There have been reports of cardiac arrest with difficult resuscitation or death during use of bupivacaine for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of bupivacaine is not recommended for obstetrical anesthesia and should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary.
Inadvertent intravascular injection could cause bupivacaine droplets to be deposited in the pulmonary and other capillary beds. Administer bupivacaine into the subacromial space at the end of arthroscopic shoulder surgery. Direct arthroscopic visualization must be used to confirm proper placement of the needle tip before injecting bupivacaine.
Implant:
Analgesia, postsurgical: 300 mg (3 × 100 mg implants) as a single dose placed into the inguinal hernia repair surgical site.
Injection:
Note: Dose varies with procedure, depth of anesthesia, vascularity of tissues, duration of anesthesia, and condition of patient. Do not use solutions containing preservatives for caudal or epidural block.
Local anesthesia: Infiltration: 0.25% infiltrated locally; maximum: 175 mg. Note: Aspiration should be performed prior to each injection; however, absence of blood in the syringe does not guarantee that intravascular injection has been avoided (Mulroy 2010).
Caudal block (preservative free): 15 to 30 mL of 0.25% or 0.5%
Epidural block (other than caudal block; preservative free): Administer in 3 to 5 mL increments, allowing sufficient time to detect toxic manifestations of inadvertent IV or intrathecal administration: 10 to 20 mL of 0.25% or 0.5%
Surgical procedures requiring a high degree of muscle relaxation and prolonged effects only: 10 to 20 mL of 0.75% (Note: Not to be used in obstetrical cases)
Peripheral nerve block: 5 mL of 0.25% or 0.5%; maximum: 400 mg/day
Sympathetic nerve block: 20 to 50 mL of 0.25%
Retrobulbar anesthesia: 2 to 4 mL of 0.75%
Spinal anesthesia: Preservative free solution of 0.75% bupivacaine in 8.25% dextrose:
Lower extremity and perineal procedures: 1 mL
Lower abdominal procedures: 1.6 mL
Labor and normal vaginal delivery: 0.8 mL (higher doses may be required in some patients)
Cesarean delivery: 1 to 1.4 mL
Combined spinal-epidural (CSE) technique for labor analgesia (off-label dosing [spinal component]): 1.75 to 2.5 mg combined with fentanyl 15 mcg (Eltzschig 2003; Ngan Kee 2014; Whitty 2007).
Combined spinal-epidural (CSE) technique for anesthesia for Cesarean delivery (off-label dosing [spinal component]): 8 to 12 mg combined with fentanyl 15 mcg; in addition to fentanyl, may also include a longer-acting opioid (ie, morphine 100 to 150 mcg) for postoperative analgesia (Ginosar 2004; Santos 2015).
Subacromial injection (Posimir): Infiltration: Arthroscopic subacromial decompression surgery: 660 mg (5 mL) as a single dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Implant: There are no specific dosage adjustments provided in the manufacturer's labeling. Risk of adverse reactions may be increased in patients with renal impairment, particularly in patients with severe kidney disease. Consider increased monitoring for toxicities.
Injection: There are no specific dosage adjustments provided in the manufacturer's labeling. Risk of adverse reactions may be increased in patients with renal impairment.
Subacromial injection (Posimir): There are no specific dosage adjustments provided in the manufacturer's labeling. Risk of adverse reactions may be increased in patients with renal impairment, particularly in patients with severe kidney disease. Consider increased monitoring for toxicities.
Implant: There are no specific dosage adjustments provided in the manufacturer's labeling. Risk of toxicity may be increased in patients with severe impairment; consider more frequent monitoring for toxicities in patients with moderate or severe impairment.
Injection: There are no specific dosage adjustments provided in the manufacturer's labeling. Risk of toxicity may be increased in patients with severe impairment; consider a reduced dose and more frequent monitoring for toxicities in patients with moderate or severe impairment.
Subacromial injection (Posimir): There are no specific dosage adjustments provided in the manufacturer's labeling. Risk of toxicity may be increased in patients with severe impairment; consider a reduced dose and more frequent monitoring for toxicities in patients with moderate or severe impairment.
