AHFS Class:

• Local Anesthetics 72:00

Generic Name(s):

• Bupivacaine Hydrochloride

• Bupivacaine Liposomal

Bupivacaine hydrochloride is a long-acting local anesthetic of the amide type.

Bupivacaine is used for local or regional anesthesia or analgesia in surgical, obstetrical, dental, diagnostic, and therapeutic procedures.211,213,214,216 The drug is commercially available as conventional bupivacaine hydrochloride preparations with or without epinephrine or as a liposomal injection containing bupivacaine in an aqueous suspension of multivesicular liposomes (Exparel^®).211,213,214,215,216

Conventional bupivacaine hydrochloride preparations are used for local infiltration anesthesia and for nerve block techniques including peripheral, sympathetic, epidural (including caudal), retrobulbar, and dental block anesthesia.211,213,215 The concentration used (0.25, 0.5 or 0.75%) is dependent on the anesthetic technique and degree of muscle relaxation desired.211,213 The 0.75% concentration of bupivacaine hydrochloride produces complete motor block and should be reserved for procedures that require a high degree of muscle relaxation and prolonged anesthetic effect (e.g., epidural block in abdominal surgeries, retrobulbar block).211,213 Use of bupivacaine hydrochloride 0.75% is not recommended for obstetrical anesthesia since such use has resulted in cardiac arrest and death, presumably from systemic toxicity following inadvertent intravascular injection.211,213 A hyperbaric solution containing 0.75% bupivacaine hydrochloride in 8.25% dextrose is used for spinal anesthesia.214

Bupivacaine liposomal injection (Exparel^®) is used for local infiltration or interscalene brachial plexus nerve block in the management of postoperative pain.216,218,222,223 Because liposomal encapsulation or incorporation into a lipid complex can substantially alter the physiochemical and functional properties of a drug, liposomal bupivacaine should not be used interchangeably with other bupivacaine-containing preparations.216,234 Efficacy of liposomal bupivacaine for local infiltration analgesia is based principally on 2 randomized, double-blind, placebo-controlled studies in adults undergoing bunionectomy or hemorrhoidectomy.216,217,218,222,223 In these studies, liposomal bupivacaine (administered directly into the surgical site at the conclusion of surgery) was substantially more effective than placebo in reducing postoperative pain; however, the treatment effect was apparent mainly during the first 12-24 hours after the drug was administered.216,221,222,223 Efficacy of liposomal bupivacaine as a brachial plexus nerve block was demonstrated in a randomized, double-blind, placebo-controlled study in patients undergoing total shoulder arthroplasty or rotator cuff repair.216 In this study, patients receiving liposomal bupivacaine (administered as a brachial plexus nerve block via interscalene approach) had substantially reduced cumulative pain scores through 48 hours compared with those receiving placebo.216 Use of liposomal bupivacaine was associated with a small reduction in opiate requirements relative to placebo in some of these studies; however, the clinical benefits of these findings are not known.216 Although liposomal bupivacaine has been evaluated for other regional nerve block techniques,216,219,232 the manufacturer states that the current data are insufficient to support use of the drug for nerve blocks other than interscalene brachial plexus nerve block because of safety concerns (e.g., risk of falls when used as a femoral nerve block) and/or lack of efficacy (e.g., when used as an intercostal nerve block).216

Local anesthetics such as bupivacaine should be used as a component of multimodal analgesia (i.e., simultaneous use of a combination of analgesic agents and techniques that target different mechanisms) in the management of postoperative pain.216,220 Studies comparing the relative efficacy of liposomal bupivacaine and conventional bupivacaine hydrochloride for postsurgical analgesia have shown variable results; some studies demonstrated improved pain relief and reduced opiate requirements with the liposomal formulation, while other studies demonstrated only minimal or no substantial differences between the formulations.218,225,226,227,228,229,230,231,232

Bupivacaine should not be used for obstetric paracervical block.211,213,216

Bupivacaine hydrochloride has been used for IV regional anesthesia† in various orthopedic and general surgical procedures; however, high plasma concentrations of the drug may occur following tourniquet release, and cardiac arrest and death have resulted. Bupivacaine therefore should not be used for IV regional anesthesia.

