Exparel

EXPAREL is for single administration only (2.1). EXPAREL is not substitutable with other bupivacaine products even if the strength is the same. Therefore, it is not possible to convert a dose from other bupivacaine products to an EXPAREL dose and vice versa (2.1, 2.5). Do not dilute EXPAREL with water or other hypotonic solutions (2.1). The recommended dose of EXPAREL for: Local infiltration in adults is up to a maximum dose of 266 mg. See Full Prescribing Information for guidance on dose selection (2.2). Local infiltration in pediatric patients aged 6 to less than 17 years is 4 mg/kg, up to a maximum of 266 mg (2.2). Interscalene brachial plexus nerve block in adults is 133 mg (2.3). Sciatic nerve block in the popliteal fossa in adults is 133 mg (2.3). Adductor canal block in adults is 133 mg (10 mL) admixed with 50 mg (10 mL) 0.5% bupivacaine HCl, for a total volume of 20 mL (2.3). For all these nerve blocks, administer additional analgesics, which may include other immediate-release local anesthetics, as appropriate (2.3). See Full Prescribing Information for important preparation and administration instructions and compatibility considerations (2.4, 2.5). 2.1 Important Dose, Preparation, and Administration Instructions EXPAREL is for single administration only. EXPAREL is not substitutable with other bupivacaine products even if the strength is the same. Therefore, it is not possible to convert a dose from other bupivacaine products to an EXPAREL dose and vice versa. Do not dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of the liposomal particles. Do not administer EXPAREL if it is suspected that the vial has been frozen or exposed to high temperature (greater than 40°C or 104°F) for an extended period. Inspect EXPAREL visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer EXPAREL if the product is discolored. Do not heat or autoclave before use. Do not filter during administration. 2.2 Recommended Dose for Local Analgesia via Infiltration Local Analgesia via Infiltration in Adults The recommended dose of EXPAREL for local infiltration in adults is up to a maximum dose of 266 mg, and is based on the following factors: Size of the surgical site Volume required to cover the area Individual patient factors that may impact the safety of an amide local anesthetic As general guidance in selecting the proper EXPAREL dose for local infiltration in adults, two examples are provided [see Clinical Studies (14.2)]. In adult patients undergoing: Bunionectomy, a total of 106 mg (8 mL) of EXPAREL was administered, with 7 mL infiltrated into the tissues surrounding the osteotomy, and 1 mL infiltrated into the subcutaneous tissue. Hemorrhoidectomy, a total of 266 mg (20 mL) of EXPAREL was diluted with 10 mL of saline, for a total of 30 mL, divided into six 5 mL aliquots, injected by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers to produce a field block. Local Analgesia via Infiltration in Pediatric Patients The recommended dose of EXPAREL for one-time infiltration in pediatric patients, aged 6 to less than 17 years, is 4 mg/kg (up to a maximum of 266 mg), and is based upon two studies of pediatric patients undergoing either spine surgery or cardiac surgery [see Use in Specific Populations (8.4)]. 2.3 Recommended Dose for Regional Analgesia The maximum recommended dose of EXPAREL via perineural use for interscalene brachial plexus nerve block, sciatic nerve block in the popliteal fossa, and adductor canal block is 133 mg. For all these nerve blocks, administer additional analgesics, which may include other immediate-release local anesthetics, as appropriate (for example, Mayo field block for bunionectomy, infiltration between the popliteal artery and capsule of the knee (IPACK) block for total knee arthroplasty). Regional Analgesia via Interscalene Brachial Plexus Nerve Block in Adults The recommended dose of EXPAREL for interscalene brachial plexus nerve block in adults is 133 mg and is based upon one study of patients undergoing either total shoulder arthroplasty or rotator cuff repair [see Clinical Studies (14.3)]. Regional Analgesia via Sciatic Nerve Block in the Popliteal Fossa in Adults The recommended dose of EXPAREL for sciatic nerve block in the popliteal fossa in adults is 133 mg and is based upon one study of patients undergoing bunionectomy [see Clinical Studies (14.3)]. Regional Analgesia via Adductor Canal Block in Adults The recommended dose of EXPAREL for adductor canal block in adults is 133 mg (10 mL) admixed with 50 mg (10 mL) 0.5% bupivacaine HCl, for a total volume of 20 mL, and is based upon one study of patients undergoing total knee arthroplasty [see Clinical Studies (14.3)]. 2.4 Preparation and Administration Instructions Invert vials of EXPAREL multiple times to re-suspend the particles immediately prior to withdrawal from the vial. Administer EXPAREL (1) undiluted or (2) diluted to increase volume up to a final concentration of 0.89 mg/mL (i.e., 1:14 dilution by volume) with 0.9% preservative-free Sodium Chloride Injection or lactated Ringer's solution. Use diluted EXPAREL within 4 hours of preparation in a syringe. Administer EXPAREL with a 25 gauge or larger bore needle to maintain the structural integrity of the liposomal bupivacaine particles. Administer EXPAREL slowly via infiltration or perineural use with frequent aspiration to check for blood and minimize the risk of inadvertent intravascular injection. Discard unused portion. 2.5 Compatibility Considerations Some physicochemical incompatibilities exist between EXPAREL and certain other drugs. Direct contact of EXPAREL with these drugs results in a rapid increase in free (unencapsulated) bupivacaine, altering EXPAREL characteristics and potentially affecting the safety and efficacy of EXPAREL. Therefore, admixing EXPAREL with other drugs prior to administration is not recommended [see Drug Interactions (7)]. Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. Bupivacaine HCl administered together with EXPAREL 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 EXPAREL if the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2. The toxic effects of these drugs are additive, and their administration should be used with caution including monitoring for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Warnings and Precautions (5.1) and Overdosage (10)]. When a topical antiseptic such as povidone iodine (e.g., Betadine) is applied, the site should be allowed to dry before EXPAREL is administered into the site. EXPAREL should not be allowed to come into contact with antiseptics such as povidone iodine in solution. Studies conducted with EXPAREL demonstrated that the most common implantable materials (polypropylene, PTFE, silicone, stainless steel, and titanium) are not affected by the presence of EXPAREL any more than they are by saline. None of the materials studied had an adverse effect on EXPAREL.

