EXPAREL for Minimally Invasive Supracervical Hysterectomies

Exparel is a local analgesic that utilizes bupivacaine in combination with the proven product
delivery platform, DepoFoam®. Exparel (bupivacaine liposome injectable suspension) is a
liposome injection of bupivacaine, an amide-type local anesthetic, indicated (bupivacaine
liposome injectable suspension) for administration into the surgical site to produce
postsurgical analgesia. Liposomal drug- containing formulations can provide for controlled
drug release over an extended period of time.

The overall length of hospital stay (LOS) for patients undergoing laparoscopic (robot-
assisted or traditional laparoscopy) supracervical hysterectomy varies widely in published
reports; typical durations range between 0 days and 4 days.

That is because in recent years there has been a trend toward use of enhanced or "fast-
track" discharge protocols to reduce LOS in patients undergoing this procedure, predicated
primarily on reducing the time to achieve tolerance of oral liquid/food intake and improved
GI function. Most patients experience moderate to extreme pain after surgery and effective
postsurgical pain management is a key factor affecting patient recovery. Multimodal analgesia
techniques involving analgesics, such as local anesthetics, oral or parenteral nonsteroidal
anti-inflammatory medications, and oral or parenteral opioids, are recommended as the safest
and effective approach to postsurgical pain control. Local anesthetics administered during
surgery are frequently used as part of multimodal analgesic regimens; however, the duration
of analgesia with these agents is short (12 hours). Bupivacaine has a long history of use in
the surgical setting, and the efficacy of bupivacaine HCl administered perioperatively via
wound infiltration or acute postsurgical pain is well established. A novel formulation of
bupivacaine, ie, liposome bupivacaine (Pacira Pharmaceuticals, Inc., Parsippany, NJ), has
been developed to address the need for longer-acting local anesthetics that can be
administered as a single dose. The question becomes whether this drug is effective for
postsurgical analgesia if given preoperatively via the intracervical stroma during minimally
invasive gynecologic surgical procedures, specifically laparoscopic (robot--assisted or
traditional laparoscopy) supracervical hysterectomy.

Paracervical/intracervical injections are used for cervical/uterine manipulation in various
obstetrical and gynecological procedures. Lukas et al used the intracervical/paracervical
block prior to hysteroscopic polypectomy, with good pain scores following the procedure and
no serious adverse effects were noted. In addition, Chauan et al also noted good pain control
with intracervical injection with lidocaine in patients undergoing a hysterosalpingography,
which involves distended the uterus and injecting dye. Mankowshi et al also studied both
intracervical and paracervical injections of lidocaine for first trimester suction curettage
and found no difference between the two forms ensuring that both effective means of
analgesia.

In the U.S., surgical site infections (SSI) affect 1 in 24 patients that undergo inpatient
surgery. Most surgical site infection take place after day 5 , which will be out of the scope
of timeframe for conduct of the survey. However a SSI can make the differentiation of pain
from the surgery itself and pain from a complication of surgery difficulty to differentiate.
The patient will be asked to specify where the pain is and ask if they have any associated
vaginal discharge, foul smelling odor, and difficulty urinating and or passing a bowel
movement. These responses will be tracked, and if the participant shows signs of a SSI, the
patients may warrant a closer followup in the office and or asked to go directly to the
Emergency Department (ED). The patients will still be included in the study but special note
will be made of how many participant had SSI in the discussion portion.

Methods:

Randomized double blind placebo controlled pilot study. After IRB approval, 52 subjects will
be consented to participate in the study. The study includes subjects undergoing minimally
invasive (robot--assisted or traditional laparoscopy) supracervical hysterectomy under
general anesthesia. This study will include women (35 - 75 years) who have American Congress
of Obstetricians and Gynecologists (ACOG) and American Association of Gynecologic
Laparoscopists (AAGL) physical classification status for a minimally invasive (robotic-
assisted or traditional laparoscopy)supracervical hysterectomy.