Administration

Conventional bupivacaine hydrochloride preparations may be administered by local infiltration or by lumbar epidural (including caudal), peripheral, retrobulbar, sympathetic, or dental block.211,213,215 For spinal anesthesia, 0.75% bupivacaine hydrochloride in 8.25% dextrose is administered by subarachnoid injection.214 Bupivacaine liposomal injection (Exparel^®) is administered by local infiltration or interscalene brachial plexus nerve block; the liposomal formulation should not be administered by epidural or intrathecal routes, and should not be used for other regional nerve blocks.216

Local anesthetics, including bupivacaine, have been administered by continuous intra-articular infusion† (e.g., for control of postoperative pain); however, such use has been associated with chondrolysis.200,201,202,203,204,205,206,207,208,209,211,213,214,216 (See Cautions: Musculoskeletal Effects in the Local Anesthetics, Parenteral, General Statement 72:00.) Bupivacaine should not be administered using the Bier block technique (IV regional anesthesia) due to the risk of cardiac arrest and death.211,213

Bupivacaine solutions containing preservatives should not be used for epidural or caudal block.211,213 Partially used solutions that do not contain preservatives should be discarded.211,213,214

The liposomal formulation is not bioequivalent to and should not be used interchangeably with other bupivacaine formulations.216

Liposomal Bupivacaine

Bupivacaine liposomal injection (Exparel^®) is commercially available in a 10- or 20-mL vial containing 13.3 mg/mL of bupivacaine in an aqueous suspension of multivesicular liposomes.216 The liposomal injection may be administered undiluted or diluted (if an increased volume of drug is necessary to cover a larger surgical area).216 If dilution is desired, the drug should be diluted with preservative-free 0.9% sodium chloride injection or lactated Ringer's injection up to a final concentration of 0.89 mg/mL (1:14 dilution by volume); sterile water for injection or other hypotonic solutions should not be used since disruption of the liposomal particles may occur.216 The diluted suspension should be used within 4 hours of preparation in a syringe.216 Any unused portions of the drug should be discarded.216

Vials of liposomal bupivacaine should be inverted multiple times to resuspend the particles immediately prior to drug withdrawal.216 Liposomal bupivacaine should be administered using a 25-gauge or larger bore needle.216 The drug should not be filtered.216

When liposomal bupivacaine is administered concomitantly with lidocaine (or other non-bupivacaine local anesthetic), immediate release of free (unencapsulated) bupivacaine may occur, potentially resulting in toxic plasma concentrations.216 Administration of liposomal bupivacaine should be delayed for at least 20 minutes after administration of lidocaine.216 The compatibility of liposomal bupivacaine and conventional bupivacaine hydrochloride is concentration dependent.216 The manufacturer states that bupivacaine hydrochloride and liposomal bupivacaine may be administered simultaneously in the same syringe, and bupivacaine hydrochloride may be injected immediately before liposomal bupivacaine as long as the ratio (based on mg dose) of conventional to liposomal drug does not exceed 1:2.216 The potential for additive toxic effects should be considered whenever these drugs are used concomitantly.216,236 Additional administration of local anesthetics should be avoided for at least 96 hours after liposomal bupivacaine is administered.216

The manufacturer states that liposomal bupivacaine should not be allowed to come into contact with topical antiseptics (e.g., povidone iodine); the topical antiseptic should be allowed to dry before liposomal bupivacaine is administered.216

Standardize 4 Safety

Standardized concentrations for epidural bupivacaine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 251Multidisciplinary expert panels were convened to determine recommended standard concentrations. 251Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 251 For additional information on S4S (including updates that may be available), see [Web].251