(For additional information see "Bupivacaine: Pediatric drug information")
Note: Dose varies with procedure, depth of anesthesia, vascularity of tissues, duration of anesthesia, and condition of patient. Preservative-free formulations are recommended for administration into the CNS space (eg, epidural, caudal, spinal). Consider incremental administration with negative aspiration prior to each injection; however, absence of blood in the syringe does not guarantee that intravascular injection has been avoided (Mulroy 2010). Should only be administered under the supervision of a qualified physician experienced in the use of anesthetics. In obese pediatric patients, the preferred weight used for dose calculation is undefined and specific pediatric data are sparse (Lerman 2018; Nafiu 2018); some have suggested the use of lean body mass/weight not ideal body weight (IBW) (Coté 2018).
Central nerve block/anesthesia:
Caudal block: Reported dosing variable based on procedure; dependent on necessary dermatome level and corresponding volume of space:
Infants and Children: Limited data available: Usual concentration ≤0.25% solution with or without epinephrine: Usual reported dose range: 0.5 to 1.3 mL/kg (maximal volume of drug: 20 mL); dose should not exceed 2 mg/kg plain solution, or 3 mg/kg with epinephrine. In infants, routine use of concentrations ≤0.25% have been suggested to reduce risk of bupivacaine cardiotoxicity (Coté 2013; Ingelmo 2007; Ivani 1998; Ivani 2002; Karkera 2016; Miller 2015; Payne 1993; Schrock 2003; Schwartz 2010).
Adolescents: Usual concentration 0.25 to 0.5% solution with or without epinephrine: 15 to 30 mL (manufacturer's labeling).
Epidural block: Reported dosing variable; among other factors, dose dependent on necessary dermatome level and corresponding volume of epidural space (Coté 2013):
Infants: Limited data available: Usual concentration ≤0.25% with or without epinephrine: 0.7 to 0.75 mL/kg; maximum dose: 2.5 mg/kg; Note: For infants (particularly young infants), if repeat injections necessary, a decreased dose may be necessary to prevent drug accumulation. Some experts suggest if at least 45 minutes since initial dose, reduce dose to 1/3 of the initial or if at least 90 minutes since initial dose, then reduce dose to half of the initial. If additional doses are necessary, doses should be reduced to half of the previous dose (Ivani 1999; Miller 2015; Monsel 2007).
Children: Limited data available: Usual concentration 0.25% solution: Initial: 0.3 to 0.6 mL/kg (maximal volume of drug: 20 mL); maximum dose: 2.5 mg/kg (Ingelmo 2007; Ingelmo 2007a).
Adolescents: 0.25% or 0.5% solution: 10 to 20 mL administered in 3 to 5 mL increments; if high degree of muscle relaxation and prolonged effects needed, may consider 0.75% solution: 10 to 20 mL (manufacturer's labeling).
Epidural, continuous infusion: Limited data available in infants and children <12 years (Berde 1992; Miller 2015; Moriarty 2012): Note: Use has generally been replaced by other agents (eg, ropivacaine) (Miller 2015; Moriarty 2012).
Loading dose: Usual concentration: 0.25%: 2 to 2.5 mg/kg.
Infusion:
Infants <4 months: 0.2 mg/kg/hour.
Infants ≥4 months: 0.25 mg/kg/hour.
Children and Adolescents: 0.3 mg/kg/hour.
Peripheral nerve block: Limited data available in infants and children: Note: Dose varies with location of block (ie, procedure), depth of anesthesia, vascularity of tissues, duration of anesthesia, and condition of patient.
Infants ≥6 months and Children: Usual concentration 0.125% or 0.25% solution with or without epinephrine: The volume of dose (mL/kg) and concentration of solution are site specific based upon anatomy and variable among patients and procedure; see below ranges. For infants <6 months, maximum doses should be reduced by 30% (Coté 2013; Miller 2015). Maximum dose plain solution: 2 mg/kg or 150 mg, whichever is less, or maximum dose with epinephrine: 3 mg/kg or 200 mg of bupivacaine, whichever is less.
Commonly suggested doses (Coté 2013):
Head and neck: 0.05 mL/kg.
Upper extremity:
Brachial plexus: 0.2 to 0.3 mL/kg.
Digital nerve: 0.05 mL/kg.
Truncal blocks:
Transversus abdominis plane: 0.2 to 0.5 mL/kg (Jöhr 2015).
Rectus sheath: 0.1 mL/kg.
Ilioinguinal: 0.075 mL/kg.
Lower extremity blocks:
Femoral nerve: 0.2 to 0.3 mL/kg.
Sciatic nerve: 0.2 to 0.3 mL/kg.
