EXPAREL

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) ].

EXPAREL is indicated to produce postsurgical: Local analgesia via infiltration in patients aged 6 years and older Regional analgesia via an interscalene brachial plexus nerve block in adults Regional analgesia via a sciatic nerve block in the popliteal fossa in adults Regional analgesia via an adductor canal block in adults EXPAREL contains bupivacaine, an amide local anesthetic, and is indicated to produce postsurgical: Local analgesia via infiltration in patients aged 6 years and older ( 1 ). Regional analgesia via an interscalene brachial plexus nerve block in adults ( 1 ). Regional analgesia via a sciatic nerve block in the popliteal fossa in adults ( 1 ). Regional analgesia via an adductor canal block in adults ( 1 ). Limitations of Use The safety and effectiveness of EXPAREL have not been established to produce postsurgical regional analgesia via other nerve blocks besides an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Limitations of Use The safety and effectiveness of EXPAREL have not been established to produce postsurgical regional analgesia via other nerve blocks besides an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block.

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.

EXPAREL is contraindicated in obstetrical paracervical block anesthesia [see Use in Specific Populations (8.1) ]. While EXPAREL has not been tested with this technique, the use of bupivacaine HCl with this technique has resulted in fetal bradycardia and death. EXPAREL is contraindicated in obstetrical paracervical block anesthesia ( 4 ).

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.

Storage Store EXPAREL vials refrigerated between 2°C to 8°C (36°F to 46°F). EXPAREL may be held at a controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 30 days in sealed, intact (unopened) vials. Do not re-refrigerate vials. Do not freeze or expose EXPAREL to high temperatures (greater than 40°C or 104°F) for an extended period. Do not administer EXPAREL if it is suspected of having been frozen or exposed to high temperatures. Do not use the vial if the stopper is bulging. Handling See Dosage and Administration (2.1 , 2.4) for important preparation instructions.