Phase 4, Controlled Study in Adult Subjects Undergoing Primary, 1-2 Level, Open Lumbar Spinal Fusion Surgery

This is a Phase 4, multicenter, randomized, double-blind, controlled study in approximately
220 adult subjects undergoing primary, 1-2 level, open lumbar spinal fusion surgery under
general anesthesia.

Subjects will be screened within 30 days prior to study drug administration and at least one
day prior to surgery. During the screening visit, subjects will be assessed for past or
present neurologic, cardiac, and general medical conditions that in the opinion of the
Investigator would preclude them from study participation. After the informed consent form
(ICF) is signed, a medical history, surgical history, physical examination, 12-lead
electrocardiogram (ECG), vital sign measurements, select clinical laboratory evaluations,
urine drug screen, alcohol breath test, and urine pregnancy test for women of childbearing
potential will be conducted. Study drug, approximately 1-2 mL every 1.0-1.5 cm, will be
administered using 20- or 22-gauge needles prior to wound closure.

Administration Instructions/Procedures

Study drug should be injected in the prescribed locations based on the areas of highest nerve
density. Study drug will be administered using syringes with 20- or 22-gauge needles prior to
wound closure. The Investigator must document the size of the incision. Each infiltration
site should be spaced 1.0-1.5 cm apart and should deliver approximately 1-2 mL into both deep
and superficial areas (para-spinous fascia, muscle, and subcutaneous layers). Total volume
administered will be depended on the number of levels of dissection, as described below.
Following infiltration, the tissue should visibly expand with minimal leakage.

Total Volume of Expansion

The Investigator must document the total volume used for each surgery.

1. Level Procedures Group 1: EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 20
mL normal saline = total volume of 60 mL Group 2: Bupivacaine HCl 0.5% in 20 mL + 40 mL
normal saline = total volume of 60 mL

2. Level Procedures Group 1: EXPAREL 266 mg in 20 mL + bupivacaine HCl 0.5% in 20 mL + 50
mL normal saline = total volume of 90 mL Group 2: Bupivacaine HCl 0.5% in 20 mL + 70 mL
normal saline = total volume of 90 mL

Drains may be used at the surgeon's discretion. In addition to LIA, all study participants
will receive a standardized approach for managing postsurgical pain that includes a scheduled
multimodal pain regimen including adjunctive analgesics, non-steroidal anti-inflammatory
drugs (NSAIDs). Rescue analgesics will be available as needed.

Postsurgical clinical assessments will include pain intensity scores using a 10-cm visual
analog scale (VAS) (see Appendix 1); overall benefit of analgesia score (OBAS) questionnaire
(see Appendix 2); total postsurgical opioid consumption; predefined opioid-related AEs; and
nurse's satisfaction with overall analgesia (see Appendix 3).

Adverse events will be recorded from the time the ICF is signed through Day 30. If a cardiac
AE (e.g., chest pain [angina, myocardial infarction], abnormal/irregular heart rate
[bradycardia, tachycardia, extrasystoles], or shortness of breath), neurological AE (e.g.,
altered mental status/altered sensorium, dizziness, dysarthria, hyperesthesia, metallic
taste, peroral numbness, seizure, tinnitus, tremors, visual disturbance, muscular twitching
or rigidity beyond 72 hours postdose, or tingling/paresthesia beyond 72 hours postdose), or
serious AE (SAE) occurs during the study a 12-lead ECG, vital signs, and any appropriate
clinical laboratory tests should be conducted.

Postsurgical health economic outcome assessments will include hospital length of stay (LOS),
use of skilled nursing facility, hospital readmissions, and use of other health services
following discharge (phone calls related to postsurgical pain, unscheduled visits related to
postsurgical pain, and visits to emergency department) through Day 30.

A follow-up visit will be scheduled for all subjects on postsurgical Day 14. A follow-up
phone call will be made on Day 30 to all subjects who received study drug to assess for
adverse events (AEs).

Number of Subjects (Planned):

Approximately 194 subjects are planned for enrollment in this study in order to have at least
184 evaluable subjects.

Inclusion Criteria:

1. Male or female, at least 18 years of age at screening.

2. Primary surgical indication is lumbar pain, radiculopathy, disc degeneration, disc
herniation, foraminal stenosis, or 1-2 level spondylolisthesis or deformity.

3. Scheduled to undergo primary, 1-2 level, open spine fusion under general anesthesia.

4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3.

