Efficacy, Safety, and Pharmacokinetics of Brachial Plexus Block With EXPAREL in Shoulder Surgery

On Day 0, eligible subjects will be randomized in a 1:1 ratio to receive a single dose of
EXPAREL 133 mg in 10 mL expanded in volume with 10 mL of normal saline for a total volume of
20 mL or placebo 20 mL. Study drug (EXPAREL or placebo) will be administered in a blinded
manner via an ultrasound guided single-dose brachial plexus block at least 1 hour prior to
surgery.

Postsurgical assessments will include pain intensity scores using a 10-cm visual analog scale
(VAS); total postsurgical opioid consumption; overall benefit of analgesia score (OBAS)
questionnaire; subject satisfaction with overall analgesia using a 5 point Likert scale;
neurological assessment; sensory function assessment; motor function assessment; discharge
readiness; unscheduled phone calls or office visits related to pain; 12-lead ECGs; vital sign
measurements; and clinical laboratory tests. Adverse events will be recorded from the time
the informed consent form is signed through postsurgical Day 29.

Follow-up visits will be scheduled for all subjects on postsurgical Days 5 and 10. A
follow-up phone call will be made on postsurgical Day 29.

A population Pharmacokinetic (PK) analysis will be utilized to limit the number of blood
draws with a sampling schedule of baseline (prior to the nerve block) through hospital
discharge. There will be two collection sequences for this study and a subject can only be
randomized to one sequence.

Inclusion Criteria:

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

2. Scheduled to undergo primary unilateral total shoulder arthroplasty or rotator cuff
repair.

3. Subjects scheduled for rotator cuff repair must have a magnetic resonance imaging
(MRI) with a reading confirming a tear of at least 1 cm.

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

5. Female subject 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 demonstrate normal motor function (by obtaining a 5 on the Lovett Scale when
exhibiting biceps, wrist, and thumb movement) and sensory function (by exhibiting
sensitivity to cold, pinprick, and light touch) in the location where sensory function
will be measured throughout the study: 2 cm superior to the coracoid process on the
skin overlying the acromioclavicular joint.

7. 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. Planned concurrent surgical procedure.

3. 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 shoulder surgery and which may confound the postsurgical assessments (e.g.,
significant pain from other joints, chronic neuropathic pain).

4. History of hypersensitivity or idiosyncratic reaction to amide-type local anesthetics.

5. Smoking history of greater than 25 pack-years.

6. Contraindication to any one of the following: bupivacaine, oxycodone, morphine, or
hydromorphone.

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

8. 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.

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

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

11. History of impaired kidney function, emphysema or other chronic respiratory disease,
rheumatoid arthritis, coagulopathy, or loss of sensation in extremities.

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

13. Uncontrolled anxiety, psychiatric, or neurological disorder that might interfere with
study assessments.

14. Any chronic neuromuscular deficit effecting the peripheral nerves or muscles of the
surgical extremity.

15. Any chronic condition or disease that would compromise neurological or vascular
assessments.

16. Malignancy in the last 2 years, with the exception of non-metastatic basal cell or
squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.

17. Suspected or known history of drug or alcohol abuse within the previous year.

18. Body weight <50 kg (110 pounds) or a body mass index >44 kg/m2.

19. Previous participation in an EXPAREL study.

20. 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.