Dispensing and Administration Precautions

Local anesthetics should only be administered by clinicians experienced in the use and complications of these agents.211,213,214,216,220 Resuscitative equipment, oxygen, drugs, and personnel required for treatment of adverse reactions should be immediately available whenever bupivacaine is administered.211,213,214,216 For specific procedures and techniques of administration, specialized references should be consulted.211,213,214

Bupivacaine should be administered slowly in incremental doses to reduce the risk of adverse effects (e.g., local anesthetic systemic toxicity).211,213,216,234 Frequent aspirations to check for blood or cerebrospinal fluid (when applicable) should be performed to avoid inadvertent intravascular administration and to either confirm entry into the subarachnoid space (for spinal anesthesia) or avoid inadvertent subarachnoid injection; however, a negative aspiration does not ensure protection against inadvertent intravascular or subarachnoid injection.211,213,214,216 During major regional nerve blocks, IV fluids should be administered via an indwelling catheter to ensure a functioning IV pathway.211,213 Injections into the head and neck area (e.g., retrobulbar, dental, or stellate ganglion blocks) require particular care since serious adverse effects have been reported due to complications from the anesthetic technique.211,213

Because of similarity in appearance (milky white suspension) and use in similar healthcare settings, the potential exists for confusion between liposomal bupivacaine and propofol.237 If liposomal bupivacaine is mistaken for propofol, accidental IV administration of liposomal bupivacaine may occur, potentially causing substantial patient harm (e.g., cardiac arrhythmias and arrest).237 The Institute for Safe Medication Practices (ISMP) recommends that special precautions (e.g., proper labeling of syringes, storage segregation, routine double-checks) be taken to ensure that such confusion and “wrong route” administration errors do not occur.237 Instructions for the treatment of bupivacaine toxicity should be readily available in all surgical areas where liposomal bupivacaine is used.237

Dosage

Dosage of bupivacaine varies with the anesthetic procedure, degree of anesthesia required, surgical site, and individual patient response.211,213,214,216 The usual dosages should generally be reduced in geriatric, debilitated, or acutely ill patients and in patients with cardiac and/or hepatic disease.211,213,214 The lowest effective dose should be used.211,213,214,234

Conventional Bupivacaine

Conventional bupivacaine hydrochloride is commercially available in concentrations of 0.25, 0.5, or 0.75% with or without epinephrine.211,213,214 The appropriate concentration should be used based on the anesthetic technique and degree of muscle relaxation desired.211,213,214 Most experience to date with conventional bupivacaine hydrochloride is with single doses up to 175 mg without epinephrine or up to 225 mg with epinephrine 1:200,000, but individual patients and procedures may require more or less of the drug.211,213 Doses should not be repeated more frequently than every 3 hours and a maximum dose of 400 mg should not be exceeded in any 24-hour period; clinical experience with higher dosages is lacking.211,213 For most indications, a single dose is usually sufficient.213 Dosage recommendations given by the manufacturer are based on use of the drug in the average adult.211,213

For infiltration anesthesia, 0.25% bupivacaine hydrochloride with or without epinephrine may be used.211,213

Solutions of 0.25 or 0.5% bupivacaine hydrochloride with or without epinephrine and containing no preservatives are used for epidural or caudal anesthesia.211,213 For caudal block, the usual adult dose of bupivacaine hydrochloride is 15-30 mL of a 0.25 or 0.5% solution (37.5-150 mg).211,213 For epidural block (other than caudal block), the usual adult dose of bupivacaine hydrochloride is 10-20 mL of a 0.25 or 0.5% solution (25-100 mg); in obstetrics, incremental doses of 3-5 mL of the 0.5% solution, not exceeding 50-100 mg at any dosing interval, are recommended.211,213 To prevent intravascular or subarachnoid injection of a large epidural dose of bupivacaine hydrochloride, a test dose of anesthetic solution should be injected prior to administering the full dose and the patient should be monitored (e.g., pulse rate, blood pressure, signs of spinal block); when a continuous catheter technique is used, a test dose should be administered prior to each dose to ensure that the catheter has not been displaced.211,213 Each test dose should contain 10-15 mg of bupivacaine hydrochloride (or an equivalent dose of another local anesthetic) to detect inadvertent subarachnoid injection and, when clinical conditions permit, epinephrine (e.g., 10-15 mcg) to detect inadvertent intravascular injection.211,213 Solutions of 0.75% bupivacaine hydrochloride with or without epinephrine should be used for single dose epidural (but not caudal) anesthesia and may be given in a dose of 10-20 mL (75-150 mg) in adults; the 0.75% solution should not be used for obstetric anesthesia (see Cautions) and should be reserved for surgical procedures in which a high degree of muscle relaxation and prolonged effect are necessary.211,213 During epidural administration, the 0.5 and 0.75% solutions should be administered in incremental doses of 3-5 mL, with sufficient time between doses to detect toxic manifestations of inadvertent intravascular or intrathecal injection.211,213 Epidural injections should be made slowly with frequent aspirations.211