Adolescents: 0.25% or 0.5% solution with or without epinephrine: 5 mL; maximum daily dose: 400 mg/day (manufacturer's labeling).
Local anesthesia: Infants, Children, and Adolescents: Limited data in infants and children: Usual concentration 0.25% solution: Infiltrate area local; maximum dose in infants and children: 2.5 mg/kg or 150 mg, whichever is less; maximum dose in adolescents: 175 mg (Coté 2013).
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Implant, Implant:
Xaracoll: 300 mg (3 x 100 mg) (3 ea)
Kit, Injection, as hydrochloride:
P-Care M: 0.5% [DSC]
Kit, Injection, as hydrochloride [preservative free]:
ReadySharp Bupivacaine: 0.5% [DSC]
Solution, Injection, as hydrochloride:
Marcaine: 0.25% (50 mL); 0.5% (50 mL) [contains methylparaben]
Sensorcaine: 0.25% (50 mL); 0.5% (50 mL) [contains methylparaben]
Generic: 0.25% (50 mL); 0.5% (50 mL)
Solution, Injection, as hydrochloride [preservative free]:
Bupivacaine Fisiopharma: 2.5 mg/mL (5 mL, 10 mL); 5 mg/mL (5 mL, 10 mL)
Marcaine: 0.75% (10 mL, 30 mL)
Marcaine Preservative Free: 0.25% (10 mL, 30 mL); 0.5% (10 mL, 30 mL)
Sensorcaine-MPF: 0.25% (10 mL, 30 mL); 0.5% (10 mL, 30 mL); 0.75% (10 mL, 30 mL) [methylparaben free]
Generic: 0.25% (10 mL, 30 mL); 0.5% (10 mL, 30 mL); 0.75% (10 mL, 30 mL)
Solution, Intrathecal, as hydrochloride:
Generic: 0.75% [7.5 mg/mL] (2 mL [DSC])
Solution, Intrathecal, as hydrochloride [preservative free]:
Bupivacaine Spinal: 0.75% [7.5 mg/mL] (2 mL)
Marcaine Spinal: 0.75% [7.5 mg/mL] (2 mL)
Sensorcaine-MPF Spinal: 0.75% [7.5 mg/mL] (2 mL [DSC])
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Marcaine: 0.75% (20 mL)
Solution, Injection, as hydrochloride:
Marcaine: 0.25% (10 mL, 20 mL, 50 mL)
Marcaine: 0.25% (50 mL) [contains methylparaben]
Marcaine: 0.5% (10 mL, 20 mL)
Marcaine: 0.5% (50 mL) [contains methylparaben]
Sensorcaine: 0.25% (10 mL, 20 mL); 0.5% (10 mL, 20 mL)
Generic: 0.25% (10 mL, 20 mL); 0.5% (10 mL, 20 mL); 0.75% (10 mL, 20 mL, 30 mL)
Solution, Intrathecal, as hydrochloride:
Marcaine Spinal: 0.75% [7.5 mg/mL] (2 mL)
Generic: 0.75% [7.5 mg/mL] (2 mL)
Posimir: FDA approved February 2021; anticipated availability is currently unknown.
Implant: Each single-dose pouch is supplied as a sterile product that should be handled using aseptic technique. Oxygen and resuscitative medications, staff, and equipment should be immediately available. Implant is a ready-to-use product and only requires cutting the individual implants as needed to accommodate the surgical space. Aseptically peel outer pouch, remove and peel open inner blister pack; do not use scissors or scalpel to open the blister packaging. Inspect each implant prior to use; do not use if packaging has been compromised, or if implant appears discolored, contains foreign particles, or is collapsed, compressed, or misshapen; avoid excessive handling and compression. Aseptically cut each implant in half prior to placement into the surgical site; place 3 halves below the site of mesh placement and 3 halves just below the skin closure. Place dry implant into surgical site; when a topical antiseptic (eg, povidone iodine) is applied, allow surgical site to dry before implantation. Avoid contact with liquids prior to placement; pre-moistening may result in premature release of bupivacaine. Avoid additional local anesthetic administration within 96 hours of inserting implant; toxic effects of local anesthetics are additive. If additional local anesthetic administration cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity. Depending on clinical situation, consider surgical removal of implant if systemic toxicity occurs.