Monitor cardiovascular status, neurological status, and vital signs during and after injection of EXPAREL (5.1). Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, use EXPAREL cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations (5.1). Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use (5.1). Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL (5.2). 5.1 Warnings and Precautions for Bupivacaine-Containing Products The safety and effectiveness of EXPAREL, other bupivacaine products, and other amide-containing products depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. As there is a potential risk of severe life-threatening adverse reactions associated with the administration of bupivacaine, any bupivacaine-containing product should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity [see Overdosage (10)]. 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 and other amide-containing products. Restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity. EXPAREL, other bupivacaine products, and other amide-containing products should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs. Injection of multiple doses of EXPAREL, other bupivacaine products, 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 to slow metabolic degradation. Tolerance to elevated blood concentrations varies with the status of the patient. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations. Central Nervous System Reactions 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. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. Neurologic effects following infiltration of soft tissue may include persistent anesthesia, paresthesia, weakness, and paralysis, all of which may have slow, incomplete, or no recovery. Central nervous system reactions are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered. Cardiovascular System Reactions Toxic blood concentrations depress cardiac conductivity and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure [See Overdosage (10)]. Allergic Reactions Allergic-type reactions are rare and may occur as a result of hypersensitivity to the local anesthetic or to other formulation ingredients. These 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 has been reported. The usefulness of screening for sensitivity has not been definitively established. Chondrolysis Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been postmarketing 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 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. 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 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 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. 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 central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue EXPAREL and any 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. 5.2 Warnings and Precautions Specific for EXPAREL As there is a potential risk of severe life-threatening adverse reactions associated with the administration of bupivacaine, EXPAREL should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity [See Overdosage (10)]. Caution should be taken to avoid accidental intravascular injection of EXPAREL. Convulsions and cardiac arrest have occurred following accidental intravascular injection of bupivacaine and other amide-containing products. Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. EXPAREL has not been evaluated for the following uses and, therefore, is not recommended for these routes of administration or types of analgesia: epidural intrathecal intravascular or intra-articular use regional nerve blocks other than interscalene brachial plexus nerve block, sciatic nerve block in the popliteal fossa, and adductor canal block EXPAREL has not been evaluated for use in the following patient populations and, therefore, is not recommended for administration to these groups. patients younger than 6 years old for infiltration patients younger than 18 years old for interscalene brachial plexus nerve block, sciatic nerve block in the popliteal fossa, and adductor canal block pregnant patients The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dose administered and may last for up to 5 days as seen in clinical trials.

The following serious adverse reactions have been associated with bupivacaine hydrochloride in clinical trials and are described in greater detail in other sections of the labeling: Central Nervous System Reactions [see Warnings and Precautions (5.1)] Cardiovascular System Reactions [see Warnings and Precautions (5.1)] Allergic Reactions [see Warnings and Precautions (5.1)] Chondrolysis [see Warnings and Precautions (5.1)] Methemoglobinemia [see Warnings and Precautions (5.1)] Accidental intravascular injection [see Warnings and Precautions (5.2)] Adverse reactions reported with an incidence greater than or equal to 10% following EXPAREL administration via: Infiltration in adults were nausea, constipation, and vomiting (6.1). Nerve block in adults were nausea, pyrexia, headache, and constipation (6.1). Infiltration in pediatric patients six to less than 17 years of age were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, blurred vision, pruritus, and tachycardia (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Pacira Pharmaceuticals, Inc. at 1-855-RX-EXPAREL (1-855-793-9727) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions Reported in All Local Infiltration Clinical Studies in Adults The safety of EXPAREL (local administration into the surgical site) was evaluated in 10 randomized, double-blind, clinical studies (including Studies 1 and 2 [see Clinical Studies (14.2)]) that included 823 adult patients who had various surgical procedures. Patients were administered an EXPAREL dose ranging from 66 to 532 mg (two times the maximum recommended dose of 266 mg). In these studies, following EXPAREL administration, the: Most common adverse reactions (incidence greater than or equal to 10%) were nausea, constipation, and vomiting. Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were pyrexia, dizziness, peripheral edema, anemia, hypotension, pruritus, tachycardia, headache, insomnia, postoperative anemia, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain. Less common adverse reactions (incidence less than 2%) were chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor, postural dizziness, paresthesia, syncope, incision site edema, procedural hypertension, procedural hypotension, procedural nausea, muscular weakness, neck pain, generalized pruritus, pruritic rash, hyperhidrosis, cold sweat, urticaria, palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular extrasystoles, ventricular tachycardia, hypertension, pallor, anxiety, confusional state, depression, agitation, restlessness, hypoxia, laryngospasm, apnea, respiratory depression, respiratory failure, increased body temperature, increased blood pressure (BP), decreased BP, decreased oxygen saturation, urinary incontinence, blurred vision, tinnitus, drug hypersensitivity, and hypersensitivity. Neurological and Cardiac Adverse Reactions In the EXPAREL surgical site infiltration studies, following EXPAREL administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were dizziness (6.2%), headache (3.8%), somnolence (2.1%), hypoesthesia (1.5%), and lethargy (1.3%). Cardiac Disorders system organ class were tachycardia (3.9%) and bradycardia (1.6%). Adverse Reactions Reported in All Local Infiltration Placebo-Controlled Trials in Adults Adverse reactions with an incidence greater than or equal to 2% reported by adult patients in clinical studies who underwent a bunionectomy (Study 1) or hemorrhoidectomy (Study 2) [see Clinical Studies (14.2)] that compared 106 mg of EXPAREL (8 mL) to placebo and 266 mg of EXPAREL (20 mL) to placebo are shown in Table 1. Table 1: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Local Infiltration Placebo-Controlled Studies in Adults (Studies 1 and 2) System Organ Class Preferred Term Study 1 Study 1: Bunionectomy; Study 2 Study 2: Hemorrhoidectomy; EXPAREL Placebo EXPAREL Placebo 106 mg (N=97) n (%) (N=96) n (%) 266 mg (N=95) n (%) (N=94) n (%) TEAE = treatment-emergent adverse event. At each level of summation (overall, system organ class, preferred term), patients are only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group. Any TEAE 53 (54.6) 59 (61.5) 10 (10.5) 17 (18.1) Gastrointestinal Disorders 41 (42.3) 38 (39.6) 7 (7.4) 13 (13.8) Nausea 39 (40.2) 36 (37.5) 2 (2.1) 1 (1.1) Vomiting 27 (27.8) 17 (17.7) 2 (2.1) 4 (4.3) Constipation 2 (2.1) 1 (1.0) 2 (2.1) 2 (2.1) Anal Hemorrhage 0 (0.0) 0 (0.0) 3 (3.2) 4 (4.3) Painful Defecation 0 (0.0) 0 (0.0) 2 (2.1) 5 (5.3) Rectal Discharge 0 (0.0) 0 (0.0) 1 (1.1) 3 (3.2) Nervous System Disorders 20 (20.6) 30 (31.3) 0 (0.0) 0 (0.0) Dizziness 11 (11.3) 25 (26.0) 0 (0.0) 0 (0.0) Headache 5 (5.2) 8 (8.3) 0 (0.0) 0 (0.0) Somnolence 5 (5.2) 1 (1.0) 0 (0.0) 0 (0.0) Syncope 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) Skin And Subcutaneous Tissue Disorders 8 (8.2) 7 (7.3) 0 (0.0) 0 (0.0) Generalized Pruritus 5 (5.2) 6 (6.3) 0 (0.0) 0 (0.0) Pruritus 3 (3.1) 1 (1.0) 0 (0.0) 0 (0.0) Investigations 5 (5.2) 3 (3.1) 4 (4.2) 3 (3.2) Increased Alanine Aminotransferase 3 (3.1) 3 (3.1) 1 (1.1) 0 (0.0) Increased Aspartate Aminotransferase 3 (3.1) 2 (2.1) 0 (0.0) 0 (0.0) Increased Blood Creatinine 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) Increased Body Temperature 0 (0.0) 0 (0.0) 3 (3.2) 3 (3.2) General Disorders And Administration Site Conditions 4 (4.1) 0 (0.0) 1 (1.1) 1 (1.1) Feeling Hot 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) Pyrexia 2 (2.1) 0 (0.0) 1 (1.1) 1 (1.1) Infections And Infestations 2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0) Fungal Infection 2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0) Injury, Poisoning And Procedural Complications 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) Post Procedural Swelling 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) Metabolism And Nutrition Disorders 2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0) Decreased Appetite 2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0) Adverse Reactions Reported in All Local Infiltration Clinical Studies in Pediatric Patients Aged 6 to Less Than 17 Years The safety of EXPAREL in 110 pediatric patients between the age of 6 and 17 years old who had spine or cardiac surgical procedures was evaluated in one randomized, open-label, clinical study in which EXPAREL was administered by infiltration into the surgical site (Study Peds-1) and one single-arm, open-label study in which EXPAREL was administered by infiltration into the surgical site (Study Peds-2) [see Use in Specific Populations (8.4)]. Patients were administered a weight-based dose of EXPAREL at 4 mg/kg (maximum dose of 266 mg) or bupivacaine HCl 2 mg/kg (maximum dose of 175 mg). In these studies, following EXPAREL administration the: Most common adverse reactions (incidence greater than or equal to 10%) were nausea, vomiting, constipation, hypotension, anemia, muscle twitching, blurred vision, pruritus, and tachycardia. Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were bradycardia, muscle spasms, tachypnea, oral hypoesthesia, postoperative anemia, dizziness, pyrexia, diarrhea, hypoacusis, hypoesthesia, back pain, hematuria, incontinence, muscular weakness, and visual impairment. Less common adverse reactions (incidence less than 2%) were flatulence, abdominal pain, dyspepsia, lip swelling, pain in extremity, musculoskeletal pain, flank pain, musculoskeletal chest pain, hypertension, sinus tachycardia, ventricular extrasystoles, dysgeusia, paresthesia, burning sensation, syncope, diplopia, eye swelling, dyspnea, atelectasis, hypopnea, hypoxia, chest pain, face edema, gait disturbance, generalized pruritus, rash, delayed recovery from anesthesia, fall, incision site hemorrhage, joint dislocation, seroma, hypomagnesemia, acidosis, hyperglycemia, metabolic acidosis, ear discomfort, decreased urine output, increased heart rate (HR), anxiety, panic attack, ear infection, and fungal wound infection. Neurological and Cardiac Adverse Reactions in Pediatric Patients Aged 6 to Less than 17 Years Old In the EXPAREL infiltration studies in pediatric patients aged 6 to less than 17 years old (Studies Peds-1 and Peds-2), following EXPAREL administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were dizziness (6.3%, n=5), and dysgeusia (1.3%, n=1). Cardiac Disorders system organ class were tachycardia (11.3%, n=9), bradycardia (8.8%, n=7), sinus tachycardia (1.3%, n=1), and ventricular extrasystoles (1.3%, n=1). Adverse Reactions Reported in All Local Infiltration Trials in Pediatric Patients Aged 6 to Less than 17 Years Old Adverse reactions with an incidence greater than or equal to 2% reported by patients in clinical studies (Studies Peds-1 and Peds-2) studying 4 mg/kg EXPAREL are shown in Table 2. Table 2: Treatment-Emergent Adverse Reactions (TEAE) with an Incidence Greater than or Equal to 2%: Local Infiltration Studies in Pediatric Patients Aged 6 to Less than 17 Years Old (Study Peds-1 and Peds-2) System Organ Class Preferred Term Study Peds-1 Study 1: Includes spine surgery patients aged 6 to less than 17 years old, and cardiac surgery patients aged 6 to less than 12 years old. Study Peds-2 Study 2: Includes spine surgery patients aged 12 to less than 17 years old. Spine Surgery EXPAREL 4 mg/kg Patients received EXPAREL 4 mg/kg, not to exceed 266 mg. (N=36) n (%) Cardiac Surgery EXPAREL 4 mg/kg (N=29) n (%) Spine Surgery EXPAREL 4 mg/kg (N=15) n (%) At each level of summation (overall, system organ class, preferred term), patients are only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group. TEAE = treatment-emergent adverse event. Patients with at least one TEAE 24 (66.7) 9 (31.0) 15 (100.0) Blood and lymphatic system disorders 0 0 15 (100) Anemia 0 0 15 (100) Cardiac disorders 3 (8.3) 1 (3.4) 12 (80.0) Bradycardia 2 (5.6) 0 5 (33.3) Sinus tachycardia 0 1 (3.4) 0 Tachycardia 1 (2.8) 0 8 (53.3) Ventricular extrasystoles 0 0 1 (6.7) Ear and labyrinth disorders 2 (5.6) 0 2 (13.3) Ear discomfort 0 0 1 (6.7) Hypoacusis 2 (5.6) 0 1 (6.7) Eye disorders 10 (27.8) 1 (3.4) 4 (26.7) Diplopia 1 (2.8) 0 0 Eye swelling 0 0 1 (6.7) Increased Lacrimation 0 0 0 Blurred Vision 7 (19.4) 1 (3.4) 3 (20.0) Visual impairment 2 (5.6) 0 0 Gastrointestinal disorders 18 (50.0) 7 (24.1) 14 (93.3) Abdominal Pain 0 0 1 (6.7) Constipation 9 (25.0) 4 (13.8) 7 (46.7) Nausea 11 (30.6) 2 (6.9) 9 (60.0) Diarrhea 3 (8.3) 0 0 Dyspepsia 1 (2.8) 0 0 Flatulence 0 0 1 (6.7) Oral Hypoesthesia 4 (11.1) 0 2 (13.3) Lip Swelling 0 0 1 (6.7) Vomiting 10 (27.8) 4 (13.8) 8 (53.3) General disorders and administration site conditions 0 1 (3.4) 3 (20.0) Chest pain 1 (2.8) 0 0 Face edema 0 1 (3.4) 0 Gait disturbance 0 0 1 (6.7) Generalized edema 0 0 0 Pyrexia 0 0 3 (20.0) Infections and infestations 1 (2.8) 1 (3.4) 0 Ear infection 1 (2.8) 0 0 Fungal wound infection 0 1 (3.4) 0 Injury, poisoning and procedural complications 8 (22.2) 0 1 (6.7) Postoperative Anemia 5 (13.9) 0 0 Delayed recovery from anesthesia 1 (2.8) 0 0 Fall 0 0 1 (6.7) Incision site hemorrhage 1 (2.8) 0 0 Joint dislocation 1 (2.8) 0 0 Procedural hemorrhage 0 0 0 Seroma 1 (2.8) 0 0 Metabolism and nutrition disorders 0 3 (10.3) 0 Acidosis 0 1 (3.4) 0 Hyperglycemia 0 1 (3.4) 0 Hypomagnesaemia 0 1 (3.4) 0 Metabolic acidosis 0 1 (3.4) 0 Musculoskeletal and connective tissue disorders 8 (22.2) 1 (3.4) 12 (80.0) Back pain 0 0 2 (13.3) Flank pain 0 0 1 (6.7) Muscle twitching 3 (8.3) 1 (3.4) 9 (60.0) Muscle spasms 4 (11.1) 0 3 (20.0) Muscular weakness 0 0 2 (13.3) Musculoskeletal pain 1 (2.8) 0 0 Musculoskeletal chest pain 0 0 1 (6.7) Pain in extremity 0 0 1 (6.7) Nervous system disorders 3 (8.3) 0 7 (46.7) Burning sensation 0 0 1 (6.7) Dizziness 2 (5.6) 0 3 (20.0) Dysgeusia 1 (2.8) 0 0 Headache 0 0 0 Hypoesthesia 0 0 3 (20.0) Paresthesia 0 0 1 (6.7) Syncope 1 (2.8) 0 0 Psychiatric disorders 0 2 (13.3) Anxiety 0 0 1 (6.7) Panic attack 0 0 1 (6.7) Renal and urinary disorders 0 0 2 (13.3) Hematuria 0 0 2 (13.3) Respiratory, thoracic and mediastinal disorders 3 (8.3) 1 (3.4) 7 (46.7) Atelectasis 0 0 1 (6.7) Bradypnea 0 0 0 Dyspnea 0 1 (3.4) 0 Hypopnea 1 (2.8) 0 0 Hypoxia 1 (2.8) 0 0 Pleural effusion 0 0 0 Tachypnea 1 (2.8) 0 6 (40.0) Skin and subcutaneous tissue disorders 4 (11.1) 0 6 (40.0) Pruritus 3 (8.3) 0 6 (40.0) Generalized Pruritus 1 (2.8) 0 0 Rash 0 0 1 (6.7) Vascular disorders 4 (11.1) 1 (3.4) 14 (93.3) Hot flush 0 0 0 Hypotension 4 (11.1) 0 14 (93.3) Hypertension 0 1 (3.4) 0 Systolic hypertension 0 0 0 Adverse Reactions Reported in Placebo-Controlled Nerve Block Clinical Studies in Adults The safety of EXPAREL was evaluated in four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) [see Clinical Studies (14.3, 14.4)] involving 469 EXPAREL-treated adult patients and 357 placebo-treated patients who had various surgical procedures. Patients were administered placebo or an EXPAREL dose of either 133 or 266 mg (two times the maximum recommended dose for these nerve blocks). In these studies, following EXPAREL administration via nerve block (perineural use) the: Most common adverse reactions (incidence greater than or equal to 10%) were nausea, pyrexia, and constipation. Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were muscle twitching, dysgeusia, urinary retention, fatigue, headache, confusional state, hypotension, hypertension, oral hypoesthesia, generalized pruritus, hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall, increased body temperature, peripheral edema, sensory loss, increased hepatic enzyme, hiccups, hypoxia, and post-procedural hematoma. Less common adverse reactions (incidence less than 2%) were arrhythmia, atrial fibrillation, first degree atrioventricular block, bradycardia, left bundle branch block, right bundle branch block, cardiac arrest, impaired hearing, blurred vision, visual impairment, asthenia, chills, hyperthermia, cellulitis, lung infection, pneumonia, procedural nausea, wound dehiscence, wound secretion, electrocardiogram QT prolonged, white blood cell count increased, arthralgia, back pain, joint swelling, decreased mobility, muscle spasms, muscular weakness, musculoskeletal pain, paraesthesia, presyncope, sedation, somnolence, syncope, delirium, dysuria, urinary incontinence, atelectasis, cough, dyspnea, lung infiltration, blister, drug eruption, erythema, rash, urticaria, deep vein thrombosis, hematoma, and orthostatic hypotension. The most common and common adverse reactions for the four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) are shown in Table 3. Neurological and Cardiac Adverse Reactions In the EXPAREL nerve block placebo-controlled studies, following EXPAREL administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were motor dysfunction (14.9%), dysgeusia (7.2%), headache (5.1%), hypoesthesia (2.3%), and sensory loss (2.3%). Cardiac Disorders system organ class were tachycardia (3%), sinus tachycardia (2.3%), and bradycardia (1.3%). Table 3: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Nerve Block Placebo-Controlled Studies (Studies 3, 6, 7, and 8) SYSTEM ORGAN CLASS Preferred Term EXPAREL 133 mg (N=168) n (%) EXPAREL 266 mg (N=301) n (%) Placebo (N=357) n (%) At each level of summation (overall, system organ class, preferred term), patients are only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group. TEAE = treatment-emergent adverse event. Number of Patients with at Least One TEAE 152 (90.5) 260 (86.4) 299 (83.8) Blood and Lymphatic System Disorders 2 (1.2) 22 (7.3) 15 (4.2) Anemia 2 (1.2) 18 (6.0) 13 (3.6) Cardiac Disorders 13 (7.7) 34 (11.3) 38 (10.6) Atrial Fibrillation 1 (0.6) 4 (1.3) 8 (2.2) Sinus Tachycardia 3 (1.8) 8 (2.7) 4 (1.1) Tachycardia 3 (1.8) 11 (3.7) 10 (2.8) Gastrointestinal Disorders 84 (50.0) 154 (51.2) 184 (51.5) Constipation 29 (17.3) 66 (21.9) 68 (19.0) Dyspepsia 3 (1.8) 7 (2.3) 7 (2.0) Oral Hypoesthesia 6 (3.6) 8 (2.7) 7 (2.0) Nausea 62 (36.9) 111 (36.9) 133 (37.3) Vomiting 17 (10.1) 55 (18.3) 73 (20.4) General Disorders And Administration Site Conditions 52 (31.0) 102 (33.9) 91 (25.5) Fatigue 7 (4.2) 15 (5.0) 15 (4.2) Feeling Cold 0 10 (3.3) 8 (2.2) Peripheral Edema 4 (2.4) 6 (2.0) 8 (2.2) Peripheral Swelling 3 (1.8) 8 (2.7) 4 (1.1) Pyrexia 36 (21.4) 70 (23.3) 64 (17.9) Injury, Poisoning And Procedural Complications 18 (10.7) 44 (14.6) 32 (9.0) Postoperative Anemia 0 8 (2.7) 10 (2.8) Contusion 4 (2.4) 1 (0.3) 0 Fall 4 (2.4) 8 (2.7) 1 (0.3) Post Procedural Hematoma 4 (2.4) 1 (0.3) 0 Procedural Hypotension 2 (1.2) 13 (4.3) 7 (2.0) Investigations 18 (10.7) 31 (10.3) 31 (8.7) Increased Body Temperature 1 (0.6) 10 (3.3) 4 (1.1) Increased Hepatic Enzyme 7 (4.2) 1 (0.3) 3 (0.8) Metabolism and Nutrition Disorders 13 (7.7) 18 (6.0) 25 (7.0) Hypokalemia 7 (4.2) 9 (3.0) 14 (3.9) Musculoskeletal And Connective Tissue Disorders 22 (13.1) 47 (15.6) 41 (11.5) Decreased Mobility 0 6 (2.0) 5 (1.4) Muscle Twitching 14 (8.3) 21 (7.0) 25 (7.0) Nervous System Disorders 72 (42.9) 101 (33.6) 112 (31.4) Dizziness 8 (4.8) 28 (9.3) 40 (11.2) Dysgeusia 12 (7.1) 22 (7.3) 21 (5.9) Headache 14 (8.3) 10 (3.3) 10 (2.8) Hypoesthesia 6 (3.6) 5 (1.7) 2 (0.6) Motor Dysfunction 35 (20.8) 35 (11.6) 37 (10.4) Sensory Loss 4 (2.4) 7 (2.3) 1 (0.3) Psychiatric Disorders 10 (6.0) 33 (11.0) 44 (12.3) Anxiety 3 (1.8) 9 (3.0) 6 (1.7) Confusional State 3 (1.8) 15 (5.0) 14 (3.9) Insomnia 5 (3.0) 10 (3.3) 19 (5.3) Renal And Urinary Disorders 9 (5.4) 31 (10.3) 31 (8.7) Urinary Retention 5 (3.0) 23 (7.6) 22 (6.2) Respiratory, Thoracic And Mediastinal Disorders 18 (10.7) 30 (10.0) 31 (8.7) Dyspnea 2 (1.2) 4 (1.3) 8 (2.2) Hiccups 4 (2.4) 4 (1.3) 1 (0.3) Hypoxia 4 (2.4) 3 (1.0) 3 (0.8) Skin And Subcutaneous Tissue Disorders 24 (14.3) 63 (20.9) 84 (23.5) Hyperhidrosis 1 (0.6) 14 (4.7) 15 (4.2) Pruritus 10 (6.0) 45 (15.0) 55 (15.4) Generalized Pruritus 6 (3.6) 7 (2.3) 14 (3.9) Vascular Disorders 16 (9.5) 30 (10.0) 44 (12.3) Hypertension 3 (1.8) 15 (5.0) 21 (5.9) Hypotension 11 (6.5) 8 (2.7) 19 (5.3) Adverse Reactions Reported in Active-Controlled Nerve Block Clinical Studies in Approved Populations The safety of EXPAREL was evaluated in two randomized, double-blind, active-controlled nerve block clinical studies in 189 adult patients who had a bunionectomy or a total knee arthroplasty (Studies 4 and 5) [see Clinical Studies (14.3)]. Via nerve block, patients received 133 mg of EXPAREL, 266 mg of EXPAREL (two times the maximum recommended EXPAREL dose) [see Dosage and Administration (2.3)] or 133 mg of EXPAREL admixed with 50 mg of bupivacaine HCl. In both of these studies the