Local Infiltration Analgesia With and Without EXPAREL Following Total Knee Arthroplasty

On Day 0, eligible subjects will be randomized 1:1 to two treatment groups. Subjects in
Group 1 will receive local infiltration analgesia (LIA) with EXPAREL 266 mg in 20 mL admixed
with bupivacaine hydrochloride (HCl) 0.5% in 20 mL and expanded in volume with 80 mL normal
saline (total volume of 120 mL). Subjects in Group 2 will receive LIA with bupivacaine HCl
0.5% in 20 mL expanded in volume with 100 mL normal saline (total volume of 120 mL).
Investigators will use their usual surgical technique to perform the TKA.

Study drug will be administered using six 20 cc syringes with 22-gauge needles prior to
wound closure. Each stick should deliver approximately 1-1.5 cc to the intended area. The
tissue should visibly expand with minimal leakage. Study drug should be injected in the
prescribed locations based on the areas of highest nerve density.

Infiltration Technique

Prior to cementation

Syringe #1: Posterior capsule (8-10 sticks medial and 8-10 sticks lateral).

Syringe #2: Femur medial and lateral periosteum, posterior periosteum,
suprapatellar/quadriceps tendon (20 sticks).

Syringe #3: Tibia fat pad (5 sticks); pes anserinus, medial collateral ligament, and gutter
(15 sticks).

Syringe #4: Circumferential periosteum (15-20 sticks).

After cementation

Syringe #5: Midline quadriceps tendon (10 sticks); retinaculum, medial gutter, femoral to
tibia (10 sticks).

Syringe #6: Lateral gutter, femoral to tibial (10 sticks); subcutaneous/closure (10 sticks).

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), and rescue analgesics as needed.

Postsurgical clinical assessments will include pain intensity scores using a 10-cm visual
analog scale (VAS); overall benefit of analgesia score (OBAS) questionnaire; total
postsurgical opioid consumption; physical therapy assessment; nurse's satisfaction with
overall analgesia; and discharge readiness. Adverse events (AEs) will be recorded from the
time the informed consent form is signed through postsurgical Day 29.

Postsurgical health economic outcome assessments will include hospital length of stay (LOS),
use of skilled nursing facility, outpatient physical therapy use, 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
postsurgical Day 29.

A follow-up visit will be scheduled for all subjects on postsurgical Day 14. A follow-up
phone call will be made on postsurgical Day 29 to all subjects who received study drug to
assess for AEs.

Inclusion Criteria:

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

2. Scheduled to undergo primary, unilateral, tricompartmental TKA under spinal
anesthesia.

3. Primary indication for TKA is degenerative osteoarthritis of the knee.

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,
transdermal, or combination oral contraceptive approved by the FDA for greater than 2
months prior to screening and 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. History of previous prior contralateral TKA or open knee surgery on the knee being
considered for TKA. Prior arthroscopy is permitted.

3. Planned concurrent surgical procedure (e.g., bilateral TKA).

4. Undergoing unicompartmental TKA or revision TKA.

5. 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 knee surgery and which may confound the postsurgical assessments (e.g.,
significant pain from other joints including the non-index knee joint, chronic
neuropathic pain, concurrent or prior contralateral TKA, concurrent foot surgery).

6. Comorbidity impacting current physical function of Investigator opinion that it may
impact postsurgical rehabilitation.

7. Allergy, hypersensitivity, or contraindication to any of the study medications (i.e.,
bupivacaine, pregabalin, acetaminophen/paracetamol, celecoxib, oxycodone, morphine,
hydromorphone, or tranexamic acid).

8. Use of any of the following medications within the times specified before surgery:
long-acting opioid medication or NSAIDs (except for low-dose aspirin used for
cardioprotection) within 3 days, or any opioid medication within 24 hours.

9. 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), gabapentin, pregabalin (Lyrica®), 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.

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

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

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

13. 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).

14. Rheumatoid or inflammatory arthritis or disease.

15. Severely impaired renal or hepatic function (e.g., serum creatinine level >2 mg/dL
[176.8 µmol/L], blood urea nitrogen level >50 mg/dL [17.9 mmol/L], serum aspartate
aminotransferase [AST] level >3 times the upper limit of normal [ULN], or serum
alanine aminotransferase [ALT] level >3 times the 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.

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

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

21. Previous participation in an EXPAREL study.

22. 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.