Bupivacaine and epinephrine
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Boxed warning
WARNING: RISK OF CARDIAC ARREST WITH USE OF MARCAINE IN OBSTETRICAL ANESTHESIA There have been reports of cardiac arrest with difficult resuscitation or death during use of MARCAINE 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 MARCAINE 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 [see Warnings and Precautions (5.1) ] . WARNING: RISK OF CARDIAC ARREST WITH USE OF MARCAINE IN OBSTETRICAL ANESTHESIA See full prescribing information for complete boxed warning. There have been reports of cardiac arrest with difficult resuscitation or death during use of MARCAINE 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 MARCAINE 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 ( 5.1 ).
Dosing in kidney impairment
Renal Impairment Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment. This should be considered when selecting the MARCAINE / MARCAINE WITH EPINEPHRINE dosage [see Use in Specific Populations ] .
Dosing in liver impairment
Hepatic Impairment Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic impairment, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations, and potentially local anesthetic systemic toxicity.
Therefore, consider reduced dosing and increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic impairment treated with MARCAINE / MARCAINE WITH EPINEPHRINE, especially with repeat doses [see Warnings and Precautions ] .
Preparation and administration
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Important Dosage and Administration Information
MARCAINE / MARCAINE WITH EPINEPHRINE is not for intrathecal use.
Avoid use of MARCAINE / MARCAINE WITH EPINEPHRINE solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia [see Warnings and Precautions ] .
Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use.
Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit. MARCAINE / MARCAINE WITH EPINEPHRINE are clear, colorless solutions. Do not administer solutions which are discolored or contain particulate matter.
Mixing or the prior or intercurrent use of any other local anesthetic with MARCAINE / MARCAINE WITH EPINEPHRINE is not recommended because of insufficient data on the clinical use of such mixtures. Administration Precautions
MARCAINE / MARCAINE WITH EPINEPHRINE are to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed.
Use MARCAINE / MARCAINE WITH EPINEPHRINE only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies [see Warnings and Precautions , Adverse Reactions , Overdosage ].
The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with MARCAINE / MARCAINE WITH EPINEPHRINE [see Warnings and Precautions , Drug Interactions , Overdosage ].
Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting MARCAINE / MARCAINE WITH EPINEPHRINE, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection. However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection [see Warnings and Precautions ] .
Avoid rapid injection of a large volume of MARCAINE / MARCAINE WITH EPINEPHRINE and use fractional (incremental) doses when feasible.
During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access. The lowest dosage of MARCAINE / MARCAINE WITH EPINEPHRINE that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions.
Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient's level of consciousness after each local anesthetic injection.
Use MARCAINE WITH EPINEPHRINE in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis [see Warnings and Precautions ] .
Use in Epidural Anesthesia During the administration of epidural anesthesia, it is recommended that a test dose of MARCAINE WITH EPINEPHRINE without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) be administered initially and the effects monitored before the full dose is given. When using a "continuous" catheter technique, test doses should be given prior to both the initial and all supplemental doses, because a catheter in the epidural space can migrate into a blood vessel or through the dura [see Dosage and Administration ] .
During epidural administration, administer MARCAINE / MARCAINE WITH EPINEPHRINE, 0.5% (5 mg/mL) and MARCAINE 0.75% (7.5 mg/mL) solutions in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection. Administer injections slowly, with frequent aspirations before and during the injection to avoid intravascular injection.
Perform syringe aspirations before and during each supplemental injection in continuous (intermittent) catheter techniques. In obstetrics, use ONLY the 0.5% (5 mg/mL) and 0.25% (2.5 mg/mL) concentrations of MARCAINE / MARCAINE WITH EPINEPHRINE [see Warnings and Precautions ] ; incremental doses of 3 mL to 5 mL of the 0.5% (5 mg/mL) solution not exceeding 50 mg to 100 mg at any dosing interval are recommended.