active comparator was 50 mg of bupivacaine HCl. The most common adverse reactions (incidence greater than or equal to 10%) in Studies 4 and 5 following: EXPAREL administration as a nerve block were nausea and constipation. Administration of EXPAREL admixed with bupivacaine as a nerve block were nausea, constipation, muscle spasms, and headache. The common adverse reactions (incidence greater than or equal to 2% to less than 10%) in Studies 4 and 5 following: EXPAREL administration as a nerve block were pruritus, vomiting, dyspepsia, headache, peroneal nerve palsy, rash and hypertension. Administration of EXPAREL admixed with bupivacaine as a nerve block were vomiting, dyspepsia, heart rate increased, hypokalaemia, hyponatraemia, back pain, disorientation, oropharyngeal pain, hypoaesthesia, pruritus, dizziness, insomnia, hypertension, hypoxia, hypotension, pyrexia, and tachycardia. The less common adverse reactions (incidence less than 2%) in Studies 4 and 5 following: EXPAREL administration as a nerve block were increased BP, pyrexia, arthralgia, insomnia, muscle spasms, asthenia, increased systolic BP, diarrhea, facial pain, migraine, muscle twitching, throat irritation, post procedural erythema, post procedural edema, dizziness, hypoesthesia, rhinorrhea, and paresthesia. Administration of EXPAREL admixed with bupivacaine as a nerve block were increased BP, procedural pain, rash, pruritic rash, anemia, anxiety, arthralgia, atrial fibrillation, decreased blood potassium, decreased BP, increased systolic BP, increased body temperature, bradycardia, confusional state, decreased appetite, diarrhea, dysarthria, fall, feeling cold, decreased HR, hot flush, joint swelling, leukocytosis, mental status changes, neuralgia, orthostatic hypotension, decreased oxygen saturation, pneumonia, post procedural hematoma, post procedural inflammation, post procedural swelling, pruritic rash, positive staphylococcus test, syncope, and urinary tract infection. The most common and common adverse reactions in adult patients in the active-controlled clinical studies are shown in Table 4. Table 4: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Nerve Block Active-Controlled Studies (Studies 4 and 5) SYSTEM ORGAN CLASS Preferred Term EXPAREL 133 mg (N=81) n (%) EXPAREL 266 mg (N=22) n (%) EXPAREL 133 mg + Bupi (N = 86) n (%) Bupi (N=162) n (%) At each level of summation (overall, system organ class, preferred term), patients were only counted once. Preferred terms are included where at least 2% of patients reported the event in any treatment group. TEAE = treatment-emergent adverse event. Number of Patients with at Least One TEAE 42 (51.9) 13 (59.1) 77 (89.5) 116 (71.6) Cardiac Disorders Tachycardia 0 0 4 (4.7) 5 (3.1) Gastrointestinal Disorders Constipation 10 (12.3) 3 (13.6) 30 (34.9) 47 (29.0) Dyspepsia 2 (2.5) 1 (4.5) 2 (2.3) 2 (1.2) Nausea 13 (16) 9 (40.9) 34 (39.5) 49 (30.2) Vomiting 4 (4.9) 5 (22.7) 5 (5.8) 13 (8.0) General Disorders And Administration Site Conditions Pyrexia 0 1 (4.5) 3 (3.5) 3 (1.9) Investigations Increased Heart rate 0 0 3 (3.5) 3 (1.9) Metabolism and Nutrition Disorders Hypokalemia 0 0 2 (2.3) 2 (1.2) Hyponatremia 0 0 2 (2.3) 2 (1.2) Musculoskeletal And Connective Tissue Disorders Back pain 0 0 2 (2.3) 3 (1.9) Muscle Spasms 2 (2.5) 0 11 (12.8) 10 (6.2) Nervous System Disorders Dizziness 2 (2.5) 0 4 (4.7) 4 (2.5) Headache 8 (9.9) 1 (4.5) 13 (15.1) 6 (3.7) Hypoaesthesia 0 9 (12.7) 2 (2.1) 0 Peroneal Nerve Palsy 3 (3.7) 0 0 0 Psychiatric Disorders Disorientation 0 0 2 (2.3) 0 Insomnia 2 (2.5) 0 5 (5.8) 14 (8.6) Respiratory, Thoracic And Mediastinal Disorders Hypoxia 0 0 4 (4.7) 4 (2.5) Oropharyngeal Pain 0 0 2 (2.3) 0 Skin And Subcutaneous Tissue Disorders Pruritus 6 (7.4) 1 (4.5) 6 (7.0) 9 (5.6) Rash 4 (4.9) 1 (4.5) 1 (1.2) 1 (0.6) Vascular Disorders Hypertension 3 (3.7) 1 (4.5) 5 (5.8) 7 (4.3) Hypotension 0 0 3 (3.5) 9 (5.6) Notable Adverse Reactions from Active-Controlled Studies in Unapproved Populations The safety of EXPAREL was evaluated in a multicenter, randomized, double-blind, active-controlled trial in 119 patients undergoing foot and ankle procedures (Study 9) [see Clinical Studies (14.3)]. Patients were administered a dose of either 266 mg EXPAREL, 266 mg EXPAREL admixed with 50 mg bupivacaine HCl, or 100 mg bupivacaine HCl. The following adverse reactions were observed following administration of EXPAREL or EXPAREL admixed with bupivacaine in Study 9 that either were not observed in Studies 4 and 5, or were observed at a higher frequency than was observed in Studies 4 and 5. These include: The most common adverse reactions (incidence greater than 10%) observed in Study 9 at higher frequencies than Studies 4 and 5: hypoesthesia (21% vs. 1% and 0%, respectively), paresthesia (10% vs. 1% and 0%, respectively). The common adverse reactions (incidence greater than or equal to 2% to less than 10%) observed in Study 9 but not in Studies 4 and 5: epistaxis, motor dysfunction, pain in extremity, skin abrasion, infusion site pain, muscular weakness. 6.2 Postmarketing Experience Because adverse reactions reported during postmarketing are 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. These adverse reactions are consistent with those observed in clinical studies and most commonly involve the following system organ classes: Injury, Poisoning, and Procedural Complications (e.g., drug-drug interaction, procedural pain), Nervous System Disorders (e.g., palsy, seizure), General Disorders And Administration Site Conditions (e.g., lack of efficacy, pain), Skin And Subcutaneous Tissue Disorders (e.g., erythema, rash), and Cardiac Disorders (e.g., bradycardia, cardiac arrest).

