Bupivacaine hydrochloride Injection, Solution

Bupivacaine hydrochloride injection is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations of bupivacaine hydrochloride injection are recommended for each type of block indicated to produce local or regional anesthesia or analgesia  [see Dosage and Administration (2.2) ].

Limitations of Use

Not all blocks are indicated for use with bupivacaine hydrochloride injection given clinically significant risks associated with use [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1, 5.4, 5.5, 5.7, 5.9)] .

Bupivacaine hydrochloride is contraindicated in:

1. obstetrical paracervical block anesthesia. Its use in this technique has resulted in fetal bradycardia and death.
2. intravenous regional anesthesia (Bier Block) [see Warnings and Precautions (5.7)] .
3. patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of bupivacaine hydrochloride injection.

Small doses of local anesthetics (e.g., bupivacaine hydrochloride) 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. Monitor circulation and respiration and constantly observe patients receiving bupivacaine hydrochloride blocks. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see Dosage and Administration (2.2)].

The following clinically significant adverse reactions have been reported and described in the Warnings and Precautions section of the labeling:

1. Cardiac Arrest in Obstetrical Anesthesia [see Warnings and Precautions (5.1)]
2. Dose-Related Toxicity [see Warnings and Precautions (5.2)]
3. Methemoglobinemia [see Warnings and Precautions (5.3)]
4. Chondrolysis with Intra-Articular Infusion [see Warnings and Precautions (5.5)]
5. Cardiac Arrest with Intravenous Regional Anesthesia Use [see Contraindications (4), Warnings and Precautions (5.7)]
6. Systemic Toxicities with Unintended Intravascular or Intrathecal Injection [see Warnings and Precautions (5.9)]
7. Respiratory Arrest Following Retrobulbar Block [see Warnings and Precautions (5.15)]

The following adverse reactions from voluntary reports or clinical studies have been reported with bupivacaine. Because many of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions to bupivacaine hydrochloride are characteristic of those associated with other 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, unintentional intravascular injection, or slow metabolic degradation.

The most commonly encountered acute adverse reactions that demand immediate counter-measures were related to the CNS and the cardiovascular system. These adverse reactions were generally dose-related and due to high plasma levels which may have resulted from overdosage, rapid absorption from the injection site, diminished tolerance, or from unintentional intravascular injection of the local anesthetic solution. In addition to systemic dose-related toxicity, unintentional intrathecal injection of drug during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) has resulted in underventilation or apnea ("Total or High Spinal"). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia have occurred. This has led to secondary cardiac arrest when untreated.

Nervous System Disorders: Adverse reactions were characterized by excitation and/or depression of the central nervous system and included restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, respiratory arrest, nausea, vomiting, chills, pupillary constriction.

In the practice of caudal or lumbar epidural block, unintentional penetration of the subarachnoid space by the catheter or needle has occurred. Subsequent adverse effects may have depended partially on the amount of drug administered intrathecally and the physiological and physical effects of a dural puncture. A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia.

Neurologic effects following epidural or caudal anesthesia have included spinal block of varying magnitude (including high or total spinal block); hypotension secondary to spinal block; urinary retention; fecal and urinary incontinence; loss of perineal sensation and sexual function; persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities and loss of sphincter control, all of which had slow, incomplete, or no recovery; headache; backache; septic meningitis; meningismus; slowing of labor; increased incidence of forceps delivery; and cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid.

Neurologic effects following other procedures or routes of administration have included persistent anesthesia, paresthesia, weakness, paralysis, all with slow, incomplete, or no recovery.

Convulsions:Incidence varied with the procedure used and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations. The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient.

Cardiac Disorders: High doses or unintentional intravascular injection have led to high plasma levels and related depression of the myocardium, decreased cardiac output, heartblock, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest [see Warnings and Precautions (5.9)] .

Immune System Disorders: Allergic-type reactions have occurred as a result of sensitivity to bupivacaine or to other formulation ingredients, such as the antimicrobial preservative methylparaben contained in multiple-dose vials. These reactions were characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and severe hypotension. Cross sensitivity among members of the amide-type local anesthetic group has been reported.