Randomization will be done prior to recruitment of patient via computer software. There will
be two groups with numbers 1-52, no numbers will be repeated. Each patient that is recruited
will be assigned a number from 1-52 (in sequential order); the master list will be kept with
the pharmacy director. Group A (control, n=26) to receive 20ml of saline while Group B
(study, n=26) to receive 20ml of liposomal bupivacaine (EXPAREL) into the stroma of the
cervix at the 4 and 8 o'clock positions (innervation insertion points of the cervix).

The MMC Pharmacy will prepare an individualized numbered bubble wrapped amber package
accordingly to the randomization. It will be prepared prior to the recruitment and kept in
the fridge in 4th floor PACU pharmacy. After the patient is consented and given a subject
number, the package with the corresponding number will be picked up from the pharmacy and
given to either the resident/attending (not involved in the study) who will share the
contents of the package with the anesthesia team. While prepping, the same individual will
inject the contents. The syringe will covered as to disguise the contents of the syringe.

The investigators will show a short video on how to prepare the Exparel as well the injection
component in order to diminish the differences between the individuals.

Measurements:

The severity of pain will be assessed preoperatively in the holding area, PACU arrival, 12,
24, and 48 hours postoperatively using a numeric rating scale (NRS) at rest for pain with 0 =
no pain and 10 = worst possible pain. Pain inquiries will assess low pelvic/suprapubic area
and lower abdominal pain, type of pain (dull, achy, sharp, stabbing, etc.) and radiation of
pain to a surrounding area. Other endpoints will include number of patients who required
break through (additional) opioid analgesic medications, median time to first break through
opioid use, total opioid analgesic requirement. The time, day and number of requests for
break through (additional) analgesia will be noted by gynecologic surgery team (Resident or
Fellow) participating in this study.

When the patient is home the patient will have a Pain Medication Diary that the investigators
will provide for the patient prior to discharge. The patient will bring at the post-operative
visit and or mail it in.

Inclusion Criteria:

1. 35--75 years of age at the Screening Visit.

2. Female subjects only.

3. Scheduled to undergo minimally invasive (robotic-assisted or laparoscopic)
supracervical hysterectomy, under general anesthesia.

4. Clinical laboratory values less than twice the upper limit of normal or, if abnormal,
deemed not clinically significant per the Investigator.

5. Ability to provide informed consent, adhere to the study visit schedule and complete
all study assessments and language specific questionnaires.

Exclusion Criteria:

1. Currently pregnant, nursing, or planning to become pregnant.

2. Use of any of the following medications within the times specified before surgery: a.
opioid, SSRI, tricyclic antidepressant, gabapentin, pregabalin within three days of
surgery. b. Use of acetaminophen within 24 hours of surgery.

3. Concurrent painful physical condition or concurrent surgery that may require analgesic
treatment (such as NSAID, opioid, SSRI, tricyclic antidepressant, gabapentin,
pregabalin) in the postoperative period for pain that is not strictly related to the
minimally invasive supracervical hysterectomy procedure and may confound the
postoperative assessments (e.g., rheumatoid arthritis, chronic neuropathic pain.

4. Chronic user of analgesic medications, including taking opioid medications for more
than 14 days in the last 3 months, or non-opioid pain medications more than 5 times
per week.

5. Current use of systemic glucocorticosteroids (e.g. Decadron) or use of glucocorticoids
within one month of enrollment into this study.

6. History of hepatitis (other than hepatitis A).

7. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription
medicine(s), or alcohol within the past 2 years.

8. Failure of presurgical drug and alcohol screen.

9. History of hypersensitivity or idiosyncratic reactions to amide-type local
anesthetics, opioids, or propofol.

10. Administration of an investigational drug within 30 days prior to study drug
administration, or planned administration of another investigational product or
procedure during the subject's participation in this study.

12. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion
of the Investigator, may interfere with study assessments or compliance. 13. Significant
medical conditions or laboratory results that, in the opinion of the Investigator indicate
an increased vulnerability to study drug and procedures, and expose subjects to an
unreasonable risk as a result of participating in this clinical trial. 14. Any clinically
significant event or condition uncovered during the surgery (e.g., excessive bleeding,
acute sepsis) that might render the subject medically unstable or complicate the subject's
postoperative course. 15. An incision length greater than 3 cm.