The toxic effects of local anesthetics are additive and concomitant use should be used with caution including monitoring for neurologic and cardiovascular effects related to local anesthetic systemic toxicity [see Dosage and Administration (2.2), Warnings and Precautions (5.1), and Overdosage (10)]. Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. Patients who are administered local anesthetics, including EXPAREL, may be at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: 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 Lidocaine or other non-bupivacaine local anesthetics: Do not admix with EXPAREL. EXPAREL may be administered at least 20 minutes or more following local administration of lidocaine (7). Bupivacaine HCl: Do not exceed a milligram dose of bupivacaine HCl solution to EXPAREL of 1:2 when admixing, as this may impact the pharmacokinetics and/or physicochemical properties of the drugs (7). Bupivacaine Bupivacaine HCl administered together with EXPAREL 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 EXPAREL as long as the ratio of the milligram dose of bupivacaine HCl solution to EXPAREL does not exceed 1:2. Non-Bupivacaine Local Anesthetics EXPAREL should not be admixed with local anesthetics other than bupivacaine. Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. There are no data to support administration of other local anesthetics prior to administration of EXPAREL. Other than bupivacaine as noted above, EXPAREL should not be admixed with other drugs prior to administration. Water and Hypotonic Agents Do not dilute EXPAREL with water or other hypotonic agents, as it will result in disruption of the liposomal particles.

Pregnancy: May cause fetal harm (8.1). 8.1 Pregnancy Risk Summary There are no studies conducted with EXPAREL in pregnant women. In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Clinical Considerations Labor or Delivery Bupivacaine is contraindicated for obstetrical paracervical block anesthesia. While EXPAREL has not been studied with this technique, the use of bupivacaine for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death. 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 [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 central nervous system, peripheral vascular tone, and cardiac function. Data Animal Data Bupivacaine hydrochloride was administered subcutaneously to rats and rabbits during the period of organogenesis (implantation to closure of the hard plate). Rat doses were 4.4, 13.3, and 40 mg/kg/day (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) and rabbit doses were 1.3, 5.8, and 22.2 mg/kg/day (equivalent to 0.1, 0.4 and 1.6 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight). No embryo-fetal effects were observed in rats at the doses tested with the high dose causing increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity. Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and post-natal development study when pregnant animals were administered subcutaneous doses of 4.4, 13.3, and 40 mg/kg/day bupivacaine hydrochloride (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) from implantation through weaning (during pregnancy and lactation). 8.2 Lactation Risk Summary 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. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EXPAREL and any potential adverse effects on the breastfed infant from EXPAREL or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of EXPAREL to produce postsurgical local analgesia via infiltration have been established in pediatric patients aged 6 years and older. Use of EXPAREL for this indication is supported by evidence from adequate and well-controlled studies in adults, and pharmacokinetic (PK) and safety data in pediatric patients aged 6 years and older from Studies Peds-1 and Peds-2 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)]. Study Peds-1 was a multicenter, randomized, open-label, two-part study (NCT03682302) to evaluate the PK and safety of EXPAREL for local infiltration in pediatric patients aged 6 to less than 17 years who were undergoing spine or cardiac surgery (postsurgically, patients were administered opioid rescue medication according to the study site's standard of care). Group 1: 61 patients aged 12 to less than 17 years, undergoing spine surgeries, were randomized 1:1 to receive either EXPAREL 4 mg/kg (maximum 266 mg) or bupivacaine HCl 2 mg/kg (maximum 175 mg). Group 2: 34 patients aged 6 to less than 12 years, undergoing either spine or cardiac surgeries, received open-label EXPAREL 4 mg/kg (maximum up to 266 mg). Study Peds-2 was a phase 1, open-label study that evaluated the PK and safety of 4 mg/kg (maximum 266 mg) of EXPAREL (administered intraoperatively prior to wound closure) in 15 pediatric patients aged 12 to less than 17 who were undergoing spinal surgery. The safety and effectiveness of EXPAREL have not been established to produce postsurgical: Local analgesia via infiltration in pediatric patients aged less than 6 years old. Regional analgesia via an interscalene brachial plexus nerve block, sciatic nerve block in the popliteal fossa, or adductor canal block in pediatric patients. 8.5 Geriatric Use Of the total number of patients in the EXPAREL local infiltration clinical studies (N=823), 171 patients were greater than or equal to 65 years of age and 47 patients were greater than or equal to 75 years of age. Of the total number of patients in the EXPAREL nerve block clinical studies (N= 1046), 312 patients were greater than or equal to 65 years of age and 70 patients were greater than or equal to 75 years of age. No overall differences in safety or effectiveness of EXPAREL have been observed between patients 65 years of age and older and younger adult patients. In clinical studies, differences in various pharmacokinetic parameters have been observed between patients 65 years of age and older and younger adult patients. Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to bupivacaine may be greater in patients with renal impairment than in patients with normal renal function. Because patients 65 years of age and older are more likely to have renal impairment, increase monitoring for EXPAREL-associated adverse reactions [see Adverse Reactions (6)]. 8.6 Hepatic Impairment Amide-type local anesthetics, such as bupivacaine, are metabolized by the liver. Patients with severe hepatic disease, 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 [see Clinical Pharmacology (12.3)]. Therefore, consider increased monitoring for local anesthetic systemic toxicity in patients with moderate to severe hepatic disease. 8.7 Renal Impairment Bupivacaine is known to be substantially excreted by the kidney, and the risk of adverse reactions to EXPAREL may be greater in patients with renal impairment than in patients with normal renal function. Therefore, in patients with renal impairment, increase monitoring for EXPAREL-associated adverse reactions [see Adverse Reactions (6)].

