bupivacaine implant (Rx)

>10%

Incision site swelling (14.6%)

1-10%

Dysgeusia (7.5%)

Postprocedural discharge (4.9%)

Headache (4.1%)

Tremor (3.6%)

Blurred vision (3.6%)

Seroma (2.9%)

Scrotal swelling (2.9%)

Pyrexia (2.4%)

Oral hypoesthesia (2.2%)

Postmarketing Reports

Nervous system disorders: Restlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness, unconsciousness, respiratory arrest, nausea, vomiting, chills, pupillary constriction

Neurological effects following routes of administration other than epidural or caudal have included persistent anesthesia, paresthesia, weakness, and paralysis, all with slow, incomplete, or no recovery

Cardiovascular (high doses): Myocardial depression, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and cardiac arrest

Immune system disorders: 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 amide-type local anesthetic group reported

Contraindications

Hypersensitivity to any amide-type local anesthetic or any component of the implant

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

Cautions

Caution with hepatic impairment; amide local anesthetics are metabolized by the liver; monitor for systemic toxicity with moderate-to-severe liver impairment

Patients with impaired cardiovascular function (eg, hypotension, heart block) may be less able to compensate for functional changes associated with prolonged atrioventricular conduction produced by bupivacaine; monitor blood pressure, heart rate, and ECG

Safety and efficacy in surgical procedures other than open inguinal hernia repair are not established; not approved for other surgical procedures (eg, orthopedic procedures); a study evaluating osteotomy in rats demonstrated inhibition of bone healing

Methemoglobinemia

• Local anesthetics may cause methemoglobinemia; signs 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; immediate treatment is required to avert more serious CNS and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death
• 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 at higher risk; if local anesthetics must be used in these patients, monitor closely for signs and symptoms
• Methemoglobin levels may continue to rise; initiate treatment immediately
• Depending on severity of signs and symptoms, patients may respond to supportive care, including oxygen therapy, hydration; a severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen

Dose-related toxicity

• Avoid additional local anesthetics within 96 hr after bupivacaine implant placement
• Monitor for neurological, cardiovascular, and respiratory symptoms related to local anesthetic systemic toxicity
• Early warning signs of CNS toxicity may include 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 acidosis, cardiac arrest, and, possibly, death
• Consider surgically removing implant depending on clinical situation

Drug interaction overview

• Local anesthetics

  • Avoid additional local anesthetic administration within 96 hr after bupivacaine implant placement
  • Toxic effects of local anesthetics are additive
  • If additional local anesthetic administration cannot be avoided, monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity

• Drugs associated with methemoglobinemia

  • Additive risk of methemoglobinemia if coadministered with other drugs that increase risk
  • Local anesthetics may increase risk of methemoglobinemia

Pregnancy

Data are not available

Based on animal data, advise pregnant females of potential risks to fetus

Animal studies

• Embryofetal lethality was noted when bupivacaine was administered SC to pregnant rabbits during organogenesis at clinically relevant doses
• Decreased pup survival observed in a rat prenatal and postnatal developmental study (dosing from implantation through weaning) at dose level comparable to the daily maximum recommended human dose

Labor or delivery

• Local anesthetics rapidly cross the placenta
• Incidence and degree of toxicity depend on procedure performed, type and amount of drug used, and technique of drug administration
• Adverse reactions in parturient, fetus, and neonate can involve alterations of the CNS, peripheral vascular tone, and cardiac function

Lactation

Excreted in human milk

Data are not available on effects in breastfed infants or 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

Collagen-matrix implant that delivers bupivacaine to the surgical site

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

Absorption

Peak plasma time: 3 hr

Peak plasma concentration: 663 ng/mL

AUC: 19,493-20,368 hr⋅ngmL

Distribution

Protein bound: 95%

Crosses placenta by passive diffusion

Metabolism

Primarily in liver via conjugation with glucuronic acid

Metabolite: Pipecoloxylidine

Elimination

Half-life: 19 hr

Excretion: Primarily via kidneys (6% unchanged)

Compatibility

Administration of additional local anesthetics, including bupivacaine, into surgical site with implant has not been studied

Studies conducted demonstrated that commonly used surgical materials (nonabsorbable surgical suture, delayed absorbable surgical suture, and surgical mesh) are not affected by bupivacaine implant

Allow surgical site to dry before placing bupivacaine implants if topical antiseptic (eg, povidone iodine) applied

Implant Preparation

Administered by or under supervision of experienced clinicians versed in the diagnosis and management of dose-related toxicity and other acute emergencies arising from bupivacaine exposure

Local anesthetic effects are additive; avoid additional local anesthetic administration within 96 hr after implantation; if additional local anesthetic administration cannot be avoided based on clinical need, monitor patients for neurologic and cardiovascular effects related to local anesthetic systemic toxicity

Immediate availability of oxygen, other resuscitative drugs, CPR equipment, and personnel needed for proper management of toxic reactions and related emergencies

Inspect outer pouch and inner blister before use; do not use if packaging compromised

Aseptically peel open package to remove the 3 inner blister packages containing the implant; to avoid cutting implants before placement, do not open the blister packaging using scissors or a scalpel

Carefully remove from inner blister packages and inspect each implant before use

Implant is white to off-white in color, has uniform thickness, and is ~5-cm x 5-cm x 0.5-cm in size

Do not use if implant appears discolored, contains foreign particulates, or is collapsed, compressed, or misshapen

Avoid excessive handling and compression

Using aseptic technique, cut each implant in half before placement into the surgical site

Implant Administration

Place halved implants into the surgical site dry; avoid contact of implant with liquids before placement; premoistening may result in premature release of bupivacaine from implant

Place 3 halves below site of mesh placement and 3 halves just below the skin closure

Implant may become difficult to move once placed in surgical site and moistened; use care when moving implant after placement

Storage

Store at 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF)

Brief exposure to temperatures up to 40ºC (104ºF) may be tolerated provided the mean kinetic temperature does not exceed 25ºC (77ºF); however, such exposure should be minimized