Repeat doses should be preceded by a test dose containing epinephrine if not clinically contraindicated. Use only the single-dose vials for caudal or epidural anesthesia; avoid use of the multiple-dose vials for these procedures, which contain a preservative [see Dosage and Administration (2.1 , 2.4) , Warnings and Precautions (5.4 , 5.9) ] .
| ✓= indicated use [see Warnings and Precautions (5.1)]. | |||||
| Type of Block | MARCAINE | MARCAINE WITH EPINEPHRINE | |||
| 0.25% (2.5 mg/mL) | 0.5% (5 mg/mL) | 0.75% (7.5 mg/mL)MARCAINE 0.75% (7.5 mg/mL) is not recommended for nonobstetrical surgical procedures in pregnant patients. | 0.25% (2.5 mg/mL) | 0.5% (5 mg/mL) | |
| Local infiltration | ✓ | ✓ | |||
| Peripheral nerve block | ✓ | ✓ | ✓ | ✓ | |
| Retrobulbar block | ✓ | ||||
| Sympathetic block | ✓ | ||||
| Caudal blockAvoid use of multiple-dose vials of MARCAINE and MARCAINE WITH EPINEPHRINE for caudal or epidural anesthesia [see Warnings and Precautions (5.4)]. | ✓ | ✓ | ✓ | ✓ | |
| Lumbar epidural block | ✓ | ✓ | ✓ (not for obstetrical anesthesia) | ✓ | ✓ |
| Epidural test dose | ✓ | ||||
| Dental block | ✓ | ||||
| MARCAINE Concentration | Motor Function |
| 0.25% (2.5 mg/mL)These products include MARCAINE and MARCAINE WITH EPINEPHRINE [the epinephrine concentration (1:200,000) is not included in the table]. | 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% (5 mg/mL) or 0.75% (7.5 mg/mL) solutions. |
| 0.5% (5 mg/mL) | 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% (7.5 mg/mL)These are only MARCAINE products [there is no 0.75% (7.5 mg/mL) concentration for MARCAINE WITH EPINEPHRINE]. | Produces complete motor block. Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia. Not for obstetrical anesthesia. |
| Type of Block | Concentration of MARCAINE | Each Dose | Motor BlockWith continuous (intermittent) techniques, repeat doses increase the degree of motor block. The first repeat dose of 0.5% (5 mg/mL) may produce complete motor block. Intercostal nerve block with 0.25% (2.5 mg/mL) also may produce complete motor block for intra-thoracic and upper intra-abdominal surgery. | |
| mL | mg of MARCAINE | |||
| Local infiltration | 0.25% (2.5 mg/mL)Solutions with or without epinephrine (i.e., applies to MARCAINE and MARCAINE WITH EPINEPHRINE). The MARCAINE WITH EPINEPHRINE products include epinephrine (1:200,000). | Up to 70 (without epinephrine) | Up to 175 (without epinephrine) | — |
| Up to 90 (with epinephrine) | Up to 225 (with epinephrine) | |||
| Peripheral nerve block | 0.5% (5 mg/mL) | 5–35 (without epinephrine) | 25–175 (without epinephrine) | moderate to complete |
| 5–45 (with epinephrine) | 25–225 (with epinephrine) | |||
| 0.25% (2.5 mg/mL) | 5–70 (without epinephrine) | 12.5–175 (without epinephrine) | moderate to complete | |
| 5–90 (with epinephrine) | 12.5–225 (with epinephrine) | |||
| Retrobulbar block [see Dosage and Administration (2.6)] | 0.75% (7.5 mg/mL) | 2–4 | 15–30 | complete |
| Sympathetic block | 0.25% (2.5 mg/mL) | 20–50 | 50–125 | — |
| Caudal block [see Dosage and Administration (2.4)] | 0.5% (5 mg/mL) | 15–30 | 75–150 | moderate to complete |
| 0.25% (2.5 mg/mL) | 15–30 | 37.5–75 | moderate | |
| Lumbar epidural block [see Dosage and Administration (2.3)] | 0.75% (7.5 mg/mL)For single-dose use; not for intermittent epidural technique. Not for obstetrical anesthesia. | 10–20 | 75–150 | complete |
| 0.5% (5 mg/mL) | 10–20 | 50–100 | moderate to complete | |
| 0.25% (2.5 mg/mL) | 10–20 | 25–50 | partial to moderate | |
| Epidural test dose [see Dosage and Administration (2.4)] | 0.5% (5 mg/mL) with epinephrine | 2–3 | 10–15 (10–15 micrograms epinephrine) | — |
| Dental [see Dosage and Administration (2.5)] | 0.5% (5 mg/mL) with epinephrine | 1.8–3.6 per site | 9–18 per site | — |
Drug interactions
Check bupivacaine and epinephrine against a medication listLabel text (11 paragraphs)
7 DRUG INTERACTIONS • Local Anesthetics : The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. ( 7.1 ) • Monoamine Oxidase Inhibitors and Tricyclic Antidepressants : Administration of MARCAINE WITH EPINEPHRINE to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. ( 5.6 , 7.2 ) • Ergot-Type Oxytocic Drugs : Concurrent administration of MARCAINE WITH EPINEPHRINE and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.