Injection: Solutions containing preservatives should not be used for epidural or caudal blocks. Addition of sodium bicarbonate to increase speed of onset may cause precipitation as pH approaches physiologic range (Peterfreund 1989). The On-Q infusion pump is used to slowly administer local anesthetics (eg, bupivacaine, lidocaine, ropivacaine) to or around surgical wound sites and/or in close proximity to peripheral nerves for postoperative analgesia. When infused directly into the shoulder, destruction of articular cartilage (chondrolysis) has occurred. On-Q pumps should never be placed directly into any joint (see https://www.ismp.org/Newsletters/acutecare/archives/May09.asp).
Subacromial injection (Posimir ): For infiltration into the subacromial space only following arthroscopic subacromial decompression surgery; not for epidural, intra-articular, intrathecal, intravascular, or regional nerve block administration. Do not use for pre-incisional or pre-procedural locoregional anesthetic techniques that require deep or complete sensory block. Do not dilute or mix with other drugs, diluents, or local anesthetics. Do not interchange with other bupivacaine formulations. Avoid use with other local anesthetics within 168 hours following administration. Draw up 5 mL into a syringe containing a large bore needle (≥16 gauge); discard needle. At the close of arthroscopic subacromial decompression surgery, administer entire dose into the subacromial space using an ≥18-gauge needle. Insert needle through an existing arthroscopic port or intact skin to reach the subacromial space; confirm placement with direct arthroscopic visualization; avoid administering into the glenohumeral intra-articular space.
Parenteral: Solutions containing preservatives should not be used for epidural or caudal blocks; for epidural infusion, may use undiluted or diluted with preservative-free NS. Consider incremental administration with negative aspiration prior to each injection; however, absence of blood in the syringe does not guarantee that intravascular injection has been avoided (Mulroy 2010).
Implant (Xaracoll): Placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair in adults.
Injection: Local or regional anesthesia; spinal anesthesia (0.75% in dextrose 8.25% injection); diagnostic and therapeutic procedures; obstetrical procedures (only 0.25% and 0.5% concentrations).
0.25%: Local infiltration, peripheral nerve block, sympathetic block, caudal or epidural block.
0.5%: Peripheral nerve block, caudal and epidural block.
0.75% (not for obstetrical anesthesia): Retrobulbar block, epidural block. Note: Reserve for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary.
Subacromial injection (Posimir): Infiltration administration in adults into the subacromial space under direct arthroscopic visualization to produce post-surgical analgesia for up to 72 hours following arthroscopic subacromial decompression.
Limitations of use: Safety and efficacy have not been established in other surgical procedures, including soft tissue surgical procedures, other orthopedic procedures, including for intra-articular administration, and boney procedures, or when used for neuraxial or peripheral nerve blockade.
Bupivacaine may be confused with mepivacaine, ropivacaine
Marcaine may be confused with Narcan
The Institute for Safe Medication Practices (ISMP) includes this medication (epidural administration) among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Implant:
>10%: Local: Edema at insertion site (15%)
1% to 10%:
Gastrointestinal: Dysgeusia (8%)
Genitourinary: Scrotal edema (3%)
Nervous system: Headache (4%)
Neuromuscular & skeletal: Tremor (4%)
Ophthalmic: Blurred vision (4%)
Miscellaneous: Fever (2%), seroma (3%)
Frequency not defined: Infection: Wound infection
Injection:
Reactions listed are based on reports for bupivacaine, bupivacaine/epinephrine, and/or other local anesthetics.