For peripheral nerve block, bupivacaine hydrochloride 0.25 or 0.5% with or without epinephrine may be given in a dose of 5 mL (12.5-25 mg) up to a maximum of 400 mg in 24 hours in adults.211,213 For sympathetic nerve block, the usual adult dose of bupivacaine hydrochloride is 20-50 mL of a 0.25% solution (50-125 mg).211,213

For retrobulbar anesthesia, the usual adult dose of bupivacaine hydrochloride with or without epinephrine is 2-4 mL of a 0.75% solution (15-30 mg).211,213 Local injections into the head and neck area should be performed carefully and dosage recommendations should not be exceeded to minimize the risk of complications from the anesthetic technique.211,213

For anesthesia in the maxillary and mandibular area when a longer duration of local anesthesia is desired (e.g., for oral surgery procedures generally associated with substantial postoperative pain), the usual adult dose of bupivacaine hydrochloride with epinephrine is 1.8 mL of a 0.5% solution (9 mg) per injection site; occasionally, a second dose of 1.8 mL (9 mg) per injection site may be necessary.211,213 Injections should be made slowly with frequent aspirations.211,213 The total dose of 0.5% bupivacaine hydrochloride solution for all injection sites spread out over a single dental sitting usually should not exceed 18 mL (90 mg) in healthy adults.211,213

If the hyperbaric solution containing 0.75% bupivacaine hydrochloride in 8.25% dextrose is used for spinal anesthesia, an adult dose of 1 mL (7.5 mg) is generally sufficient for lower extremity and perineal procedures.214 For lower abdominal procedures, a dose of 1.6 mL (12 mg) may be used.214 For obstetrical spinal anesthesia in vaginal deliveries, doses as low as 0.8 mL (6 mg) have been used.214 For spinal anesthesia in cesarean section, doses of 1-1.4 mL (7.5-10.5 mg) have been used.214 Complete sensory and motor blockade are generally achieved with recommended doses of bupivacaine hydrochloride in dextrose injection for spinal anesthesia.214

Liposomal Bupivacaine

A single dose of up to 266 mg of liposomal bupivacaine is recommended in adults for local infiltration analgesia; the dose should be individualized based on the surgical site, volume of drug required to cover the area, and individual patient factors (e.g., physical status, presence of renal or hepatic impairment).216 In the bunionectomy study, a total dose of 106 mg (8 mL) was administered, with 7 mL infiltrated into the tissues surrounding the osteotomy and 1 mL infiltrated throughout the subcutaneous tissue.216 In the hemorrhoidectomy study, a single dose of 266 mg (20 mL of drug diluted with 10 mL of 0.9% sodium chloride injection) was administered; the total volume of 30 mL was divided into 5-mL increments and infiltrated into 6 sites in the perianal tissue using a standard anal block procedure with moving-needle technique.216,222

If liposomal bupivacaine is used for interscalene brachial plexus nerve block, the recommended adult dose based on the study in patients undergoing total shoulder arthroplasty or rotator cuff repair is 133 mg (10 mL).216

Precautions

Bupivacaine shares the toxic potentials of the local anesthetics, and the usual precautions of local anesthetic therapy should be observed. (See Cautions in the Local Anesthetics, Parenteral, General Statement 72:00.)