• Dose-Related Toxicity

: Monitor cardiovascular and respiratory vital signs and patient’s state of consciousness after injection of bupivacaine hydrochloride. (5.2)

• Methemoglobinemia

: Cases of methemoglobinemia have been reported in association with local anesthetic use. See full prescribing information for more detail on managing these risks. (5.3)

• Chondrolysis with Intra-Articular Infusion

: Intra-articular infusions of local anesthetics including bupivacaine hydrochloride following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. (5.5)

• Risk of Cardiac Arrest with Intravenous Regional Anesthesia Use (Bier Block)

: There have been reports of cardiac arrest and death during the use of bupivacaine for intravenous regional anesthesia (Bier Block). (5.7)

• Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection

: Unintended intravascular or intrathecal injection may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Aspirate for blood or cerebrospinal fluid (where applicable) prior to each dose. (5.9) 5.1 Risk of Cardiac Arrest with Use of Bupivacaine Hydrochloride in Obstetrical Anesthesia

There have been reports of cardiac arrest with difficult resuscitation or death during use of bupivacaine hydrochloride 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 hydrochloride 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. 5.2 Dose-Related Toxicity

The safety and effectiveness of bupivacaine hydrochloride depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be performed after injection of bupivacaine hydrochloride solution.

Possible early warning signs of central nervous system (CNS) toxicity are restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, CNS depression, or drowsiness. Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and, possibly, death.

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. Use the lowest dosage of bupivacaine hydrochloride that results in effective anesthesia to avoid high plasma levels and serious adverse effects. Avoid rapid injection of a large volume of bupivacaine hydrochloride solution and administer fractional (incremental) doses when feasible.

Injection of repeated doses of bupivacaine hydrochloride may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients and acutely ill patients should be given reduced doses commensurate with their age and physical status. 5.3 Methemoglobinemia

Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition

[see

Drug Interactions (7.5)]. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.

Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious CNS and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue bupivacaine hydrochloride and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. 5.4 Antimicrobial Preservatives in Multiple-Dose Vials

Avoid use of bupivacaine hydrochloride solutions containing antimicrobial preservatives, i.e., those supplied in multiple-dose vials, for epidural or caudal anesthesia because safety has not been established with such use. 5.5 Chondrolysis with Intra-Articular Infusion

Intra-articular infusions of local anesthetics including bupivacaine hydrochloride following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are associated with chondrolysis. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2

ndmonth after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. 5.7 Risk of Cardiac Arrest with Intravenous Regional Anesthesia Use (Bier Block)

There have been reports of cardiac arrest and death during the use of bupivacaine for intravenous regional anesthesia (Bier Block). Information on safe dosages and techniques of administration of bupivacaine hydrochloride in this procedure is lacking. Therefore, bupivacaine hydrochloride is contraindicated for use with this technique

[see

Contraindications (4)]. 5.9 Risk of Systemic Toxicities with Unintended Intravascular or Intrathecal Injection

Unintended intravascular or intrathecal injection of bupivacaine hydrochloride may be associated with systemic toxicities, including CNS or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Unintentional intrathecal injection during the intended performance of caudal or lumbar epidural block or nerve blocks near the vertebral column has resulted in underventilation or apnea (“Total or High Spinal”). A high spinal has been characterized by paralysis of the legs, loss of consciousness, respiratory paralysis, and bradycardia

[see

Adverse Reactions (6)].