>10%:
Dermatologic: Pruritus (3% to 19%; including eye pruritus and anorectal pruritus)
Gastrointestinal: Constipation (7% to 42%), dysgeusia (15% to 18%), nausea (39% to 60%, including post-procedural nausea), vomiting (10% to 29%)
Nervous system: Dizziness (21% to 40%), drowsiness (32% to 41%), headache (6% to 32%), paresthesia (4% to 18%)
Otic: Tinnitus (13%)
1% to 10%:
Cardiovascular: Angina pectoris (<2%), flattened T wave on ECG (<2%), hypertension (4%), inversion T wave on ECG (4%), peripheral edema (4%)
Dermatologic: Injection site pruritus (3%), skin rash (4%)
Gastrointestinal: Upper abdominal pain (1%)
Genitourinary: Dysmenorrhea (3%), urinary retention (1% to 3%)
Hematologic & oncologic: Bruise (3%)
Nervous system: Fatigue (<2%), hypoesthesia (≤17%), insomnia (3% to 7%)
Neuromuscular & skeletal: Limb pain (3%), muscle twitching (4%), musculoskeletal pain (5%)
Ophthalmic: Blepharospasm (<2%)
Respiratory: Cough (2%), dyspnea (4%), exacerbation of pulmonary arterial hypertension (<2%), nasal congestion (3%), oropharyngeal pain (1%)
Miscellaneous: Fever (6% to 9%)
Frequency not defined:
Cardiovascular: Bradycardia, cardiac insufficiency, circulatory shock, heart block, hypotension, low cardiac output, ventricular arrhythmia
Gastrointestinal: Fecal incontinence, loss of anal sphincter control
Genitourinary: Prolonged labor, sexual disorder (loss of function), urinary incontinence
Hematologic & oncologic: Methemoglobinemia
Hypersensitivity: Hypersensitivity reaction
Infection: Septic meningitis
Nervous system: Anxiety, arachnoiditis, central nervous system depression, central nervous system stimulation, chills, coma, confusion, cranial nerve palsy, localized numbness (perineal), loss of consciousness, meningism, paralysis, paraplegia, persistent anesthesia, restlessness, seizure, shivering
Neuromuscular & skeletal: Asthenia, back pain, lower extremity weakness, tremor
Ophthalmic: Blurred vision, miosis
Respiratory: Apnea, hypoventilation, respiratory depression, respiratory paralysis
Hypersensitivity to bupivacaine hydrochloride, amide-type local anesthetics, or any component of the formulation; obstetrical paracervical block anesthesia; IV regional anesthesia (Bier block) (injection only).
Canadian labeling: Additional contraindications (not in US labeling): Severe shock and in heart block where there is inflammation and/or sepsis near the proposed injection site (Marcaine only).
Concerns related to adverse effects:
• Cardiovascular effects: Bupivacaine-containing products have been associated with rare occurrences of arrhythmias, cardiac arrest, and death.
• Intra-articular infusion related chondrolysis: Continuous intra-articular infusion of local anesthetics after arthroscopic or other surgical procedures is not an approved use; chondrolysis (primarily shoulder joint) has occurred following infusion, with some patients requiring arthroplasty or shoulder replacement.
• Methemoglobinemia: Has been reported with local anesthetics; clinically significant methemoglobinemia requires immediate treatment along with discontinuation of the anesthetic and other oxidizing agents. Onset may be immediate or delayed (hours) after anesthetic exposure. Patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, exposure to oxidizing agents or their metabolites, or infants <6 months of age are more susceptible and should be closely monitored for signs and symptoms of methemoglobinemia (eg, cyanosis, headache, rapid pulse, shortness of breath, light-headedness, fatigue).
• Respiratory arrest: Local anesthetics have been associated with rare occurrences of sudden respiratory arrest, especially when administered near the head or neck.
• Seizures: Convulsions due to systemic toxicity leading to cardiac arrest have also been reported, presumably following unintentional intravascular injection or administration near the head or neck.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with cardiovascular disease including patients with hypotension or heart block.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
Special populations:
• Acutely ill patients: Use with caution in acutely ill patients; dose reduction may be required.
• Debilitated patients: Use with caution in debilitated patients; dose reduction may be required.
• Elderly: Use with caution in the elderly; dose reduction may be required.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP 1997; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Interchangeability: Subacromial injection is not interchangeable with other bupivacaine formulations; bioequivalence is not the same even when milligram dosage is the same.
• Obstetrical anesthesia: The bupivacaine 0.75% concentration is not recommended for obstetrical anesthesia. There have been reports of cardiac arrest with difficult resuscitation or death during use of bupivacaine for epidural anesthesia in obstetrical patients.
• Preservative-containing solutions: Do not use solutions containing preservatives for caudal or epidural block.
• Sodium metabisulfite: May contain sodium metabisulfite; use caution in patients with asthma or a sulfite allergy.
Other warnings/precautions:
• Administration:
- Injection: Use the lowest effective dose and fractional (incremental) doses when possible; repeat administration may result in accumulation of bupivacaine and metabolites. Intravascular and intrathecal injections should be avoided; aspiration should be performed prior to administration; the needle must be repositioned until no return of blood can be elicited by aspiration; however, absence of blood in the syringe does not guarantee that intravascular or intrathecal injection has been avoided. IV regional anesthesia (Bier block) is contraindicated; cardiac arrest and death have occurred with this method of administration.
