6 ADVERSE REACTIONS

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)]

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 2†
	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.
* Study 1: Bunionectomy; † Study 2: Hemorrhoidectomy;
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 Peds-2†
System Organ Class Preferred Term	Spine Surgery EXPAREL 4 mg/kg‡ (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.
* 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 2: Includes spine surgery patients aged 12 to less than 17 years old. ‡ Patients received EXPAREL 4 mg/kg, not to exceed 266 mg.
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).