( 5.6 , 7.3 ) • Nonselective Beta-Adrenergic Antagonists : Administration of MARCAINE WITH EPINEPHRINE (containing a vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. ( 5.6 , 7.4 ) • Drugs Associated with Methemoglobinemia : Patients are at increased risk of developing methemoglobinemia when concurrently exposed to nitrates, nitrites, local anesthetics, antineoplastic agents, antibiotics, antimalarials, anticonvulsants, and other drugs.
( 7.5 ) • Potent Inhalation Anesthetics : Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine are used in patients during or following the administration of potent inhalation anesthetics. ( 5.13 , 7.6 )
7.1 Local Anesthetics The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with MARCAINE / MARCAINE WITH EPINEPHRINE cannot be avoided, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration (2.1) , Warnings and Precautions (5.2) ] .
7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants The administration of MARCAINE WITH EPINEPHRINE to patients receiving monoamine oxidase inhibitors, or tricyclic antidepressants may produce severe, prolonged hypertension. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's hemodynamic status is essential [see Warnings and Precautions (5.6) ] .
7.3 Ergot-Type Oxytocic Drugs Concurrent administration of MARCAINE WITH EPINEPHRINE and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents. Avoid use of MARCAINE WITH EPINEPHRINE concomitantly with ergot-type oxytocic drugs [see Warnings and Precautions (5.6) ].
7.4 Nonselective Beta-Adrenergic Antagonists Administration of MARCAINE WITH EPINEPHRINE (containing a vasoconstrictor) in patients receiving nonselective beta-adrenergic antagonists may cause severe hypertension and bradycardia. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful monitoring of the patient's blood pressure and heart rate is essential [see Warnings and Precautions (5.6) ].
7.5 Drugs Associated with Methemoglobinemia Patients who are administered MARCAINE / MARCAINE WITH EPINEPHRINE are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics [see Warnings and Precautions (5.3) ] .
Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine
7.6 Potent Inhalation Anesthetics Serious dose-related cardiac arrhythmias may occur if preparations containing a vasoconstrictor such as epinephrine (e.g., MARCAINE WITH EPINEPHRINE) are used in patients during or following the administration of potent inhalation anesthetics [see Warnings and Precautions (5.13) ] .
7.7 Phenothiazines and Butyrophenones Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of MARCAINE WITH EPINEPHRINE and these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential.
Contraindications
4 CONTRAINDICATIONS MARCAINE / MARCAINE WITH EPINEPHRINE is contraindicated in: • obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. • intravenous regional anesthesia (Bier Block) [see Warnings and Precautions (5.7) ] . • patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of MARCAINE / MARCAINE WITH EPINEPHRINE. • Obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death. ( 4 ) • Intravenous regional anesthesia (Bier Block).
( 4 ) • Known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of MARCAINE / MARCAINE WITH EPINEPHRINE. ( 4 )
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary MARCAINE / MARCAINE WITH EPINEPHRINE is contraindicated for obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death [see Contraindications (4) , Warnings and Precautions (5.1) ] . There are no available data on use of MARCAINE / MARCAINE WITH EPINEPHRINE in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at clinically relevant doses.
Decreased pup survival was observed in a rat pre- and post-natal developmental study (dosing from implantation through weaning) at a dose level comparable to the daily maximum recommended human dose (MRHD) on a body surface area (BSA) basis. Based on animal data, advise pregnant women of the potential risks to a fetus (see Data ). 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 [see Clinical Pharmacology (12.3) ].
The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the CNS, peripheral vascular tone, and cardiac function. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Maternal Adverse Reactions Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus.
Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished. Elevating the patient's legs will also help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously and…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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