- Subacromial injection: For infiltration into the subacromial space only; not for epidural, intra-articular, intrathecal, intravascular, or regional nerve block administration. Avoid inadvertent intravascular administration; cardiac arrest and seizures have occurred. May be used with implantable materials (eg, polypropylene, polyester) and gut, nylon, polydioxanone, polypropylene, polyglycolic acid, and silk sutures.
• Test dose: A test dose is recommended prior to epidural administration (prior to initial dose) and all reinforcing doses with continuous catheter technique.
• Trained personnel: Clinicians using local anesthetic agents should be well trained in diagnosis and management of emergencies that may arise from the use of these agents. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use.
Infants may be at greater risk for bupivacaine toxicity because α1-acid-glycoprotein concentration, the major serum protein to which bupivacaine is bound, is lower in neonates and infants compared with older children leading to an increase of free fraction of local anesthetic; use epidural infusions with caution in neonates and infants and monitor closely. Fat emulsion has been used to manage local anesthetic toxicity (refer to Fat Emulsion (Plant Based) monograph for additional information) (McCloskey 1992).
Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2D6 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amisulpride (Oral): May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Beta-Blockers: May increase the serum concentration of Bupivacaine. Risk C: Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
Bupivacaine (Liposomal): Bupivacaine may enhance the adverse/toxic effect of Bupivacaine (Liposomal). Management: Bupivacaine may be administered immediately before, or administered in the same admixture syringe as liposomal bupivacaine as long as the ratio of the milligram dose of bupivacaine to liposomal bupivacaine does not exceed 1:2. Risk D: Consider therapy modification
Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modification
Cyclophosphamide: May enhance the adverse/toxic effect of Bupivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination
Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hyaluronidase: May enhance the adverse/toxic effect of Local Anesthetics. Risk C: Monitor therapy
Hydroxyurea: May enhance the adverse/toxic effect of Bupivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Ifosfamide: May enhance the adverse/toxic effect of Bupivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy
Local Anesthetics: May enhance the adverse/toxic effect of Bupivacaine. Management: Avoid using any additional local anesthetics within 96 hours after insertion of the bupivacaine implant (Xaracoll) or bupivacaine and meloxicam periarticular solution (Zynrelef) or within 168 hours after subacromial infiltration (Posimir brand). Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methemoglobinemia Associated Agents: May enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Neuromuscular-Blocking Agents: Local Anesthetics may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Nitrous Oxide: May enhance the adverse/toxic effect of Bupivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification
Technetium Tc 99m Tilmanocept: Local Anesthetics may diminish the diagnostic effect of Technetium Tc 99m Tilmanocept. Management: Avoid mixing and simultaneously co-injecting technetium Tc 99m tilmanocept with local anesthetics. This interaction does not appear to apply to other uses of these agents in combination. Risk C: Monitor therapy
Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Valproate Products: May enhance the adverse/toxic effect of Bupivacaine. Specifically, the risk of methemoglobinemia may be increased. Risk C: Monitor therapy
Bupivacaine crosses the placenta.
Small amounts of bupivacaine can be found in maternal plasma following epidural, caudal, or pudendal nerve block anesthesia, and potentially causing varying degrees of maternal, fetal, and neonatal toxicity involving the CNS, peripheral vascular tone, and cardiac function.
Bupivacaine is approved for use at term in obstetrical anesthesia or analgesia. It is used as a component of regional anesthesia for labor analgesia and operative anesthesia, for intra-incisional analgesia at the end of a cesarean section, and for pudendal nerve blocks used in the second stage of labor or for repairing perineal lacerations (ACOG 2019). Use in obstetrical paracervical block anesthesia is contraindicated (may cause fetal bradycardia and death).
The bupivacaine 0.75% concentration is not recommended for obstetrical anesthesia. There have been reports of cardiac arrest with difficult resuscitation or death during use of bupivacaine for epidural anesthesia in obstetrical patients. In most cases, this has followed use of the 0.75% concentration. Resuscitation has been difficult or impossible despite apparently adequate preparation and appropriate management. Cardiac arrest has occurred after convulsions resulting from systemic toxicity, presumably following unintentional intravascular injection. The 0.75% concentration should be reserved for surgical procedures where a high degree of muscle relaxation and prolonged effect are necessary.
