bupivacaine liposome (Rx)

>10%

Adults

• Nausea (2.1-40.2%)
• Vomiting (2.1-27.8%)
• Dizziness (11.3%)

Children

• Hypotension (11.1-93.3%)
• Muscle twitching (8.3-60%)
• Nausea (6.9-60%)
• Tachycardia (2.8-53.3%)
• Vomiting (13.8-53.3%)
• Constipation (13.8-46.7%)
• Pruritus (8.3-40%)
• Tachypnea (2.8-40%)
• Bradycardia (5.6-33.3%)
• Pyrexia (20%)
• Hypoesthesia (20%)
• Muscle spasms (20%)
• Dizziness (5.6-20%)
• Blurred vision (3.4-20%)
• Anemia (13.9%)
• Muscle weakness (13.3%)
• Back pain (13.3%)
• Oral hypoesthesia (11.1-13.3%)
• Hematuria (13%)

1-10%

Adults

• Headache (5.2%)
• Somnolence (5.2%)
• Tachycardia (3.9%)
• Pruritus (3.1-5.2%)
• AST increased (3.1%)
• Body temperature increased (3.2%)
• ALT increased (1.1-3.1%)
• BUN increased (2.1%)
• Constipation (2.1%)
• Syncope (2.1%)
• Pyrexia (2.1%)
• Fungal infection (2.1%)
• Postprocedural swelling (2.1%)
• Decreased appetite (2.1%)
• Bradycardia (1.6%)
• Hypoesthesia (1.5%)
• Lethargy (1.3%)

Postmarketing Reports

Injury, poisoning, and procedural complications: Drug-drug interaction, procedural pain

Nervous system disorders: Palsy, seizure

General disorders and administration site conditions: Lack of efficacy, pain

Skin and subcutaneous tissue disorders: Erythema, rash

Cardiac disorders: Bradycardia, cardiac arrest

Contraindications

Obstetrical paracervical block anesthesia; use of bupivacaine for paracervical block has resulted in fetal bradycardia and death

Cautions

For infiltrative use only; do not use for epidural, intrathecal, intravascular, intra-articular administration; not for regional nerve blocks other than interscalene brachial plexus nerve block, sciatic nerve block in the popliteal fossa, and adductor canal block; caution to avoid accidental intravascular injection; convulsions and cardiac arrest have occurred following intravascular injection

Use only in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity

Monitor cardiovascular/neurological status and vital signs during and after injection

Bupivacaine and other amide-containing products should be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with prolongation of AV conduction produced by these drugs

CNS reactions may occur, including excitation and/or depression, restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, or convulsions; other CNS effects may include nausea, vomiting, chills, miosis, twitching, depression, or drowsiness, which may be early warning signs of central nervous system toxicity

Toxic blood concentrations may depress cardiac conductivity and excitability that leads to AV block, ventricular arrhythmias, and cardiac arrest; additionally, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure

Injection of multiple doses of bupivacaine and other amide-containing products may cause significant increases in plasma concentrations with each repeated dose due to slow accumulation of the drug or its metabolites, or slow metabolic degradation; tolerance to elevated blood concentrations varies with the status of the patient

Allergic-type reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly anaphylactoid-like symptoms (including severe hypotension); cross-sensitivity among members of the amide-type local anesthetic group reported; the usefulness of screening for sensitivity has not been definitively established

Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, use cautiously with hepatic disease; greater risk for toxic plasma concentrations with severe hepatic disease

Adverse reactions may be greater in patients with renal impairment than in patients with normal renal function; in patients with renal impairment, increase monitoring for therapy-associated adverse reactions; because patients 65 years of age and older are more likely to have renal impairment, increase monitoring for therapy-associated adverse reactions

Sensory and/or motor loss with therapy may occur but is temporary and varies in degree and duration depending on site of injection and dosage administered and may last for up to 5 days as seen in clinical trials

The potential sensory and/or motor loss with this drug is temporary and varies in degree and duration depending on site of injection and dosage administered and may last for up to 5 days

Avoid additional use of local anesthetics within 96 hours following administration of this drug

Chondrolysis

• There have been postmarketing reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures, which is an unapproved use
• Majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis described in pediatric patients and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours
• There is insufficient information to determine whether shorter infusion periods are not associated with these findings; time of onset of symptoms, such as joint pain, stiffness, and loss of motion can be variable, but may begin as early as the second month after surgery
• Currently, there is no effective treatment for chondrolysis; patients who have experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement

Methemoglobinemia

• Cases of methemoglobinemia 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
• If local anesthetics must be used, close monitoring for symptoms and signs of methemoglobinemia recommended; signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by 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 central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death; discontinue treatment and any oxidizing agents
• Depending on severity of signs and symptoms, patients may respond to supportive care, eg, oxygen therapy, hydration; a more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen

Drug interactions overview

• Other local anesthetics

  • Avoid use of other local anesthetics within 94 hr after bupivacaine liposome administration
  • Potential for additive adverse effects
  • Increased risk of developing methemoglobinemia if coadministered with other local anesthetics, nitrates/nitrites, acetaminophen, metoclopramide, quinine, sulfasalazine, or other certain antineoplastic agents, antibiotics, antimalarials, or anticonvulsants