5. Female subjects must be surgically sterile; or at least 2 years postmenopausal; or
have a monogamous partner who is surgically sterile; or practicing double-barrier
contraception; or practicing abstinence (must agree to use double-barrier
contraception in the event of sexual activity); or using an insertable, injectable, or
transdermal, contraceptive approved by the FDA for greater than 2 months prior to
screening. All women of childbearing potential (ie, premenopausal without permanent
sterilization) must commit to the use of an acceptable form of birth control for the
duration of the study and for 30 days after completion of the study.

6. Able to provide informed consent, adhere to the study visit schedule, and complete all
study assessments

Exclusion Criteria:

1. Currently pregnant, nursing, or planning to become pregnant during the study or within
1 month after study drug administration.

2. Serious spinal conditions (to include cauda equina syndrome, infection, tumor,
fracture, or severe osteoporosis [i.e., if taking Bisphosphonate or TNF-α blockers]).

3. Previous spinal surgery at the same level other than microdiscectomy (e.g.,
laminectomy, fusion).

4. Planned concurrent surgical procedure.

5. Identification of a dural tear during surgery will be an intra-operative exclusion
unless it is well repaired (no evidence of CSF leak with Valsalva and no plan to
restrict activity post-operatively). Any injury to the nerve root occurring during
surgery will also be considered an intra-operative exclusion.

6. Concurrent painful physical condition that may require analgesic treatment (such as an
NSAID or opioid) in the postsurgical period for pain that is not strictly related to
the spinal surgery and which may confound the postsurgical assessments.

7. Comorbidity impacting current physical function or Investigator opinion that it may
impact postsurgical rehabilitation.

8. Allergy, hypersensitivity, or contraindication to any of the study medications (i.e.,
bupivacaine, oxycodone, morphine, hydromorphone, gabapentin, acetaminophen, celecoxib,
or cyclobenzaprine) for which an alternative medication is not provided in the
protocol.

9. Use of any of the following medications within the times specified before surgery:
long-acting opioid medication (eg, morphine including MS Contin®, hydromorphone
[Dilaudid®], oxycodone [Oxycontin®], methadone) daily for more than 3 months duration
or within 3 days of surgery or NSAIDs (except for low-dose aspirin used for
cardioprotection) within 3 days, or any opioid medication within 24 hours. Patients
receiving short-acting opioids or NSAIDs should be at a steady or plateau dose. Such
patients should require or receive no more than 20 morphine equivalents (eg, 4
Percocet) within 24 hours of surgery.

10. Initiation of treatment with any of the following medications within 1 month of study
drug administration or if the medication(s) are being given to control pain: selective
serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors
(SNRIs), or duloxetine (Cymbalta). If a subject is taking one of these medications for
a reason other than pain control, he or she must be on a stable dose for at least 1
month prior to study drug administration. Gabapentin (Neurotin) or pregabalin (Lyrica)
is permitted pre-operatively if the duration has been less than 12 weeks.

11. Current use of systemic glucocorticosteroids within 1 month of enrollment in this
study.

12. Use of dexmedetomidine HCl (Precedex) within 3 days of study drug administration.

13. History of coronary or vascular stent placed within the past 3 months (may be extended
to 1 year if medically indicated per physician discretion).

14. Have been treated for a deep vein thrombosis, pulmonary embolism, myocardial
infarction, or ischemic stroke within the past 6 months (may be extended to 1 year if
medically indicated per physician discretion).

15. Severely impaired renal (e.g., serum creatinine clearance ≤ 30) or hepatic function
(e.g., serum AST level >3 x ULN or serum ALT level >3 x ULN).

16. Any neurologic or psychiatric disorder that might impact postsurgical pain or
interfere with study assessments.

17. Malignancy in the last 2 years, per physician discretion.

18. History of misuse, abuse, or dependence on opioid analgesics, other prescription
drugs, illicit drugs, or alcohol. Dependence or chronic opioid use will be defined as
use of more than 30 morphine equivalents per day during the prior 90 days.

19. Failure to pass the urine drug screen or alcohol breath test.

20. Body weight <50 kg (110 pounds) or a body mass index >40 kg/m2.

21. Subjects receiving Worker's compensation for a disability or who are involved in
litigation.

22. Previous participation in an EXPAREL study.

23. Administration of an investigational drug within 30 days or 5 elimination half-lives
of such investigational drug, whichever is longer, prior to study drug administration,
or planned administration of another investigational product or procedure during the
subject's participation in this study