Aspirate for blood or cerebrospinal fluid (where applicable) before injecting bupivacaine hydrochloride, 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. 5.10 Risk of Toxicity in Patients with Hepatic Impairment

Because amide local anesthetics such as bupivacaine are metabolized by the liver, consider reduced dosing and increased monitoring for bupivacaine systemic toxicity in patients with moderate to severe hepatic impairment who are treated with bupivacaine hydrochloride, especially with repeat doses

[see

Use in Specific Populations (8.6)]. 5.11 Risk of Use in Patients with Impaired Cardiovascular Function

Bupivacaine hydrochloride should be given in reduced doses in patients with impaired cardiovascular function (e.g., hypotension, heartblock) because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by bupivacaine hydrochloride. Monitor patients closely for blood pressure, heart rate, and ECG changes. 5.14 Risk of Adverse Reactions with Use in Head and Neck Area

Small doses of local anesthetics (e.g., bupivacaine hydrochloride) 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. Monitor circulation and respiration and constantly observe patients receiving bupivacaine hydrochloride blocks. Resuscitative equipment and drugs, and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded

[see

Dosage and Administration (2.2)]. 5.15 Risk of Respiratory Arrest with Use in Ophthalmic Surgery

Clinicians who perform retrobulbar blocks should be aware that there have been reports of respiratory arrest following local anesthetic injection. Prior to retrobulbar block (e.g., with bupivacaine hydrochloride), as with all other regional procedures, resuscitative equipment and drugs, and personnel to manage respiratory arrest or depression, convulsions, and cardiac stimulation or depression should be immediately available

[see

Warnings and Precautions (5.14)]. 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

[see

Indications and Usage (1)].

1. Bupivacaine hydrochloride injection is not for intrathecal use.
2. Avoid use of bupivacaine hydrochloride injection solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia  [see Warnings and Precautions (5.4)] .
3. Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use.
4. Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit. Bupivacaine hydrochloride injection is clear, colorless solution. Do not administer solutions which are discolored or contain particulate matter.
5. Mixing or the prior or intercurrent use of any other local anesthetic with bupivacaine hydrochloride injection is not recommended because of insufficient data on the clinical use of such mixtures.

Administration Precautions

1. Bupivacaine hydrochloride injection is 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.
2. Use bupivacaine hydrochloride injection 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 (5.2), Adverse Reactions (6), Overdosage (10)].
3. 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 bupivacaine hydrochloride injection [see Warnings and Precautions (5.2), Drug Interactions (7.1), Overdosage (10)].
4. Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting bupivacaine hydrochloride injection, 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 (5.9)] .
5. Avoid rapid injection of a large volume of bupivacaine hydrochloride injection and use fractional (incremental) doses when feasible.
6. 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 bupivacaine hydrochloride injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions.
7. 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.

The dosage of bupivacaine hydrochloride injection administered varies with the anesthetic procedure, 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, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient. Administer the smallest dosage and concentration required to produce the desired result.

The types of block and recommended bupivacaine hydrochloride injection concentrations are shown in Table 1.

At recommended dosages, bupivacaine hydrochloride injection produces complete sensory block, but the effect on motor function differs among the three concentrations. Table 2 provides information on the expected effect on motor function for the three concentrations.

The duration of anesthesia with bupivacaine hydrochloride injection is such that for most indications, a single-dose is sufficient.

The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site.

The dosages in Table 3 are recommended as a guide for use in the average adult. These doses may be repeated once every three hours. Do not exceed a total daily dosage of 400 mg in 24 hours. The duration of anesthetic effect may be prolonged by the addition of epinephrine. 

Bupivacaine hydrochloride injection, USP is a clear, colorless solution and is available as:

1. 0.25% (125 mg/50 mL) (2.5 mg/mL) in multiple-dose vials.

• Local Anesthetics

: The toxic effects of local anesthetics are additive. Monitor for neurologic and cardiovascular effects when additional local anesthetics are administered. (7.1)

• 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) 7.1 Local Anesthetics

The toxic effects of local anesthetics are additive. If coadministration of other local anesthetics with bupivacaine hydrochloride 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)]. 7.5 Drugs Associated with Methemoglobinemia

Patients who are administered bupivacaine hydrochloride are at increased risk of developing methemoglobinemia when concurrently exposed to 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, isofamide, rasburicase

Antibiotics

dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides

Antimalarials

chloroquine, primaquine

Anticonvulsants

phenobarbital, phenytoin, sodium valproate

Other drugs

acetaminophen, metoclopramide, quinine, sulfasalazine