PK Study of EXPAREL in Subjects Undergoing Open Spinal Fusion or Reconstructive Surgery

This is a Phase 1, multi-center, open-label study designed to evaluate the safety and pharmacokinetics of EXPAREL when administered via local wound infiltration to subjects undergoing open cervical or thoracic spinal fusion or reconstructive surgery.

Fifteen subjects are planned for enrollment. Eligible subjects, whose surgical incision must be at least 8 cm in length, will receive a single dose of EXPAREL (266 mg/20 mL) expanded in volume with 20-60 mL normal saline, depending on the size of the incision. Incision will be performed using a posterior surgical approach.

Administration Technique:

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 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 1-1.5 mL into both deep and superficial areas (para-spinous fascia, muscle, and subcutaneous layers). As each incision will have three layers of infiltration, the total volume to be infiltrated can range from 40-80 mL (please refer to below specifics on how to determine total volume of expansion). 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.

• EXPAREL (20 mL) + normal saline (20-60 mL based on the incision size) = total volume.
• For example: If the infiltration sites are 1.5 cm apart, then a 10 cm incision would be 10 × 2 sides × 3 layers = 60 cm. If there is 1 mL infiltrated every 1.5 cm, the total volume would be 40 mL.

Screening:

Subjects will be screened within 30 days prior to study drug administration. During the screening visit, which must take place at least 1 day prior to surgery, 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/surgical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), neurological assessment, alcohol breath test, urine drug screen, and urine pregnancy test for women of childbearing potential will be conducted.

Trained and qualified Investigators will use their usual standard of care surgical technique to perform the surgery. The use of fentanyl or analogues will be permitted (during surgery only). Intraoperative administration of other opioids or any other analgesic, local anesthetics, or anti-inflammatory agents will be prohibited unless needed to treat an adverse event (AE).

Subjects must remain in the hospital for at least 72 hours after surgery in order to undergo postsurgical assessments. In addition, subjects must return for the 84 hour and 96 hour study assessments.

Day 7 Follow-Up Visit:

All subjects will return on Day 7 for a follow-up visit, which will include vital sign measurements, 12-lead ECG, neurological assessment, blood sample collection for PK analysis, and an AE assessment.

Postsurgical Safety Assessments:

This will include a cardiac assessment (i.e., 12-lead ECG), neurological assessment, and vital signs. Adverse events will be recorded from the time the ICF is signed through Day 30. If a cardiac or neurological AE of special interest or SAE occurs during the study, an unscheduled PK blood sample must be collected. In addition, a 12-lead ECG, vital signs, and any appropriate clinical laboratory tests must be conducted. Cardiac AEs of special interest include chest pain (angina, myocardial infarction), abnormal/irregular heart rate (bradycardia, tachycardia, extrasystoles), and shortness of breath requiring intervention. Neurologic AEs of special interest include altered mental status/altered sensorium, rigidity, dysarthria, seizure, tremors, metallic taste, tinnitus, perioral numbness, visual disturbance, and severe or worsening dizziness. Additionally, the following events are of special interest if they persist or occur beyond 72-hours postdose: dizziness, hyperesthesia, muscular twitching, and tingling/paresthesia.

Postsurgical Efficacy Assessments

Will include pain intensity scores using a 10 cm visual analog scale (VAS) and use of supplemental opioid rescue medication.

Pharmacokinetic Assessment:

Blood samples for PK analysis will be obtained predose (on Day 1 prior to study drug administration); 15 minutes, 30 minutes, 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96 hours after the beginning of study drug administration; and on Day 7.

Number of Planned Patients for enrollment is 15 adult subjects.