningitis, with fever, neck rigidity, and cloudy spinal fluid, have been reported with the use of other spinal anesthetics. The course is usually brief and benign, terminating in complete recovery. In a few, permanent paralysis (sometimes terminating fatally) and sensory disturbances have been observed. This type of meningitis has also been observed in rare instances following ordinary diagnostic lumbar puncture. 2. Palsies. These are rare and affect either the extraocular muscles or the legs and the anal and vesical sphincters (cauda equina syndrome). Paralysis of extraocular muscles usually clears up spontaneously by the third or fourth week. Cauda equina and lumbosacral cord complications (usually consisting of arachnoiditis and demyelinization) result in loss or impairment of motor and sensory function of the saddle area (bladder, rectum) and one or both legs. The complications have occurred after the use of most, if not all, spinal anesthetics. The loss or impairment of motor function may be permanent or partial recovery may slowly occur. Various explanations for such complications have been advanced, such as hypersensitivity or intolerance to the anesthetic agent with a resultant myelolytic or neurotoxic effect; pooling of relatively high concentrations of anesthetic solution around the cauda equina and spinal cord before diffusion; and accidental injection of irritating antiseptics or detergents (as when syringes are incompletely cleansed or when ampul storage solution enters a cracked ampul). Hence, most anesthesiologists prefer to autoclave ampuls in order to destroy bacteria on the exterior before opening. 3. Headache. This may largely be prevented by using a small gauge needle to prevent spinal fluid leakage and by placing the patient in the supine position after operation and providing adequate hydration. 4. Nausea and vomiting. These may be due to a drop in blood pressure, undue intra-abdominal manipulation or to preoperative medication.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution. The first consideration in the management of the emergencies is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient's state of consciousness after each local anesthetic injection.

The first step in the management of systemic toxic reactions, as well as underventilation or apnea, consists of the immediate establishment and maintenance of a patent airway and assisted or controlled ventilation with 100% oxygen. Supportive treatment of the cardiovascular system includes i.v. fluids and, when appropriate, vasopressors (such as epinephrine or ephedrine which enhance myocardial contractility).

If necessary, use drugs to control convulsions. A bolus i.v. injection of succinylcholine will paralyze the patient without depressing the CNS or cardiovascular system and facilitate ventilation. A bolus i.v. dose of diazepam or thiopental will permit ventilation and counteract central nervous system stimulation, but these drugs also depress CNS, respiratory, and cardiac function, add to possible depression, and may result in apnea. I.V. barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. For specific techniques and procedures, refer to standard textbooks.

Recent clinical data from patients experiencing local anesthetic-induced convulsions demonstrated rapid development of hypoxia, hypercarbia and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts.

Dosage And Administration: As with all local anesthesias, the dosage 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 needed to provide effective anesthesia should be administered.

In recommended doses, bupivacaine produces complete sensory block, but the effect on motor function differs between the 3 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.

0.50% provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential.

0.75% provides 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 medication, 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 patient's size and physical status and 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 kg 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 up to a maximum dose of 400 mg in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine.

The 0.75% concentration of isotonic bupivacaine is not recommended for obstetrical anesthesia or analgesia (see Warnings). The 0.5% and 0.25% concentrations of isotonic bupivacaine and the 0.75% hyperbaric solution of bupivacaine in dextrose are recommended at term for obstetrical anesthesia and analgesia.

Table I 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 adjustment in relation to age and the physical condition of the patient.

Children: Until further experience is gained, the following restrictions apply to the use of bupivacaine; isotonic bupivacaine solutions with or without epinephrine are not recommended for spinal use; the 0.75% isotonic solution of bupivacaine with or without epinephrine is not recommended in patients younger than 12 years; spinal bupivacaine HCI 0.75% hyperbaric solution in dextrose is not recommended for spinal use in patients younger than 18 years.

The 0.25 and 0.5% solutions of bupivacaine, with or without epinephrine, are recommended in children older than 2 years. For the appropriate suggested concentrations and dosage see Table II.

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 (see Table III).

Bupivacaine in dextrose (0.75% hyperbaric solution) is not recommended in pediatric patients younger than 18 years of age.

The extent and degree of spinal anesthesia depend on: (1) the dose of anesthetic (see Table III), (2) the specific gravity of the anesthetic solution, (3) the volume of solution administered, (4) the force of injection, (5) the level of puncture and (6) 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 1 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 And Storage: Isotonic Solutions: These solutions are not for spinal anesthesia. Solutions of bupivacaine HCl that do not contain epinephrine may be autoclaved. Autoclave at 15 pound pressure, 121°C for 15 minutes. Do not use if solution is discolored or contains a precipitate.

0.25%: Each mL contains: bupivacaine HCl 2.5 mg. Single dose vials of 10 mL (without preservative); boxes of 5. Single dose vials of 20 mL (without preservative); boxes of 5. Multiple dose vials of 50 mL (with methylparaben as preservative); boxes of 1.

0.5%: Each mL contains: bupivacaine HCl 5 mg. Single dose vials of 10 mL (without preservative); boxes of 5. Single dose vials of 20 mL (without preservative); boxes of 5. Multiple dose vials of 50 mL (with methylparaben as preservative); boxes of 1.

0.75%: Each mL contains: bupivacaine HCl 7.5 mg. Single dose vials of 20 mL (without preservative); boxes of 5.

Bupivacaine HCl with epinephrine 1: 200 000 (as bitartrate): These solutions 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.

0.25% with epinephrine 1:200 000: Each mL contains: bupivacaine HCl 2.5 mg. Single dose vials of 20 mL (without preservative); boxes of 5.

0.5% with epinephrine 1:200 000: Each mL contains: bupivacaine HCl 5 mg. Single dose ampuls of 3 mL (without preservative); boxes of 10. Single dose vials of 20 mL (without preservative); boxes of 5.

These solutions are made isotonic with NaCl and the pH is adjusted with NaOH or HCl. The pH range for solutions without epinephrine is 4 to 6.5 and for solutions with epinephrine is 3.3 to 5.5. Each mL of solution with epinephrine contains epinephrine bitartrate 0.0091 mg and, as nonmedicinal ingredients, sodium metabisulfite, monothioglycerol and ascorbic acid as antioxidants, sodium lactate buffer and edetate calcium disodium as stabilizer.

0.75% Hyperbaric Solution for Spinal Use Only: Each mL of solution contains: bupivacaine HCl 7.5 mg and dextrose 82.5 mg in Water for Injection. The pH is adjusted between 4 and 6.5 with NaOH or HCl. The solution may be autoclaved once at 15 pound pressure, 121°C for 15 minutes. Do not administer any solution which is discolored or contains particulate matter. Single dose ampuls of 2 mL; boxes of 10.