Risk Summary There are no studies conducted with EXPAREL in pregnant women. In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Clinical Considerations Labor or Delivery Bupivacaine is contraindicated for obstetrical paracervical block anesthesia. While EXPAREL has not been studied with this technique, the use of bupivacaine for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death. 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 [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 central nervous system, peripheral vascular tone, and cardiac function. Data Animal Data Bupivacaine hydrochloride was administered subcutaneously to rats and rabbits during the period of organogenesis (implantation to closure of the hard plate). Rat doses were 4.4, 13.3, and 40 mg/kg/day (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) and rabbit doses were 1.3, 5.8, and 22.2 mg/kg/day (equivalent to 0.1, 0.4 and 1.6 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight). No embryo-fetal effects were observed in rats at the doses tested with the high dose causing increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity. Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and post-natal development study when pregnant animals were administered subcutaneous doses of 4.4, 13.3, and 40 mg/kg/day bupivacaine hydrochloride (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) from implantation through weaning (during pregnancy and lactation).

The safety and effectiveness of EXPAREL to produce postsurgical local analgesia via infiltration have been established in pediatric patients aged 6 years and older. Use of EXPAREL for this indication is supported by evidence from adequate and well-controlled studies in adults, and pharmacokinetic (PK) and safety data in pediatric patients aged 6 years and older from Studies Peds-1 and Peds-2 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)]. Study Peds-1 was a multicenter, randomized, open-label, two-part study (NCT03682302) to evaluate the PK and safety of EXPAREL for local infiltration in pediatric patients aged 6 to less than 17 years who were undergoing spine or cardiac surgery (postsurgically, patients were administered opioid rescue medication according to the study site's standard of care). Group 1: 61 patients aged 12 to less than 17 years, undergoing spine surgeries, were randomized 1:1 to receive either EXPAREL 4 mg/kg (maximum 266 mg) or bupivacaine HCl 2 mg/kg (maximum 175 mg). Group 2: 34 patients aged 6 to less than 12 years, undergoing either spine or cardiac surgeries, received open-label EXPAREL 4 mg/kg (maximum up to 266 mg). Study Peds-2 was a phase 1, open-label study that evaluated the PK and safety of 4 mg/kg (maximum 266 mg) of EXPAREL (administered intraoperatively prior to wound closure) in 15 pediatric patients aged 12 to less than 17 who were undergoing spinal surgery. The safety and effectiveness of EXPAREL have not been established to produce postsurgical: Local analgesia via infiltration in pediatric patients aged less than 6 years old. Regional analgesia via an interscalene brachial plexus nerve block, sciatic nerve block in the popliteal fossa, or adductor canal block in pediatric patients.

Clinical Presentation Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution [See Warnings and Precautions (5) and Adverse Reactions (6)]. Signs and symptoms of overdose include CNS symptoms (perioral paresthesia, dizziness, dysarthria, confusion, mental obtundation, sensory and visual disturbances, and eventually convulsions) and cardiovascular effects (that range from hypertension and tachycardia to myocardial depression, hypotension, bradycardia, and asystole). Plasma levels of bupivacaine associated with toxicity can vary. Although concentrations of 2,500 to 4,000 ng/mL have been reported to elicit early subjective CNS symptoms of bupivacaine toxicity, symptoms of toxicity have been reported at levels as low as 800 ng/mL. Management of Local Anesthetic Overdose At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine to enhance myocardial contractile force). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias, and cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated.

EXPAREL (bupivacaine liposome injectable suspension) is a sterile, non-pyrogenic white to off-white preservative-free aqueous suspension consisting of multivesicular liposomes containing bupivacaine. Bupivacaine is present at a concentration of 13.3 mg/mL. After injection of EXPAREL, bupivacaine is released from the multivesicular liposomes. EXPAREL is for infiltration or perineural use. Active Ingredient Bupivacaine is related chemically and pharmacologically to the amide-type local anesthetics. It is a homologue of mepivacaine and is related chemically to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. Chemically, bupivacaine is 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide with a molecular weight of 288.4. Bupivacaine has the following structural formula: Chemical Structure EXPAREL The median diameter of the liposome particles in EXPAREL ranges from 24 to 31 μm. The liposomes are suspended in a 0.9% Sodium Chloride Injection. Each vial contains bupivacaine at a nominal concentration of 13.3 mg/mL. Inactive ingredients and their nominal concentrations are: cholesterol, 4.7 mg/mL; 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) sodium salt (DPPG), 0.9 mg/mL; tricaprylin, 2.0 mg/mL; 1, 2-dierucoylphosphatidylcholine (DEPC), 8.2 mg/mL; phosphoric acid to adjust pH; and sodium chloride to adjust tonicity. The pH of EXPAREL is in the range of 5.8 to 7.4. Bupivacaine in EXPAREL has different functional properties relative to those of the unencapsulated or nonlipid-associated bupivacaine products. Bupivacaine that is released from EXPAREL has a different pharmacokinetic and systemic profile relative to other bupivacaine products. In addition, the nominal weight percent concentration of bupivacaine in EXPAREL is based on bupivacaine free base rather than bupivacaine HCl (100 mg of bupivacaine HCl contains 88.6 mg of bupivacaine free base) [see Dosage and Administration (2.1)].