Bupivacaine and its active metabolite are present in breast milk.
Breast milk concentrations of bupivacaine were evaluated in a study of 27 women (~38 weeks gestation) administered bupivacaine 0.5% combined with lidocaine 2% for local anesthesia prior to cesarean delivery. Maternal serum and breast milk were sampled prior to, then at 2, 6, and 12 hours after the epidural infusion. Peak breast milk concentrations occurred 2 hours after the maternal dose for bupivacaine and 12 hours after the dose for the active metabolite. Adverse events were not observed in the breastfed infants (Ortega 1999). In a second study, bupivacaine was not detected in the serum of a breastfed 10-month old infant, feeding 4 times daily following maternal use of a continuous intrapleural bupivacaine 0.25% infusion (10 mL/hour) after a cholecystectomy. Breastfeeding resumed ~22 hours after the maternal infusion began; infant blood was sampled ~5 hours after a morning feed and ~52 hours after a maternal bolus dose (Baker 1989).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. However, the Academy of Breast Feeding Medicine considers local anesthetics such as bupivacaine compatible with breastfeeding. Elective surgery should be postponed until milk supply and breastfeeding are established. Milk should be expressed ahead of surgery when possible. In general, when the child is healthy and full term, breastfeeding may resume, or milk may be expressed once the mother is awake and in recovery. For children who are at risk for apnea, hypotension, or hypotonia, milk may be saved for later use when the child is at lower risk (ABM [Reece-Stremtan 2017]).
Vital signs, state of consciousness; signs of CNS toxicity
Blocks both the initiation and conduction of nerve impulses by decreasing the neuronal membrane's permeability to sodium ions, which results in inhibition of depolarization with resultant blockade of conduction
Onset of action: Anesthesia (route and dose dependent):
Epidural: Up to 17 minutes to spread to T6 dermatome (Scott 1980).
Infiltration: Fast (Barash 2009); Dental injection: 2 to 10 minutes.
Spinal: Within 1 minute; maximum dermatome level achieved within 15 minutes in most cases.
Duration (route and dose dependent):
Epidural: 2 to 7.7 hours (Barash 2009).
Implant: Variable: Up to ~72 hours (Velanovich 2020).
Infiltration: 2 to 8 hours (Barash 2009); Dental injection: Up to 7 hours.
Spinal: 1.5 to 2.5 hours (Tsai 2007).
Subacromial injection: ~72 hours.
Distribution: Vd: Infants: 3.9 ± 2 L/kg; Children: 2.7 ± 0.2 L/kg.
Protein binding: 84% to 95%.
Metabolism: Hepatic; forms metabolite (pipecoloxylidine [PPX]).
Half-life elimination (age dependent): Implant: 19 hours; Injection: Neonates: 8.1 hours; Adults: 2.7 hours; Subacromial injection: 16.4 to 26.1 hours.
Time to peak, plasma: Caudal, epidural, or peripheral nerve block: 30 to 45 minutes; Implant: Median: 3 hours (range: 1.5 to 24 hours); Subacromial injection: Median: ~6 to 8 hours (range: 1 to ~27 hours).
Excretion: Urine (~6% unchanged).
Clearance: Infants: 7.1 ± 3.2 mL/kg/minute; Children: 10 ± 0.7 mL/kg/minute.
Geriatric: 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.
Implant (Xaracoll Implant)
3 x 100 mg (per each): $93.60
Solution (Bupivacaine HCl (PF) Injection)
0.25% (per mL): $0.06 - $0.12
0.5% (per mL): $0.07 - $0.12
0.75% (per mL): $0.24 - $0.36
Solution (Bupivacaine HCl Injection)
0.25% (per mL): $0.07 - $0.10
0.5% (per mL): $0.06 - $0.08
Solution (Marcaine Injection)
0.25% (per mL): $0.14
0.5% (per mL): $0.12
0.75% (per mL): $0.47
Solution (Marcaine Preservative Free Injection)
0.25% (per mL): $0.40
0.5% (per mL): $0.47
Solution (Marcaine Spinal Intrathecal)
0.75-8.25% (per mL): $0.72
Solution (Sensorcaine Injection)
0.25% (per mL): $0.24
0.5% (per mL): $0.27
Solution (Sensorcaine-MPF Injection)
0.25% (per mL): $0.26
0.5% (per mL): $0.25
0.75% (per mL): $0.57
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