Adverse effects of bupivacaine generally are limited when administered locally at the recommended dosages and routes.211,213,216 However, excessive plasma concentrations can lead to systemic toxicity manifesting principally as CNS and cardiovascular effects.211,213,216,236

The 0.75% solution of bupivacaine hydrochloride is not recommended for obstetric anesthesia since use of this concentration for epidural anesthesia in obstetric patients has been associated with cardiac arrest with difficult resuscitation or death.211,213 Cardiac arrest has occurred after seizures resulting from systemic toxicity, apparently following inadvertent intravascular injection.211,213

Some commercially available formulations of bupivacaine hydrochloride contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.211,213 The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.211,213

Pediatric Precautions

Pending accumulation of further data on the use of the drug in pediatric patients, bupivacaine hydrochloride with or without epinephrine should not be used in children younger than 12 years of age and the hyperbaric bupivacaine hydrochloride in dextrose solution for spinal anesthesia should not be used in children younger than 18 years of age.211,213,214 Efficacy and safety of bupivacaine liposomal injection have not been established in pediatric patients.216

Continuous infusions of bupivacaine in children have resulted in high plasma concentrations and seizures; high plasma concentrations also may be associated with adverse cardiovascular effects.211,213

Pharmacokinetics

Absorption

Bupivacaine has a long duration of action. Onset of anesthesia following administration of 0.5% solutions of bupivacaine hydrochloride for dental anesthesia occurs in about 2-10 minutes and duration of action is up to 7 hours in many patients. Onset of anesthesia following administration of 0.25 or 0.5% solutions of bupivacaine hydrochloride in epidural, including caudal block, and peripheral or sympathetic nerve block occurs in about 4-17 minutes and duration of action ranges from 3-7 hours. In epidural block, 0.75% solutions of bupivacaine hydrochloride produce a slightly shorter onset of action; duration of action may be from 6-9 hours. Although 0.25 and 0.5% solutions provide adequate sensory blockade in single doses, they do not produce complete muscle relaxation. If given by the continuous block method, however, repeat doses will increase the degree of motor block. The first repeat dose of 0.5% bupivacaine hydrochloride may give complete motor block. Single-dose epidural block with usual doses of 0.75% bupivacaine hydrochloride or single-dose intercostal nerve block with usual doses of a 0.25% solution may produce complete motor blockade which is necessary for abdominal surgery. In spinal anesthesia, a 0.75% solution of bupivacaine hydrochloride in 8.25% dextrose has an onset of sensory blockade within 1 minute and motor blockade and dermatome level are usually maximal within 15 minutes; the duration of sensory blockade averages 2 hours and complete return of motor ability averages 3.5 hours following a 12-mg dose. Epinephrine may prolong the duration of action of bupivacaine. The onset of action of liposomal bupivacaine is less than 2 minutes, which appears to be similar to conventional bupivacaine hydrochloride, and the duration of analgesic effect based on the principal efficacy studies appears to be no more than 24 hours.221

Systemic absorption of bupivacaine (administered either as the conventional or liposomal formulation) is dependent on the total dose administered, route of administration, vascularity at the site of administration, and presence or absence of epinephrine in the formulation.211,213,214,216 After epidural or caudal administration of 125 or 150 mg of bupivacaine hydrochloride, peak plasma concentrations of 0.45-1.25 mcg/mL have been demonstrated. After administration of bupivacaine hydrochloride for caudal, epidural, or peripheral nerve block, peak blood bupivacaine concentrations occur within 30-45 minutes. Accumulation of the drug occurs with multiple doses; however, the long duration of bupivacaine hydrochloride anesthesia reduces the need for repeated doses. Following local infiltration of liposomal bupivacaine in patients undergoing bunionectomy or hemorrhoidectomy, peak plasma concentrations were 0.17 or 0.87 mcg/mL, respectively; following administration as an interscalene brachial plexus nerve block, peak plasma concentration was 0.21 mcg/mL.216 Systemic concentrations of liposomal bupivacaine can persist for up to 96 hours after local infiltration or up to 120 hours after interscalene brachial plexus nerve block; however, systemic concentrations are not correlated with local efficacy.216