Pregnancy

There are no studies conducted with pregnant women

In animal reproduction studies, embryofetal deaths were observed with SC administration of bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg; SC administration of bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD

Based on animal data, advise pregnant women of the potential risks to a fetus

Contraindicated for obstetrical paracervical block anesthesia (see Contraindications)

Bupivacaine can rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity

Lactation

Limited published literature reports that bupivacaine and its metabolite, pipecoloxylidide, are present in human milk at low levels

There is no available information on effects of the drug in the breastfed infant or effects of the drug on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Local anesthetic; blocks generation and conduction of nerve impulses presumably by increasing the electrical excitation threshold in the nerve, by slowing nerve impulse propagation, and by reducing the rate of action potential rise

Liposomal suspension of bupivacaine

Absorption

Absorption rate dependent on total dose, administration route, and administration site vascularity

Adults

• Duration: Up to 96 hr after local infiltration; 120 hr after interscalene brachial plexus nerve block
• Peak plasma time: 2 hr (bunionectomy); 0.5 hr (hemorrhoidectomy); 48 hr (total shoulder arthroplasty)
• Peak plasma concentration: 166 ng/mL (bunionectomy); 867 ng/mL (hemorrhoidectomy); 207 ng/mL (total shoulder arthroplasty)
• AUC: 5864-7105 hr⋅ng/mL (bunionectomy); 16,867-18,289 hr⋅ng/mL; 11,484 hr⋅ng/mL (total shoulder arthroplasty)

Children

• Peak plasma time: 1.2 hr (spine surgery); 23 hr (cardiac surgery)
• Peak plasma concentration: 353 ng/mL (spine surgery); 447 ng/mL (cardiac surgery)
• AUC (0-40 hr): 8,782 hr⋅ng/mL (spine surgery); 11,296 hr⋅ng/mL (cardiac surgery)

Distribution

Protein Bound: 95%

Widely distributed to some extent to all body tissues; high concentrations found in highly perfused organs (eg, liver, lungs, heart, brain)

Metabolism

Metabolized primarily by the liver via conjugation with glucuronic acid

Metabolites: ~5% converted to the major metabolite, pipecolylxylidine (PPX)

Elimination

Half-life: 34.1 hr (bunionectomy); 23.8 hr (hemorrhoidectomy); 11 hr (total shoulder arthroplasty)

Excretion: Urine (mainly metabolites; 6% [unchanged])

Compatibility Considerations

Incompatibilities: Nonbupivacaine based local anesthetics (eg, lidocaine) may cause an immediate release of bupivacaine from the drug if administered together locally

Bupivacaine liposome may follow lidocaine administration after waiting at least 20 minutes

Bupivacaine HCl administered together with bupivacaine liposome suspension may impact the pharmacokinetic and/or physicochemical properties of Exparel, and this effect is concentration dependent; therefore, bupivacaine HCl and Exparel may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before; ratio of dose of bupivacaine HCl solution to bupivacaine liposome suspension should not exceed 1:2

Toxic effects of simultaneous use of both forms of bupivacaine are additive and their administration should be used with caution including monitoring for neurologic and cardiovascular effects related to toxicity

Using Exparel followed by other bupivacaine formulations has not been studied in clinical trials; formulations of bupivacaine other than Exparel should not be administered within 96 hr following administration of Exparel

When a topical antiseptic (eg, povidone iodine) is applied, the site should be allowed to dry before bupivacaine liposome is administered into the surgical site; bupivacaine liposome should not be allowed to come into contact with antiseptics such as povidone iodine in solution

Preparation

For single-dose infiltration only

Different formulations of bupivacaine are not bioequivalent even if the milligram strength is the same; therefore, it is not possible to convert dosing from any other formulations of bupivacaine to bupivacaine liposome

Invert vial multiple times to resuspend particles immediately prior to withdrawing drug from vial; multiple inversions may be necessary to resuspend if particles have settled

Use diluted suspensions within 4 hr of preparation in a syringe

Visually inspect vials before use

Do not filter; do not heat before use; do not autoclave

Administration

For infiltrative use only; do not use for epidural, intrathecal, regional nerve blocks, or intravascular or intra-articular administration

Inject slowly into soft tissue via infiltration surgical site with frequent aspiration to check for blood and minimize the risk of intravascular injection

Do not exceed 266 mg (20 mL, 1.3% of undiluted drug) for infiltration and 133 mg (10 mL) for interscalene brachial plexus nerve block

Administer undiluted or diluted up to 0.89 mg/mL (ie, 1:14 dilution by volume) with preservative-free 0.9% NaCl or Lactated ringer’s solution

Invert vials of multiple times to resuspend the particles immediately prior to withdrawal from the vial Administer with a 25 gauge or larger

Do not administer if product discolored

Do not administer if the vial has been frozen as reflected by the temperature indicator or exposed to high temperature (>40°C or 104°F) for an extended period

Storage

Unopened vials

• Store refrigerated between 2-8°C (36-46°F)
• May store at room temperature of 20-25°C (68-77°F) for up to 1 month in sealed, intact (unopened) vials; do not be re-refrigerated
• Should not be frozen as reflected by the temperature indicator or exposed to high temperatures (>40°C [104°F]) for an extended period

Opened vials

• Store at controlled room temperature of 20-25°C (68-77°F) for up to 4 hr prior to administration