Distribution

After absorption into the blood, bupivacaine hydrochloride is more highly bound to plasma proteins than are any other local anesthetics; bupivacaine is reportedly 82-96% bound. Bupivacaine hydrochloride has the lowest degree of placental transmission of parenteral local anesthetics and may cause the least fetal depression.

Distribution of liposomal bupivacaine is expected to be similar to that of other bupivacaine formulations after bupivacaine is released from the multivesicular liposome.216

Elimination

The elimination half-life of bupivacaine hydrochloride is 1.5-5.5 hours in adults and 8.1 hours in neonates. Bupivacaine hydrochloride is principally metabolized to pipecolylxylidine (PPX) by N -dealkylation, probably in the liver. Bupivacaine is excreted in urine as small amounts of PPX, unchanged drug (5%), and other metabolites as yet unidentified.

Elimination of liposomal bupivacaine is expected to be similar to that of other bupivacaine formulations after bupivacaine is released from the multivesicular liposome.216

Chemistry and Stability

Chemistry

Bupivacaine occurs as a 50:50 racemic mixture of the R - and S -enantiomers. Bupivacaine is a local anesthetic of the amide type with a long duration of action. The drug is commercially available as a conventional bupivacaine hydrochloride formulation or a liposomal formulation containing bupivacaine (as the free base) in a white to off-white preservative-free aqueous suspension of multivesicular liposomes.211,213,216,221 A hyperbaric solution of 0.75% bupivacaine hydrochloride in 8.25% dextrose injection also is commercially available for spinal anesthesia.214 Bupivacaine hydrochloride differs structurally from mepivacaine hydrochloride only in the substitution of a butyl group for the N -methyl group. Bupivacaine hydrochloride occurs as a white, odorless, crystalline powder and is freely soluble in water and in alcohol. The pK_a of bupivacaine hydrochloride is 8.1.

Commercially available solutions of bupivacaine hydrochloride have a pH of 4-6.5.211,213 Bupivacaine hydrochloride solutions that contain epinephrine bitartrate have a pH of 3.3-5.5.211 Bupivacaine hydrochloride solutions, with or without epinephrine, in multiple-dose vials may contain methylparaben 0.1% as a preservative.211,213 A hyperbaric solution for spinal anesthesia is commercially available and contains 0.75% bupivacaine hydrochloride in 8.25% dextrose.214 The hyperbaric solution has a pH of 4-6.5 and a specific gravity of 1.030-1.035 at 25°C and 1.03 at 37°C.214 Bupivacaine liposomal injection has a pH of 5.8-7.4.216

Stability

Bupivacaine hydrochloride solutions should be stored at 20-25°C; solutions containing epinephrine should be protected from light.211,213,214 Bupivacaine hydrochloride solutions should not be used if their color is pinkish or darker than slightly yellow or if a precipitate is present.211

Bupivacaine hydrochloride solutions that do not contain epinephrine may be autoclaved at 15 PSI at 121°C for 15 minutes; solutions containing epinephrine should not be autoclaved. Hyperbaric solutions for spinal anesthesia should not be resterilized more than once.214 Liposomal bupivacaine should not be autoclaved.216

Bupivacaine liposomal injection should be stored at 2-8°C prior to use; the drug should not be frozen or exposed to high temperatures (exceeding 40°C).216 Alternatively, intact vials of liposomal bupivacaine may be stored at room temperature (20-25°C) for up to 30 days; the drug should not be re-refrigerated once it has been stored at room temperature.216

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, and dosage and administration of bupivacaine hydrochloride, see the Local Anesthetics, Parenteral, General Statement 72:00.

Only references cited for selected revisions after 1984 are available electronically.

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